The DOI matches its Crossref record; 152 of the 153 references it cites were found in a registry or an index, and 1 are not checked yet; 67 of the 174 sources its claims cite were checked for support.
Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome
Open accessAbstract
The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.
Verified 2026-11-09 · 1 reference not checked yet
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Written from the paper’s full text.
TL;DR
The paper combines X-ray crystallography, cryo-EM, and AlphaFold2 modeling to build a complete structural model of the 16-subunit Commander complex, revealing how Retriever, the CCC complex, and DENND10 assemble. It maps disease-causing mutations in Ritscher-Schinzel syndrome and X-linked intellectual disability onto subunit interfaces and shows that many perturb Commander assembly.
Key findings
- Retriever is a VPS26C:VPS35L:VPS29 heterotrimer with a unique N-terminal VPS35L region that binds VPS29 via Pro-Leu motifs, including a VPS35L peptide–VPS29 crystal structure at 1.35 Å and a peptide Kd of 1.8 ± 0.8 μM; this occludes the VPS29 surface used by Retromer accessory proteins such as TBC1D5, ANKRD27, and RidL.
- The ten COMMD proteins form a hetero-decameric ring with strict subunit order (COMMD1-6)-(COMMD4-8)-(COMMD2-3)-(COMMD10-5)-(COMMD7-9); a COMMD5-10-7-9 subcomplex crystal structure was solved at 3.3 Å, and the CCC dodecamer cryo-EM structure was determined at 3.1 Å (CryoSPARC) and 3.5 Å (RELION).
- CCDC22 and CCDC93 link the COMMD ring to Retriever and recruit DENND10 through their central coiled-coil regions; DENND10 bound the CCDC22-CCDC93 CC1-CC2 dimer with an affinity of 28 ± 6 nM.
- Disease mutations causing XLID and RSS cluster at interfaces between Retriever and CCC or within structural elements, and tested mutants showed loss of VPS29 and/or CCC complex association, providing a molecular explanation for destabilized Commander assembly.
Methods
- Recombinant human Retriever, Retromer, CCC complex, COMMD subcomplexes, CCDC22/CCDC93 fragments, and DENND10 were expressed in insect cells or E. coli and purified by affinity, size-exclusion, and ion-exchange chromatography.
- Structural approaches included single-particle cryo-EM of Retriever and the CCC complex, X-ray crystallography of COMMD subcomplex C and a VPS29–VPS35L peptide complex, and AlphaFold2 Multimer/ColabFold predictions for assembly and evolutionary comparisons.
- Functional validation used structure-based mutagenesis, isothermal titration calorimetry, GFP/mCherry nanotraps, Western blotting, confocal microscopy, CRISPR/Cas9 knockout cell lines (HeLa, eHap), and label-free or TMT quantitative proteomics.
Limitations
- Stated by the authors: the coiled-coil regions of CCDC22/CCDC93 remain unresolved experimentally, Retriever cryo-EM revealed overall architecture but not its entire atomic structure, and high-resolution structures of CCC–DENND10, CCC–Retriever, and the full 16-subunit holo-complex are still needed.
- Evident from the text: the Retriever cryo-EM map suffered from preferred particle orientation, overestimated resolution, and was insufficient for ab initio model building, so AlphaFold2 models were used for that assembly.
- Evident from the text: the complete Commander holo-complex is a composite model combining experimental structures with AlphaFold2 predictions, and the authors note it will require full structural confirmation.
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Claims the paper makes
67 of 174 cited sources checked · 21 supported · 2 flagged · accuracy not yet measured
- Premisecitation
The CCC complex comprises twelve components: CCDC22, CCDC93, and ten COMMD family members COMMD1-COMMD10.
“The CCC complex comprises twelve components, the coiled coil domain-containing proteins CCDC22 and CCDC93 and ten COMMD (copper metabolism MURR1 [Mouse U2af1-rs1 region 1) domain) family members COMMD1-COMMD10.2,16,17,18,19”
Quote in the paperNot a substantial claim2 of 5 sources checked- cites [2] Mallam A.L. Marcotte E.M. Systems-wide studies uncover commander, a multiprotein complex essential to human development Cell Syst. 4 2017 483 494 10.1016/j.cels.2017.04.006 28544880 PMC5541947 source
In “Discovery of the 14-subunit Commander complex” (page unavailable), the paper describes CCC as a three-subunit complex of a COMMD protein, CCDC22, and CCDC93, with different COMMD proteins observed in variants. It lists COMMD1–COMMD10, CCDC22, and CCDC93 among the proposed components of the larger Commander complex, not as twelve components of CCC. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [16] Hein M.Y. Hubner N.C. Poser I. Cox J. Nagaraj N. Toyoda Y. Gak I.A. Weisswange I. Mansfeld J. Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances Cell 163 2015 712 723 10.1016/j.cell.2015.09.053 26496610 source
- cites [17] Wan C. Borgeson B. Phanse S. Tu F. Drew K. Clark G. Xiong X. Kagan O. Kwan J. Bezginov A. Panorama of ancient metazoan macromolecular complexes Nature 525 2015 339 344 10.1038/nature14877 26344197 PMC5036527
- cites [18] Dey G. Jaimovich A. Collins S.R. Seki A. Meyer T. Systematic discovery of human gene function and principles of modular organization through phylogenetic profiling Cell Rep. 10 2015 993 1006 10.1016/j.celrep.2015.01.025 25683721 PMC5016211
- cites [19] Huttlin E.L. Ting L. Bruckner R.J. Gebreab F. Gygi M.P. Szpyt J. Tam S. Zarraga G. Colby G. Baltier K. The bioplex network: a systematic exploration of the human interactome Cell 162 2015 425 440 10.1016/j.cell.2015.06.043 26186194 PMC4617211 source
The Results sections on known complexes and community structure discuss other protein complexes, but the passages found do not describe the CCC complex or give its component count. Searches for CCDC22, CCDC93, COMMD family members, and the CCC complex found no passage supporting the stated twelve-component composition. (LLM, conf=0.74)
Experimental — accuracy not yet measured
- Premisecitation
In proteomic studies, the entire set of COMMD proteins are always identified in a complex together with other Commander subunits.
“However, in proteomic studies, the entire set of COMMD proteins are always identified in a complex together with other Commander subunits (this study and others6,16,17,20,21,22).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
In Results, under “Proteomic identification of retromer-independent endosomal sorting machinery,” the paper reports identifying seven of the ten human COMMD proteins alongside CCDC22 and CCDC93. Its proteomic study therefore contradicts the claim that the entire set is always identified together with the other subunits. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [16] Hein M.Y. Hubner N.C. Poser I. Cox J. Nagaraj N. Toyoda Y. Gak I.A. Weisswange I. Mansfeld J. Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances Cell 163 2015 712 723 10.1016/j.cell.2015.09.053 26496610 source
- cites [17] Wan C. Borgeson B. Phanse S. Tu F. Drew K. Clark G. Xiong X. Kagan O. Kwan J. Bezginov A. Panorama of ancient metazoan macromolecular complexes Nature 525 2015 339 344 10.1038/nature14877 26344197 PMC5036527
- Premisecitation
The 16th subunit of Commander is DENND10 (also called FAM45A).
“The 16th subunit is DENND10 (differentially expressed in normal and neoplastic cells-containing protein 10, also called FAM45A)6,16,20,21,22”
Quote in the paperNot a substantial claim3 of 5 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
The Results section on proteomic identification names CCC-complex proteins and retriever-associated proteins, but does not identify DENND10 or FAM45A as a Commander subunit. Searches for DENND10, FAM45A, and a 16th Commander subunit found no passage addressing the claim; no page number is available in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measured - cites [16] Hein M.Y. Hubner N.C. Poser I. Cox J. Nagaraj N. Toyoda Y. Gak I.A. Weisswange I. Mansfeld J. Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances Cell 163 2015 712 723 10.1016/j.cell.2015.09.053 26496610 source
- cites [20] Healy M.D. Sacharz J. McNally K.E. McConville C. Tillu V.A. Hall R.J. Chilton M. Cullen P.J. Mobli M. Ghai R. Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins Structure 30 2022 1590 1602.e6 10.1016/j.str.2022.10.001 36302387
- cites [21] Singla A. Fedoseienko A. Giridharan S.S.P. Overlee B.L. Lopez A. Jia D. Song J. Huff-Hardy K. Weisman L. Burstein E. Billadeau D.D. Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling Nat. Commun. 10 2019 4271 10.1038/s41467-019-12221-6 31537807 PMC6753146 source
The Results section (“Defining the CCC and retriever interactomes”; page unavailable) identifies FAM45A as an additional factor that binds components of both complexes. The paper does not call it Commander’s 16th subunit or identify it as DENND10; the Discussion describes it as a CCC- and retriever-binding protein rather than an established subunit. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [22] Huttlin E.L. Bruckner R.J. Paulo J.A. Cannon J.R. Ting L. Baltier K. Colby G. Gebreab F. Gygi M.P. Parzen H. Architecture of the human interactome defines protein communities and disease networks Nature 545 2017 505 509 10.1038/nature22366 28514442 PMC5531611 source
The passages on protein complexes in the main text and Extended Data discuss other complexes, including WASH, but do not identify a Commander subunit. Searches of our copy for DENND10, FAM45A, and Commander found no passage establishing that DENND10 is Commander’s 16th subunit or that it is also called FAM45A. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Premisecitation
Commander is composed of sixteen subunits.
“Commander is composed of sixteen subunits, arranged in two sub-assemblies, the CCC and Retriever complexes.”
Quote in the paperNot a substantial claim2 of 5 sources checked- cites [2] Mallam A.L. Marcotte E.M. Systems-wide studies uncover commander, a multiprotein complex essential to human development Cell Syst. 4 2017 483 494 10.1016/j.cels.2017.04.006 28544880 PMC5541947
- cites [16] Hein M.Y. Hubner N.C. Poser I. Cox J. Nagaraj N. Toyoda Y. Gak I.A. Weisswange I. Mansfeld J. Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances Cell 163 2015 712 723 10.1016/j.cell.2015.09.053 26496610 source
- cites [20] Healy M.D. Sacharz J. McNally K.E. McConville C. Tillu V.A. Hall R.J. Chilton M. Cullen P.J. Mobli M. Ghai R. Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins Structure 30 2022 1590 1602.e6 10.1016/j.str.2022.10.001 36302387
- cites [21] Singla A. Fedoseienko A. Giridharan S.S.P. Overlee B.L. Lopez A. Jia D. Song J. Huff-Hardy K. Weisman L. Burstein E. Billadeau D.D. Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling Nat. Commun. 10 2019 4271 10.1038/s41467-019-12221-6 31537807 PMC6753146 source
In Results (‘Defining the CCC and retriever interactomes’; page not specified), the paper identifies 15 components of CCC and Retriever and an additional protein, FAM45A, that binds to them. It does not identify FAM45A as a sixteenth subunit. The Discussion (page not specified) also describes CCC and Retriever as separable assemblies rather than one Commander complex. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [22] Huttlin E.L. Bruckner R.J. Paulo J.A. Cannon J.R. Ting L. Baltier K. Colby G. Gebreab F. Gygi M.P. Parzen H. Architecture of the human interactome defines protein communities and disease networks Nature 545 2017 505 509 10.1038/nature22366 28514442 PMC5531611 source
The passages on protein communities and multi-subunit complexes (Abstract; no page provided) do not identify Commander or give its subunit count. Further searches for Commander, sixteen subunits, CCC, and Retriever returned no passage addressing its composition. (LLM, conf=0.72)
Experimental — accuracy not yet measured
- Premisecitation
Most transmembrane proteins sorted by Commander contain ΦxNxx[YF] sequence motifs that are recruited to Commander via the sorting nexin 17 (SNX17) cargo adaptor.
“Most transmembrane proteins sorted by Commander, including α5β1 integrin, the amyloid precursor protein (APP), and lipoprotein receptors contain ΦxNxx[YF] sequence motifs (where Φ is a hydrophobic amino acid) that are recruited to Commander via the sorting nexin 17 (SNX17) cargo adaptor.6,20,23,24,25,26,27,28,29”
Quote in the paperNot a substantial claim7 of 9 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
The Results and Discussion (page unavailable) show that SNX17 binds NPxY/NxxY cargo motifs and couples cargo such as α5β1 integrin and LRP1 to retriever. They do not establish that most Commander-sorted proteins have the more specific ΦxNxx[YF] motif or that APP is sorted by this pathway; the Results say only that some identified proteins contain NxxY motifs. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [20] Healy M.D. Sacharz J. McNally K.E. McConville C. Tillu V.A. Hall R.J. Chilton M. Cullen P.J. Mobli M. Ghai R. Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins Structure 30 2022 1590 1602.e6 10.1016/j.str.2022.10.001 36302387
- cites [23] Ghai R. Bugarcic A. Liu H. Norwood S.J. Skeldal S. Coulson E.J. Li S.S.C. Teasdale R.D. Collins B.M. Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins Proc. Natl. Acad. Sci. USA 110 2013 E643 E652 10.1073/pnas.1216229110 23382219 PMC3581954 source
The ‘Mechanism of NPxY/NxxY Cargo Recognition’ section identifies APP, integrins, and LDL-receptor family members as SNX17 cargos, and the Discussion describes a preferred ϕxNPx(F/Y) binding sequence. The paper supports SNX17 recognition of these cargo motifs, but it does not establish that most Commander-sorted proteins carry them or that SNX17 recruits those proteins to Commander. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [24] Burden J.J. Sun X.M. García A.B.G. Soutar A.K. Sorting motifs in the intracellular domain of the low density lipoprotein receptor interact with a novel domain of sorting nexin-17 J. Biol. Chem. 279 2004 16237 16245 10.1074/jbc.M313689200 14739284 source
The paper’s Results report that mutations in the LDL receptor’s NPVY motif reduce its interaction with SNX17. This supports the lipoprotein-receptor example, but the paper does not establish that most Commander-sorted proteins carry the stated motif or that SNX17 recruits them to Commander. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [25] Farfán P. Lee J. Larios J. Sotelo P. Bu G. Marzolo M.P. A sorting nexin 17-binding domain within the LRP1 cytoplasmic tail mediates receptor recycling through the basolateral sorting endosome Traffic 14 2013 823 838 10.1111/tra.12076 23593972 PMC3679278 source
The Introduction reports that LDL-receptor family members, APP, and β1-integrin bind SNX17 through NPxY motifs; the Results identify an IxNPxY motif in LRP1. The paper does not establish that most Commander-sorted proteins carry the stated ΦxNxx[YF] motif or that SNX17 recruits these proteins to Commander. The cited passages have no page numbers in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [26] Lee J. Retamal C. Cuitiño L. Caruano-Yzermans A. Shin J.E. van Kerkhof P. Marzolo M.P. Bu G. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes J. Biol. Chem. 283 2008 11501 11508 10.1074/jbc.M800642200 18276590 PMC2431074 source
- cites [27] Steinberg F. Heesom K.J. Bass M.D. Cullen P.J. SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways J. Cell Biol. 197 2012 219 230 10.1083/jcb.201111121 22492727 PMC3328392 source
The Results and discussion section (page not supplied) shows that SNX17 binds the membrane-distal NPXY motif of integrin β subunits and supports α5β1 integrin recycling. It also mentions SNX17 in connection with APP trafficking and an LDL receptor–related protein, but does not establish that most Commander cargoes carry the specified ΦxNxx[YF] motif or are recruited to Commander through SNX17. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [28] Fedoseienko A. Wijers M. Wolters J.C. Dekker D. Smit M. Huijkman N. Kloosterhuis N. Klug H. Schepers A. Willems van Dijk K. The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking Circ. Res. 122 2018 1648 1660 10.1161/CIRCRESAHA.117.312004 29545368 source
The Discussion (page not provided) says LDLR and LRP1 contain an NPxY motif that binds SNX17 and COMMD1, and proposes that SNX17 and the CCC complex participate in their recycling. It does not establish that most Commander-sorted transmembrane proteins have the specified ΦxNxx[YF] motif, or address α5β1 integrin and APP as examples; the proposed trafficking mechanism is also presented as speculation. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [29] Rimbert A. Dalila N. Wolters J.C. Huijkman N. Smit M. Kloosterhuis N. Riemsma M. van der Veen Y. Singla A. van Dijk F. A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor Eur. Heart J. 41 2020 1040 1053 10.1093/eurheartj/ehz727 31630160 source
The Discussion (page not supplied) says SNX17 has a positive role in LDLR sorting, and the Results section on CCDC93 and LDLR recycling (page not supplied) links the CCC complex to LDLR trafficking. Our copy does not say that most Commander-sorted proteins carry ΦxNxx[YF] motifs, that SNX17 recruits them to Commander, or that the listed integrin and APP are examples. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Premisecitation
Mutations in Commander lead to hypercholesterolemia through reduced trafficking of LDLRs.
“Mutations in Commander lead to hypercholesterolemia through reduced trafficking of LDLRs.7,8,9,10,12,13,14”
Quote in the paperNot a substantial claim3 of 7 sources checked- cites [7] Gjerulfsen C.E. Møller R.S. Fenger C.D. Hammer T.B. Bayat A. Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised? Eur. J. Med. Genet. 64 2021 104246 10.1016/j.ejmg.2021.104246 34020006
- cites [8] Kato K. Oka Y. Muramatsu H. Vasilev F.F. Otomo T. Oishi H. Kawano Y. Kidokoro H. Nakazawa Y. Ogi T. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex J. Med. Genet. 57 2020 245 253 10.1136/jmedgenet-2019-106213 31712251 source
- cites [9] Kolanczyk M. Krawitz P. Hecht J. Hupalowska A. Miaczynska M. Marschner K. Schlack C. Emmerich D. Kobus K. Kornak U. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome Eur. J. Hum. Genet. 23 2015 720 10.1038/ejhg.2014.278 25880334 PMC4402643 source
- cites [10] Neri S. Maia N. Fortuna A.M. Damasio J. Coale E. Willis M. Jorge P. Højte A.F. Fenger C.D. Møller R.S. Bayat A. Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes Eur. J. Med. Genet. 65 2022 104624 10.1016/j.ejmg.2022.104624 36130690
- cites [12] Starokadomskyy P. Gluck N. Li H. Chen B. Wallis M. Maine G.N. Mao X. Zaidi I.W. Hein M.Y. McDonald F.J. CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappaB signaling J. Clin. Invest. 123 2013 2244 2256 10.1172/JCI66466 23563313 PMC3635737 source
The section ‘CCDC22 regulates the cellular localization of COMMD proteins’ reports that the CCDC22 T17A mutation impairs binding to COMMD1. That supports a mutation affecting a COMMD-associated protein, but our copy does not connect it to LDLR trafficking or hypercholesterolemia; searches for those terms found no such passage. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [13] Bartuzi P. Billadeau D.D. Favier R. Rong S. Dekker D. Fedoseienko A. Fieten H. Wijers M. Levels J.H. Huijkman N. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL Nat. Commun. 7 2016 10961 10.1038/ncomms10961 26965651 PMC4792963 source
- cites [14] Voineagu I. Huang L. Winden K. Lazaro M. Haan E. Nelson J. McGaughran J. Nguyen L.S. Friend K. Hackett A. CCDC22: a novel candidate gene for syndromic X-linked intellectual disability Mol. Psych. 17 2012 4 7 10.1038/mp.2011.95 PMC3586744 21826058 source
The paper’s main text reports a CCDC22 mutation associated with X-linked intellectual disability and reduced CCDC22 mRNA. Searches for hypercholesterolemia, LDLR trafficking, and Commander found no passage addressing the claimed cholesterol mechanism; the reported mutation alone does not establish it. No page number is available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Premisecitation
The Commander complex is required for endosomal recycling of diverse transmembrane cargos.
“The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome.”
- Also stated in: § Introduction · plain
“Commander regulates Retromer-independent retrieval and recycling of hundreds of proteins including integrins and lipoprotein receptors,6”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
- Also stated in: § Introduction · plain
- Findingcitation
VPS26C associates with the second and third α-helical repeats in VPS35L via its C-terminal β-sandwich subdomain.
“Analogous to VPS26A/B binding to VPS35,58,60,61 VPS26C associates with the second and third α-helical repeats in VPS35L via its C-terminal β-sandwich subdomain (Figure 1C).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [58] Kendall A.K. Xie B. Xu P. Wang J. Burcham R. Frazier M.N. Binshtein E. Wei H. Graham T.R. Nakagawa T. Jackson L.P. Mammalian retromer is an adaptable scaffold for cargo sorting from endosomes Structure 28 2020 393 405.e4 10.1016/j.str.2020.01.009 32027819 PMC7145723
- cites [60] Leneva N. Kovtun O. Morado D.R. Briggs J.A.G. Owen D.J. Architecture and mechanism of metazoan retromer:SNX3 tubular coat assembly Sci. Adv. 7 2021 eabf8598 10.1126/sciadv.abf8598 33762348 PMC7990337
- cites [61] Lucas M. Gershlick D.C. Vidaurrazaga A. Rojas A.L. Bonifacino J.S. Hierro A. Structural mechanism for cargo recognition by the retromer complex Cell 167 2016 1623 1635.e14 10.1016/j.cell.2016.10.056 27889239 PMC5147500 source
- Findingown data
A high confidence AlphaFold2 model of Retriever aligned well with the low-resolution 3D cryo-EM envelope.
“However, a high confidence AlphaFold254,55,56 model of Retriever aligned well with the low-resolution 3D cryo-EM envelope (Figure 1B; Methods S1; Video S1).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [54] Evans R. O’Neill M. Pritzel A. Antropova N. Senior A. Green T. Žídek A. Bates R. Blackwell S. Yim J. Protein complex prediction with AlphaFold-Multimer Preprint at bioRxiv 2022 10.1101/2021.10.04.463034 source
- cites [55] Jumper J. Evans R. Pritzel A. Green T. Figurnov M. Ronneberger O. Tunyasuvunakool K. Bates R. Žídek A. Potapenko A. Highly accurate protein structure prediction with AlphaFold Nature 596 2021 583 589 10.1038/s41586-021-03819-2 34265844 PMC8371605 source
- cites [56] Mirdita M. Schütze K. Moriwaki Y. Heo L. Ovchinnikov S. Steinegger M. ColabFold: making protein folding accessible to all Nat. Methods 19 2022 679 682 10.1038/s41592-022-01488-1 35637307 PMC9184281 source
- Premiseown data
Commander comprises two sub-assemblies: Retriever and the CCC complex.
“It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93.”
Quote in the paperSubstantial claim2 of 5 sources checked- cites [2] Mallam A.L. Marcotte E.M. Systems-wide studies uncover commander, a multiprotein complex essential to human development Cell Syst. 4 2017 483 494 10.1016/j.cels.2017.04.006 28544880 PMC5541947 source
The section on discovery of the 14-subunit Commander complex identifies CCC as a Commander subcomplex and lists COMMD1–10, CCDC22, and CCDC93 among Commander’s proposed components (page not provided). It does not describe a second subassembly called Retriever; the section on trafficking and transport instead identifies VPS29 as a retromer component. Thus the source supports the CCC portion, but not the stated two-subassembly composition. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [16] Hein M.Y. Hubner N.C. Poser I. Cox J. Nagaraj N. Toyoda Y. Gak I.A. Weisswange I. Mansfeld J. Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances Cell 163 2015 712 723 10.1016/j.cell.2015.09.053 26496610 source
- cites [17] Wan C. Borgeson B. Phanse S. Tu F. Drew K. Clark G. Xiong X. Kagan O. Kwan J. Bezginov A. Panorama of ancient metazoan macromolecular complexes Nature 525 2015 339 344 10.1038/nature14877 26344197 PMC5036527
- cites [18] Dey G. Jaimovich A. Collins S.R. Seki A. Meyer T. Systematic discovery of human gene function and principles of modular organization through phylogenetic profiling Cell Rep. 10 2015 993 1006 10.1016/j.celrep.2015.01.025 25683721 PMC5016211
- cites [19] Huttlin E.L. Ting L. Bruckner R.J. Gebreab F. Gygi M.P. Szpyt J. Tam S. Zarraga G. Colby G. Baltier K. The bioplex network: a systematic exploration of the human interactome Cell 162 2015 425 440 10.1016/j.cell.2015.06.043 26186194 PMC4617211 source
The Results section discusses sub-assemblies of other complexes, including RBBP7-associated complexes, but does not describe Commander. Searches for Commander, Retriever, the CCC complex, and the named subunits found no passage in our copy addressing the claimed composition. (LLM, conf=0.74)
Experimental — accuracy not yet measured
- Interpretationreasoning
This clustering provides insight into the destabilization of protein expression observed in patients harboring these mutations.
“providing insight into the destabilization of protein expression observed in patients harboring these mutations.8,9,11,12”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [8] Kato K. Oka Y. Muramatsu H. Vasilev F.F. Otomo T. Oishi H. Kawano Y. Kidokoro H. Nakazawa Y. Ogi T. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex J. Med. Genet. 57 2020 245 253 10.1136/jmedgenet-2019-106213 31712251 source
- cites [9] Kolanczyk M. Krawitz P. Hecht J. Hupalowska A. Miaczynska M. Marschner K. Schlack C. Emmerich D. Kobus K. Kornak U. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome Eur. J. Hum. Genet. 23 2015 720 10.1038/ejhg.2014.278 25880334 PMC4402643 source
- cites [11] Otsuji S. Nishio Y. Tsujita M. Rio M. Huber C. Antón-Plágaro C. Mizuno S. Kawano Y. Miyatake S. Simon M. Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome J. Med. Genet. 60 2023 359 367 10.1136/jmg-2022-108602 36113987 PMC10086474 source
- Findingcitation
The structure is consistent with truncation analyses that found N-terminal regions of CCDC22 and CCDC93 could interact with COMMD proteins but not Retriever.
“The structure is also consistent with truncation analyses that found N-terminal regions of CCDC22 and CCDC93 could interact with COMMD proteins but not Retriever.21,65”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [21] Singla A. Fedoseienko A. Giridharan S.S.P. Overlee B.L. Lopez A. Jia D. Song J. Huff-Hardy K. Weisman L. Burstein E. Billadeau D.D. Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling Nat. Commun. 10 2019 4271 10.1038/s41467-019-12221-6 31537807 PMC6753146 source
The Results sections ‘Defining the CCC and retriever interactomes’ and ‘CCC and retriever are closely linked but distinct complexes’ place CCDC22, CCDC93, and COMMD proteins in CCC and describe CCC and Retriever as distinct assemblies. They do not report truncation analyses or show that the N-terminal regions of CCDC22 and CCDC93 bind COMMD proteins but not Retriever; searches for truncation, N-terminal, and fragment interactions did not find that result. Page numbers are unavailable in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [65] Phillips-Krawczak C.A. Singla A. Starokadomskyy P. Deng Z. Osborne D.G. Li H. Dick C.J. Gomez T.S. Koenecke M. Zhang J.S. COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A Mol. Biol. Cell 26 2015 91 103 10.1091/mbc.E14-06-1073 25355947 PMC4279232 source
In Results, ‘Organization of the CCC complex’ (page unavailable), the truncation analysis places CCDC22–COMMD1 binding in CCDC22’s N-terminal region and describes N-terminal interactions between CCDC22 and CCDC93. The copy also reports that CCDC93 interacts with COMMD proteins, but it does not establish here that CCDC93’s N-terminal region mediates that interaction. It does not address whether either N-terminal region binds Retriever. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingcitation
Our proteomic analyses routinely identified DENND10 as a Commander subunit.
“As seen previously,6,16,20,21,22,68,69 our proteomic analyses routinely identified DENND10 as a Commander subunit (Figure S5C)”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
The Results section on proteomic identification names CCDC22, CCDC93, COMMD proteins and C16orf62 among the proteins identified, but does not name DENND10. A search of our copy for DENND10 found no passage identifying it as a Commander subunit; the cited paper therefore does not verify this specific claim. (LLM, conf=0.74)
Experimental — accuracy not yet measured - cites [16] Hein M.Y. Hubner N.C. Poser I. Cox J. Nagaraj N. Toyoda Y. Gak I.A. Weisswange I. Mansfeld J. Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances Cell 163 2015 712 723 10.1016/j.cell.2015.09.053 26496610 source
- cites [20] Healy M.D. Sacharz J. McNally K.E. McConville C. Tillu V.A. Hall R.J. Chilton M. Cullen P.J. Mobli M. Ghai R. Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins Structure 30 2022 1590 1602.e6 10.1016/j.str.2022.10.001 36302387 source
The Results (page unavailable) report that the proteomic experiment enriched known Retriever and CCC components, and the Figure 1 caption says it identified the entire Commander assembly. Our copy does not name DENND10 or establish that it was routinely identified, so those specifics cannot be verified from this source. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Findingcitation
DENND10 is not required for Commander stability.
“although it is not required for Commander stability, and its deletion does not affect recycling of α5 integrin.21”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] Singla A. Fedoseienko A. Giridharan S.S.P. Overlee B.L. Lopez A. Jia D. Song J. Huff-Hardy K. Weisman L. Burstein E. Billadeau D.D. Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling Nat. Commun. 10 2019 4271 10.1038/s41467-019-12221-6 31537807 PMC6753146 source
- Findingown data
The subcomplex C structure closely matches that predicted by AlphaFold2 multimer.
“Notably, the structure closely matches that predicted by AlphaFold2 multimer56,66 (Methods S1).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [56] Mirdita M. Schütze K. Moriwaki Y. Heo L. Ovchinnikov S. Steinegger M. ColabFold: making protein folding accessible to all Nat. Methods 19 2022 679 682 10.1038/s41592-022-01488-1 35637307 PMC9184281 source
- cites [66] Lacey S.E. Foster H.E. Pigino G. The molecular structure of IFT-A and IFT-B in anterograde intraflagellar transport trains Nat. Struct. Mol. Biol. 2023 10.1038/s41594-022-00905-5 PMC10191852 36593313
- Findingown data
An initial model of the dodecamer including all ten COMMD proteins and the N-terminal regions of CCDC22 and CCDC93 was constructed using AlphaFold2 multimer.
“Initially, a model of the dodecamer including all ten COMMD proteins and the N-terminal regions of CCDC22 and CCDC93 was constructed using AlphaFold2 multimer54,55,56 (Figure S3A).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [54] Evans R. O’Neill M. Pritzel A. Antropova N. Senior A. Green T. Žídek A. Bates R. Blackwell S. Yim J. Protein complex prediction with AlphaFold-Multimer Preprint at bioRxiv 2022 10.1101/2021.10.04.463034 source
- cites [55] Jumper J. Evans R. Pritzel A. Green T. Figurnov M. Ronneberger O. Tunyasuvunakool K. Bates R. Žídek A. Potapenko A. Highly accurate protein structure prediction with AlphaFold Nature 596 2021 583 589 10.1038/s41586-021-03819-2 34265844 PMC8371605 source
The cited paper describes AlphaFold as a protein-structure prediction method, supporting the identification of the underlying method. But in “MSA depth and cross-chain contacts” (page unavailable), it describes prediction of full hetero-complexes as a goal for a future system; it does not describe AlphaFold2 multimer. The dodecamer model is the citing authors’ own work, not a result attributed to this paper. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [56] Mirdita M. Schütze K. Moriwaki Y. Heo L. Ovchinnikov S. Steinegger M. ColabFold: making protein folding accessible to all Nat. Methods 19 2022 679 682 10.1038/s41592-022-01488-1 35637307 PMC9184281 source
- Interpretationown data
The structure provides an atomic level description of its organization that explains previous results including the co-dependence of each of the COMMD, CCDC, and VPS35L proteins for complex stability.
“the structure provides an atomic level description of its organization that explains previous results including the co-dependence of each of the COMMD, CCDC, and VPS35L proteins for complex stability.13,28”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [13] Bartuzi P. Billadeau D.D. Favier R. Rong S. Dekker D. Fedoseienko A. Fieten H. Wijers M. Levels J.H. Huijkman N. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL Nat. Commun. 7 2016 10961 10.1038/ncomms10961 26965651 PMC4792963 source
The Results sections on COMMD1-deficient dogs and hepatic Commd1 or Commd9 ablation report reduced CCDC22 and CCDC93 levels, supporting a link between some COMMD and CCDC proteins and complex stability. They do not establish co-dependence of each COMMD, CCDC, and VPS35L protein, or provide an atomic-level structure explaining it. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [28] Fedoseienko A. Wijers M. Wolters J.C. Dekker D. Smit M. Huijkman N. Kloosterhuis N. Klug H. Schepers A. Willems van Dijk K. The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking Circ. Res. 122 2018 1648 1660 10.1161/CIRCRESAHA.117.312004 29545368 source
In “Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins” (page unavailable), the paper reports that loss of COMMD proteins reduces other COMMD proteins and the CCC components CCDC22, CCDC93, and C16orf62. It does not establish the claimed co-dependence of each COMMD, CCDC, and VPS35L protein: the reported experiments primarily test COMMD loss, and the copy does not identify VPS35L by that name. The atomic-level structural description is the citing authors’ own finding, not a finding attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Interpretationreasoning
This explains why synthetic macrocyclic peptides targeting the conserved pocket on VPS29 interact with Retromer but not Retriever.
“which also explains why synthetic macrocyclic peptides targeting the conserved pocket on VPS29 interact with Retromer but not Retriever.44”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [44] Chen K.E. Guo Q. Hill T.A. Cui Y. Kendall A.K. Yang Z. Hall R.J. Healy M.D. Sacharz J. Norwood S.J. De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex Sci. Adv. 7 2021 eabg4007 10.1126/sciadv.abg4007 34851660 PMC8635440 source
The Results section reports that the macrocyclic peptides bind a conserved groove on VPS29 and interact with Retromer. The Discussion does not establish that they fail to interact with Retriever; it says the peptides may be useful for studying Retriever and that accessibility of the VPS29 binding site in that complex remains unconfirmed. Page numbers were not provided in our copy's passages. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Premisecitation
Endosomal recycling by Commander requires dynamic organization of actin-rich domains on the endosomal surface.
“Endosomal recycling by Commander requires dynamic organization of actin-rich domains on the endosomal surface.4”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [4] Simonetti B. Cullen P.J. Actin-dependent endosomal receptor recycling Curr. Opin. Cell Biol. 56 2019 22 33 10.1016/j.ceb.2018.08.006 30227382 source
The Figure 4 caption (p. 23) says regulated receptor recycling depends on actin dynamics at the endosomal surface and involves actin-enriched subdomains. The section “Actin and WASH in the organization of the retrieval subdomains” (p. 6) links WASH-mediated domain organization to the retriever complex via the CCC complex. The paper does not name Commander or establish that recycling by Commander specifically requires this organization. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Findingown data
The second unique VPS29 interaction involves the first ∼40 residues of the extended N-terminal region of VPS35L.
“The second unique VPS29 interaction involves the first ∼40 residues of the extended N-terminal region of VPS35L (see inset (iv) in Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
The authors assembled a complete structural model of the sixteen-subunit Commander complex.
“Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander.”
- Also stated in: § Introduction · plain
“Here we present a complete model of the sixteen subunit Commander complex.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Findingown data
Reciprocal mutations VPS29(I91D) and VPS29(W93A) decreased VPS35L binding.
“reciprocal mutations VPS29(I91D) and VPS29(W93A) also decreased VPS35L binding (Figure 1E).”
Quote in the paperSubstantial claim - Findingown data
Reciprocal mutant VPS29(L67D) reduced binding to VPS35L by approximately 30%.
“while reciprocal mutant VPS29(L67D) reduced binding to VPS35L by approximately 30% (Figure 1E).”
Quote in the paperSubstantial claim - Findingown data
A β-sheet extension at the base of VPS35L contacts VPS29.
“Firstly, a β-sheet extension at the base of VPS35L contacts VPS29 (see inset (iii) in Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Mutagenesis of VPS35L(H826E) and VPS35L(S781D) resulted in >95% loss of VPS29 binding.
“Mutagenesis of key binding residues, VPS35L(H826E) and VPS35L(S781D) (see inset (ii) in Figure 1B), resulted in >95% loss of VPS29 binding (Figure 1D)”
Quote in the paperSubstantial claim - Findingown data
Mutation VPS35L(I761G) or complete deletion of the β-sheet extension induced >50% reduction in VPS29 interaction with CCC complex retained.
“Mutation of this interface with VPS35L(I761G) or complete deletion induced >50% reduction in VPS29 interaction (with CCC complex retained) (Figure 1F)”
Quote in the paperSubstantial claim - Findingown data
Recombinant human Retriever forms a stable 1:1:1 heterotrimer of VPS26C, VPS35L, and VPS29.
“The resultant peak contained VPS26C, VPS35L, and VPS29 in a stable 1:1:1 heterotrimer (Methods S1).”
Quote in the paperSubstantial claim - Findingown data
The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93.
“The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93.”
Quote in the paperSubstantial claim - Findingcitation
The two CCDC proteins share distant structural similarity with IFT subunits of the intraflagellar transport (IFT) machinery.
“Interestingly, the two CCDC proteins share distant structural similarity with IFT subunits of the intraflagellar transport (IFT) machinery, which form comparable coiled-coil dimers with N-terminal CH domains (Methods S1).71,72”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [71] Petriman N.A. Loureiro-López M. Taschner M. Zacharia N.K. Georgieva M.M. Boegholm N. Wang J. Mourão A. Russell R.B. Andersen J.S. Lorentzen E. Biochemically validated structural model of the 15-subunit intraflagellar transport complex IFT-B EMBO J. 41 2022 e112440 10.15252/embj.2022112440 36354106 PMC9753473
- cites [72] Wachter S. Jung J. Shafiq S. Basquin J. Fort C. Bastin P. Lorentzen E. Binding of IFT22 to the intraflagellar transport complex is essential for flagellum assembly EMBO J. 38 2019 e101251 10.15252/embj.2018101251 30940671 PMC6484408
- Findingown data
Mutations in the predicted interface DENND10(L27E), -(M123E), and -(I127E) either reduced or abolished these interactions.
“mutations in the predicted interface DENND10(L27E), -(M123E), and -(I127E) either reduced or abolished these interactions.”
Quote in the paperSubstantial claim - Findingown data
We developed a structure of the sixteen subunit Commander complex.
“By combining our experimental structures with AlphaFold2-derived models, we developed a structure of the sixteen subunit Commander complex (Figure 6A; Methods S1; Video S3).”
Quote in the paperSubstantial claim - Findingown data
The subsets of COMMD proteins enriched with COMMD2,4,5,8,10 correlated with the sub-complexes observed in bacterial co-expression experiments in the absence of the CCDC proteins.
“which correlated with the sub-complexes observed in bacterial co-expression experiments in the absence of the CCDC proteins.”
Quote in the paperSubstantial claim - Findingown data
We identified an unambiguous interaction linking the CCC and Retriever complexes between a conserved surface on VPS35L (opposite the VPS29-binding site) and the CCDC22-CCDC93 proteins.
“After comprehensive testing of potential assemblies, we identified an unambiguous interaction linking the CCC and Retriever complexes between a conserved surface on VPS35L (opposite the VPS29-binding site) and the CCDC22-CCDC93 proteins (Methods S1).”
Quote in the paperSubstantial claim - Findingown data
The distribution of the ten COMMD subunits across extant eukaryotes involves parallel, lineage-specific loss in some species.
“The distribution of the ten subunits across extant eukaryotes involves parallel, lineage-specific loss in some species.”
Quote in the paperNot a substantial claim - Findingown data
AlphaFold2 predicted a high confidence complex between DENND10 and a dimer of two central coiled-coil regions from CCDC22 and CCDC93 (CC1 and CC2).
“AlphaFold2 predicted a high confidence complex between DENND10 and a dimer of two central coiled-coil regions from CCDC22 and CCDC93 (CC1 and CC2) (Figures 5A and S6A).”
Quote in the paperSubstantial claim - Findingown data
The arrangement of subunits around the COMMD ring follows a strict order of five heterodimers: (COMMD1-6)-(COMMD4-8)-(COMMD2-3)-(COMMD10-5)-(COMMD7-9).
“The arrangement of subunits around the ring follows a strict order of five heterodimers of (COMMD1-6)-(COMMD4-8)-(COMMD2-3)-(COMMD10-5)-(COMMD7-9) (Figures 4B and 4C).”
Quote in the paperSubstantial claim - Findingown data
COMMD2, 4, 5, 8, and 10 FLAG-tagged proteins were enriched only with specific subsets of COMMD proteins.
“In contrast we noted that COMMD2, 4, 5, 8, and 10 FLAG-tagged proteins were enriched only with specific subsets of COMMD proteins”
Quote in the paperSubstantial claim - Findingcitation
VPS35L N-terminal sequences closely mimic VPS29 association with PL motifs in Retromer accessory proteins, including ANKRD27, TBC1D5, and RidL.
“Although covering a more extensive binding surface, VPS35L N-terminal sequences closely mimic VPS29 association with PL motifs in Retromer accessory proteins, including the RAB guanine nucleotide exchange factor ANKRD27, and the RAB7 GTPase-activating protein (GAP) TBC1D5, and in the Retromer hijacking effector RidL from Legionella pneumophila46,47,63 (Figure S1B).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [46] Crawley-Snowdon H. Yang J.C. Zaccai N.R. Davis L.J. Wartosch L. Herman E.K. Bright N.A. Swarbrick J.S. Collins B.M. Jackson L.P. Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29 Nat. Commun. 11 2020 5031 10.1038/s41467-020-18773-2 33024112 PMC7539009
- cites [47] Jia D. Zhang J.S. Li F. Wang J. Deng Z. White M.A. Osborne D.G. Phillips-Krawczak C. Gomez T.S. Li H. Structural and mechanistic insights into regulation of the retromer coat by TBC1d5 Nat. Commun. 7 2016 13305 10.1038/ncomms13305 27827364 PMC5105194
- cites [63] Hesketh G.G. Pérez-Dorado I. Jackson L.P. Wartosch L. Schäfer I.B. Gray S.R. McCoy A.J. Zeldin O.B. Garman E.F. Harbour M.E. VARP is recruited on to endosomes by direct interaction with retromer, where together they function in export to the cell surface Dev. Cell 29 2014 591 606 10.1016/j.devcel.2014.04.010 24856514 PMC4059916
- Findingown data
The CCDC93 CH domain is partly stabilized by direct interactions with the COMMD ring via the HN domain of COMMD4.
“while the CCDC93 CH domain is partly stabilized by direct interactions with the COMMD ring via the HN domain of COMMD4 (Figure 4E).”
Quote in the paperNot a substantial claim - Findingown data
Weak density is observed for the CH domain of CCDC93, which is stabilized by its interaction with the HN domain of COMMD4.
“Weak density is observed for the CH domain of CCDC93, which is stabilized by its interaction with the HN domain of COMMD4.”
Quote in the paperNot a substantial claim - Findingown data
The electrostatic surface does not reveal any regions suggestive of binding to negatively charged phospholipid membranes.
“The electrostatic surface does not reveal any regions suggestive of binding to negatively charged phospholipid membranes.60,73,74”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [60] Leneva N. Kovtun O. Morado D.R. Briggs J.A.G. Owen D.J. Architecture and mechanism of metazoan retromer:SNX3 tubular coat assembly Sci. Adv. 7 2021 eabf8598 10.1126/sciadv.abf8598 33762348 PMC7990337
- cites [73] Harrison M.S. Hung C.S. Liu T.T. Christiano R. Walther T.C. Burd C.G. A mechanism for retromer endosomal coat complex assembly with cargo Proc. Natl. Acad. Sci. USA 111 2014 267 272 10.1073/pnas.1316482111 24344282 PMC3890810
- cites [74] Purushothaman L.K. Arlt H. Kuhlee A. Raunser S. Ungermann C. Retromer-driven membrane tubulation separates endosomal recycling from Rab7/Ypt7-dependent fusion Mol. Biol. Cell 28 2017 783 791 10.1091/mbc.E16-08-0582 28100638 PMC5349785
- Findingown data
An X-ray crystal structure of the VPS29-peptide complex confirmed that Leu27 to Leu35 of VPS35L interact with two hydrophobic pockets on VPS29.
“An X-ray crystal structure of the VPS29-peptide complex unambiguously confirmed that Leu27 to Leu35 of VPS35L interact with two hydrophobic pockets on VPS29 (Figure 2B; Table S2).”
Quote in the paperSubstantial claim - Findingown data
The interaction of the CCDC proteins with Retriever is mediated by the V-shaped CC3-CC4 segment at their C terminus associating with VPS35L at a conserved surface distal from VPS26C and VPS29.
“As mentioned, the interaction of the CCDC proteins with Retriever is mediated by the V-shaped CC3-CC4 segment at their C terminus associating with VPS35L at a conserved surface distal from VPS26C and VPS29.”
Quote in the paperSubstantial claim - Findingown data
Our cryoEM structure shows that the N-terminal CH domain of CCDC93 is closely associated with the COMMD ring via the COMMD4 HN domain.
“Our cryoEM structure shows that the N-terminal CH domain of CCDC93 is closely associated with the COMMD ring via the COMMD4 HN domain (Figure 4).”
Quote in the paperSubstantial claim - Findingown data
Mapping mutations causative for XLID and RSS onto the Commander model reveals clustering of VPS35L and CCDC22 pathogenic mutations around the interface between Retriever and CCC complexes.
“Finally, we mapped mutations causative for XLID and RSS7,8,9,10,11,12 onto the Commander model (Figure 7A). This reveals clustering of VPS35L and CCDC22 pathogenic mutations around the interface between Retriever and CCC complexes”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] Gjerulfsen C.E. Møller R.S. Fenger C.D. Hammer T.B. Bayat A. Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised? Eur. J. Med. Genet. 64 2021 104246 10.1016/j.ejmg.2021.104246 34020006 source
- cites [8] Kato K. Oka Y. Muramatsu H. Vasilev F.F. Otomo T. Oishi H. Kawano Y. Kidokoro H. Nakazawa Y. Ogi T. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex J. Med. Genet. 57 2020 245 253 10.1136/jmedgenet-2019-106213 31712251 source
- cites [9] Kolanczyk M. Krawitz P. Hecht J. Hupalowska A. Miaczynska M. Marschner K. Schlack C. Emmerich D. Kobus K. Kornak U. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome Eur. J. Hum. Genet. 23 2015 720 10.1038/ejhg.2014.278 25880334 PMC4402643 source
- Findingown data
The human COMMD proteins assemble into a hetero-decameric closed ring.
“The human COMMD proteins assemble into a remarkable hetero-decameric closed ring (Figures 4 and S3B).”
Quote in the paperSubstantial claim - Findingown data
The conserved 34PL35 side chains of VPS35L bind the VPS29 pocket defined by Val174 and Leu152.
“The conserved 34PL35 side chains of VPS35L bind the VPS29 pocket defined by Val174 and Leu152 respectively”
Quote in the paperSubstantial claim - Findingown data
In the subcomplex C structure, the four COMM domains form an intimately assembled core structure with HN domains of COMMD9 and COMMD10 located peripherally.
“The four COMM domains form an intimately assembled core structure with HN domains of COMMD9 and COMMD10 located peripherally.”
Quote in the paperSubstantial claim - Findingown data
The CH domain of CCDC22 is predicted to form an intramolecular interaction with the two C-terminal coiled-coil regions (CC3-CC4).
“In contrast, the CH domain of CCDC22, (which is not visible in the cryoEM map) is predicted to form an intramolecular interaction with the two C-terminal coiled-coil regions (CC3-CC4).”
Quote in the paperNot a substantial claim - Findingown data
A second pocket is formed by the interface between VPS35L and VPS26C.
“A second pocket is formed by the interface between VPS35L and VPS26C (Figure S7C).”
Quote in the paperNot a substantial claim - Findingown data
Re-processing the data in RELION4.0 yielded a reconstruction with overall resolution of 3.5 Å.
“Several rounds of 3D particle classification with and without alignment combined with 3D refinement yielded a reconstruction with overall resolution of 3.5 Å (Figure S2; Methods S1; Table S1).”
Quote in the paperNot a substantial claim - Findingown data
VPS35L(L27D) and VPS35L(L35D) mutations block peptide binding by ITC.
“VPS35L(L27D) and VPS35L(L35D) mutations block peptide binding by ITC (Figure 2A)”
Quote in the paperSubstantial claim - Findingown data
Mutations in CCDC22 and CCDC93 within the predicted binding interface either reduced or abolished the interaction to below detectable levels.
“Mutations in CCDC22 and CCDC93 within the predicted binding interface either reduced or abolished the interaction to below detectable levels (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
A synthetic VPS35L peptide (Glu16-Ile38) showed modest affinity for recombinant VPS29 with a Kd of 1.8 ± 0.8 μM.
“A synthetic VPS35L peptide (Glu16-Ile38) representing the predicted VPS29-binding sequence showed modest affinity for recombinant VPS29 (Kd of 1.8 ± 0.8 μM) (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
The surface of the CCDC93 CH domain is very highly conserved.
“Lastly, the surface of the CCDC93 CH domain is very highly conserved (Figure S7D).”
Quote in the paperNot a substantial claim - Findingown data
Recombinant Retriever failed to bind recombinant TBC1D5.
“Indeed, recombinant Retriever failed to bind recombinant TBC1D5 (Figure S1C)”
Quote in the paperSubstantial claim - Findingown data
The central ring of COMM domains was more clearly resolved than the peripheral HN domains due to their relative flexibility.
“The central ring of the COMM domains was more clearly resolved than the peripheral HN domains due to their relative flexibility (Video S2; Methods S1).”
Quote in the paperNot a substantial claim - Findingown data
When used as bait, COMMD1, 3, 6, 7, and 9 specifically isolated the entire Commander assembly.
“When used as bait, COMMD1, 3, 6, 7, and 9 specifically isolated the entire Commander assembly, confirming the overall inter-stability of the complex.”
Quote in the paperSubstantial claim - Findingown data
CCDC22 and CCDC93 linkers make extensive contacts with the central COMM domain ring and the peripheral HN domains.
“In this structure, the CCDC22 and CCDC93 linkers make extensive contacts with the central COMM domain ring and the peripheral HN domains (Figures 4D, S4B, and S4C)”
Quote in the paperSubstantial claim - Findingown data
Each interface involves the HN domain enfolding the loop between the β1-β2 strands of the COMM domain from their respective dimerization partner.
“Each of these interfaces involves the HN domain enfolding the loop between the β1-β2 strands of the COMM domain from their respective dimerization partner.”
Quote in the paperSubstantial claim - Findingown data
The formation of a high-affinity trimer was shown by size-exclusion chromatography.
“The formation of a high-affinity trimer was also shown by size-exclusion chromatography (Figures 5C and S6C).”
Quote in the paperSubstantial claim - Findingown data
Reciprocal mutations in CCDC22 and CCDC93 perturbed cellular interaction with DENND10.
“Reciprocal mutations in CCDC22 and CCDC93 also perturbed cellular interaction with DENND10”
Quote in the paperSubstantial claim - Findingown data
Unbiased interactome analysis comparing wild type VPS35L with the three mutants confirmed a pronounced loss in VPS29 and CCC complex association.
“Unbiased interactome analysis comparing wild type VPS35L with the three mutants confirmed a pronounced loss in VPS29 and CCC complex association (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
In the predicted structure, CCDC22 and CCDC93 form a V-shaped coiled-coil dimer bridged by conserved elements of the DENND10 DENN domain.
“In this predicted structure, CCDC22 and CCDC93 form a V-shaped coiled-coil dimer bridged by conserved elements of the DENND10 DENN domain (Figures 5A and S6B).”
Quote in the paperSubstantial claim - Findingown data
Data processing in CryoSPARC yielded a 3D reconstruction of the CCC dodecameric complex with overall resolution 3.1 Å.
“Data processing in CryoSPARC yielded a 3D reconstruction (overall resolution 3.1 Å) (Figure S2; Methods S1; Table S1).”
Quote in the paperSubstantial claim - Findingown data
Estimates of the molecular mass of the entire Commander complex are broadly consistent with the predicted molecular weight (570 kDa) if all subunits of Commander are present in a single copy.
“Estimates of the molecular mass of the entire Commander complex are broadly consistent with the predicted molecular weight (570 kDa) if all subunits of Commander are present in a single copy.”
Quote in the paperNot a substantial claim - Findingown data
The COMMD5-COMMD10 and COMMD7-COMMD9 dimers interact primarily via an extended β-sheet augmentation between COMMD5 and COMMD7 COMM domains.
“The COMMD5-COMMD10 and COMMD7-COMMD9 dimers interact primarily via an extended β-sheet augmentation between COMMD5 and COMMD7 COMM domains (Figures 3B–3D).”
Quote in the paperSubstantial claim - Findingown data
CCDC93(H406R) and CCDC93(E410K) mutations showed the strongest effect in line with the in vitro ITC measurements.
“with the CCDC93(H406R) and CCDC93(E410K) mutations showing the strongest effect in line with the in vitro ITC measurements.”
Quote in the paperNot a substantial claim - Findingown data
Contacts between the HN and COMM domains of all four COMMD proteins contribute to the overall specificity of assembly.
“In addition, contacts between the HN and COMM domains of all four COMMD proteins contribute to the overall specificity of assembly.”
Quote in the paperSubstantial claim - Findingown data
There are surfaces that show a high degree of conservation.
“In contrast, there are surfaces that show a high degree of conservation.”
Quote in the paperNot a substantial claim - Findingown data
The AlphaFold2 model predicts a specific arrangement of the COMMD proteins in a heterodecameric ring, with linker regions of CCDC22 and CCDC93 between their N-terminal calponin-homology (CH) domains and their C-terminal coiled-coil domains entwined through the COMMD assembly.
“This predicts a specific arrangement of the COMMD proteins in a heterodecameric ring, with linker regions of CCDC22 and CCDC93 between their N-terminal calponin-homology (CH) domains and their C-terminal coiled-coil domains entwined through the COMMD assembly.”
Quote in the paperSubstantial claim - Findingnone given
The DENND10 sequence is highly divergent from DENND1B.
“The DENND10 sequence is highly divergent from DENND1B”
Quote in the paperSubstantial claim - Findingown data
The interface between each COMMD heterodimer is mediated by specific contacts involving the four adjacent protomers, resulting in the precise organization of the heterodecameric ring.
“As seen in the crystal structure of the COMMD5-7-9-10 heterotetramer, the interface between each COMMD heterodimer is mediated by specific contacts involving the four adjacent protomers (Figure S4A), resulting in the precise organization of the heterodecameric ring.”
Quote in the paperSubstantial claim - Findingown data
This interaction is mediated primarily by the C-terminal CC3-CC4 coiled-coil structures with a minor interface involving the second CC2 region.
“This is mediated primarily by the C-terminal CC3-CC4 coiled-coil structures with a minor interface involving the second CC2 region.”
Quote in the paperSubstantial claim - Findingown data
GFP-tagged DENND10 was able to precipitate Commander subunits.
“GFP-tagged DENND10 was able to precipitate Commander subunits, while mutations in the predicted interface DENND10(L27E), -(M123E), and -(I127E) either reduced or abolished these interactions.”
Quote in the paperSubstantial claim - Findingown data
An essentially identical ab initio structure was built using Modelangelo, although incomplete in many HN domains due to poorer density.
“Notably, an essentially identical ab initio structure was built using the machine-learning guided modeling software Modelangelo,67 although incomplete in many HN domains due to poorer density (not shown).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [67] Jamali K. Kimanius D. Scheres S. ModelAngelo: Automated Model Building in Cryo-EM Maps Preprint at arXiv 2022 10.48550/arXiv.2210.00006 PMC11006616 38408488
- Findingown data
The first 17 residues of VPS35L form an intramolecular interaction with the carboxy-terminal region of the VPS35L α-solenoid.
“The first 17 residues form an intramolecular interaction with the carboxy-terminal region of the VPS35L α-solenoid (Figure 1B), with the same structure predicted for all VPS35L orthologues across species (not shown).”
Quote in the paperSubstantial claim - Findingnone given
The central coiled-coil regions of the CCDC22-CCDC93 dimer mediate recruitment of the peripheral subunit DENND10.
“The central coiled-coil regions of the CCDC22-CCDC93 dimer mediate recruitment of the peripheral subunit DENND10”
Quote in the paperSubstantial claim - Findingown data
Deletion and frameshift mutations in VPS35L proximal to the VPS29 binding site specifically impact VPS29 interaction without seriously affecting overall Commander assembly.
“In contrast, we found that deletion and frameshift mutations in VPS35L proximal to the VPS29 binding site specifically impact VPS29 interaction without seriously affecting overall Commander assembly.”
Quote in the paperSubstantial claim - Findingown data
The various AlphaFold2-predicted complexes invariably displayed highly consistent interfaces across multiple predictions.
“Notably, the various complexes invariably displayed highly consistent interfaces across multiple predictions.”
Quote in the paperNot a substantial claim - Findingnone given
The coiled-coil regions of the CCDC proteins remain unresolved by experimental methods.
“the coiled-coil regions of the CCDC proteins remain unresolved by experimental methods”
Quote in the paperNot a substantial claim - Findingreasoning
No electron density was observed for the N-terminal HN domains of either COMMD5 or COMMD7.
“Despite the quality of the final structure and resulting maps, no electron density was observed for the N-terminal HN domains of either COMMD5 or COMMD7.”
Quote in the paperNot a substantial claim - Findingnone given
Stable COMMD assembly requires the intercalation of CCDC22 and CCDC93 linker sequences, which make extensive contacts with different COMMD subunits to tie the assembly together.
“One important finding is that stable COMMD assembly requires the intercalation of CCDC22 and CCDC93 linker sequences, which make extensive contacts with different COMMD subunits to tie the assembly together.”
Quote in the paperSubstantial claim - Findingcitation
This sequence mimics Pro-Leu-containing motifs found in Retromer-interacting proteins, including TBC1D5, VARP/ANKRD27, and RidL.
“This sequence mimics Pro-Leu-containing motifs found in Retromer-interacting proteins, including the RAB7 GAP TBC1D5,47 the RAB32/RAB38 GEF and SNARE trafficking protein VARP/ANKRD27,46 and the secreted L. pneumophila effector RidL.48,50,51”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [47] Jia D. Zhang J.S. Li F. Wang J. Deng Z. White M.A. Osborne D.G. Phillips-Krawczak C. Gomez T.S. Li H. Structural and mechanistic insights into regulation of the retromer coat by TBC1d5 Nat. Commun. 7 2016 13305 10.1038/ncomms13305 27827364 PMC5105194
- cites [46] Crawley-Snowdon H. Yang J.C. Zaccai N.R. Davis L.J. Wartosch L. Herman E.K. Bright N.A. Swarbrick J.S. Collins B.M. Jackson L.P. Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29 Nat. Commun. 11 2020 5031 10.1038/s41467-020-18773-2 33024112 PMC7539009
- cites [48] Bärlocher K. Hutter C.A.J. Swart A.L. Steiner B. Welin A. Hohl M. Letourneur F. Seeger M.A. Hilbi H. Structural insights into Legionella RidL-Vps29 retromer subunit interaction reveal displacement of the regulator TBC1D5 Nat. Commun. 8 2017 1543 10.1038/s41467-017-01512-5 29146912 PMC5691146
- Findingown data
Analysis of the unit cell volume and Matthews Coefficient estimated that a single copy of the COMMD5-7-9-10 tetramer was present in the asymmetric unit.
“From analysis of the unit cell volume and Matthews Coefficient using XTRIAGE,102 it was estimated that a single copy of the COMMD5-7-9-10 tetramer was present in the asymmetric unit.”
Quote in the paperNot a substantial claim - Findingown data
Mutations designed based on AlphaFold2 modeling specifically block CCC and Retriever interaction.
“we show that mutations designed based on AlphaFold2 modeling specifically block CCC and Retriever interaction.”
Quote in the paperSubstantial claim - Findingown data
The resulting model and electron density were sufficient to unambiguously determine the identities of each individual COMM domain.
“The resulting model and electron density was sufficient to unambiguously determine the identities of each individual COMM domain.”
Quote in the paperSubstantial claim - Findingown data
CTF refinement and Bayesian polishing improved the global resolution of the CCC complex map to 4.1 Å.
“This further improved the global resolution of the map to 4.1 Å.”
Quote in the paperNot a substantial claim - Findingown data
The ∼4.2 Å resolution of the Retriever map is an overestimation because Retriever particles displayed preferred orientation.
“However, this is an overestimation of the resolution of the map, as it was very clear from the reference-free 2D classification classes and 3D refinement jobs that Retriever particles displayed preferred orientation.”
Quote in the paperSubstantial claim - Findingown data
The final Retriever cryo-EM map has an overall resolution of ∼4.2 Å according to gold-standard FSC, directional FSC and sphericity measurements.
“Gold-standard Fourier Shell Correlations (FSCs) and directional FSC plots and measurements of sphericity (calculated using the online 3DFSC tool) indicate that the final map has an overall resolution of ∼4.2 Å.”
Quote in the paperSubstantial claim - Findingcitation
The structure of the Commander complex has allowed us to map the locations of causative mutations for XLID and RSS.
“The structure of the Commander complex has allowed us to map the locations of causative mutations for XLID and RSS.7,8,9,10,11,12,13,14”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] Gjerulfsen C.E. Møller R.S. Fenger C.D. Hammer T.B. Bayat A. Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised? Eur. J. Med. Genet. 64 2021 104246 10.1016/j.ejmg.2021.104246 34020006 source
- cites [8] Kato K. Oka Y. Muramatsu H. Vasilev F.F. Otomo T. Oishi H. Kawano Y. Kidokoro H. Nakazawa Y. Ogi T. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex J. Med. Genet. 57 2020 245 253 10.1136/jmedgenet-2019-106213 31712251 source
- cites [9] Kolanczyk M. Krawitz P. Hecht J. Hupalowska A. Miaczynska M. Marschner K. Schlack C. Emmerich D. Kobus K. Kornak U. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome Eur. J. Hum. Genet. 23 2015 720 10.1038/ejhg.2014.278 25880334 PMC4402643 source
- Findingown data
The final CCC complex cryo-EM reconstruction has an overall resolution of 3.1 Å.
“The classes were opened in Chimera and the best class consisting of 153,104 particles was chosen for homo refinement followed by NU refinement to give a final reconstruction with an overall resolution of 3.1 Å.”
Quote in the paperSubstantial claim - Study design and conductown data
The major interactions within Retriever were validated by structure-based mutagenesis.
“The major interactions within Retriever were validated by structure-based mutagenesis.”
Quote in the paperSubstantial claim - Premisecitation
The COMM domain forms obligate dimers with a left-handed handshake topology.
“The structure of the COMM domain requires it to form obligate dimers, where the β-strands and α-helix of two monomers are tightly interlocked in a “left-handed handshake” topology that buries otherwise solvent exposed hydrophobic sidechains.42”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
- Interpretationreasoning
The COMMD protein family likely originated on the eukaryotic stem and proliferated via a series of gene duplications prior to the radiation of the modern eukaryotic groups.
“Based on the absence of COMMD homologues in Bacteria and Archaea, this protein family likely originated on the eukaryotic stem and proliferated via a series of gene duplications prior to the radiation of the modern eukaryotic groups.”
Quote in the paperNot a substantial claim - Interpretationreasoning
All ten COMMD subunits were already present in the last eukaryotic common ancestor.
“this implies that all ten COMMD subunits were already present in the last eukaryotic common ancestor (that is, LECA appears 10 times in the tree)”
Quote in the paperNot a substantial claim - Interpretationown data
The 34PL35-VPS29 association is centrally important for Retriever assembly.
“confirming the central importance of the 34PL35-VPS29 association for Retriever assembly (Figure 1E).”
Quote in the paperSubstantial claim - Interpretationreasoning
The conserved structure strongly implies that COMMD and CCDC22/CCDC93 proteins will function strictly as a dodecameric complex in the cell.
“The conserved structure strongly implies that COMMD and CCDC22/CCDC93 proteins will function strictly as a dodecameric complex in the cell.”
Quote in the paperSubstantial claim - Interpretationreasoning
COMMD genes have been lost independently in different eukaryotic lineages.
“The presence-absence pattern of COMMD genes in modern eukaryotes, taken together with the phylogeny in (A), indicates that these genes have been lost independently in different eukaryotic lineages.”
Quote in the paperNot a substantial claim - Interpretationown data
These structural data provide a molecular explanation for the perturbed stability and assembly of the Commander complex associated with XLID and RSS.
“these structural data provide a molecular explanation for the perturbed stability and assembly of the Commander complex associated with XLID and RSS.”
Quote in the paperSubstantial claim - Interpretationreasoning
Retriever will be excluded from interacting with Retromer accessory proteins such as ANKRD27, TBC1D5, and RidL.
“This implies that Retriever will be excluded from interacting with these Retromer accessory proteins.”
Quote in the paperSubstantial claim - Interpretationreasoning
A cluster of disease-causing mutations (T17A, T30A, V38M, R128Q) are predicted to destabilize this domain and its intramolecular interaction.
“and a cluster of disease-causing mutations (T17A, T30A, V38M, R128Q) are predicted to destabilize this domain and its intramolecular interaction.”
Quote in the paperSubstantial claim - Interpretationreasoning
The interdependency of the COMMD and CCDC proteins for Commander organization provides a molecular explanation for the high degree of subunit conservation across species.
“The interdependency of the COMMD and CCDC proteins for Commander organization provides a molecular explanation for the high degree of subunit conservation across species.”
Quote in the paperSubstantial claim - Interpretationreasoning
Comparison with the DENND1B-RAB35 complex suggests that the CCDC proteins bind to DENND10 using an overlapping surface.
“Comparison with the DENND1B-RAB35 complex suggests that the CCDC proteins bind to DENND10 using an overlapping surface.”
Quote in the paperSubstantial claim - Interpretationown data
The conservation of this complex confirms its essential role throughout evolution.
“The conservation of this complex confirms its essential role throughout evolution”
Quote in the paperNot a substantial claim - Interpretationown data
The COMMD subunits likely arose by gene origination followed by gene duplication along the eukaryotic stem lineage, prior to LECA.
“This suggests the COMMD subunits likely arose by gene origination followed by gene duplication along the eukaryotic stem lineage, prior to LECA.”
Quote in the paperNot a substantial claim - Interpretationown data
The overall shape of the complex is restrained by the predicted intramolecular interaction between the CCDC22 CH domain with this CCDC22/93 C-terminal structure.
“The overall shape of the complex is restrained by the predicted intramolecular interaction between the CCDC22 CH domain with this CCDC22/93 C-terminal structure.”
Quote in the paperNot a substantial claim - Interpretationown data
This structure indicates that each of the subunits act in unison to mediate Commander activity.
“This structure also indicates that each of the subunits act in unison to mediate Commander activity”
Quote in the paperSubstantial claim - Interpretationown data
The CH domain of CCDC22 is predicted to form a key interaction with the C-terminal coiled-coil domains of CCDC22 and CCDC93 resulting in an overall compact Commander structure.
“The CH domain of CCDC22 is predicted to form a key interaction with the C-terminal coiled-coil domains of CCDC22 and CCDC93 resulting in an overall compact Commander structure (Figure 6A)”
Quote in the paperSubstantial claim - Interpretationreasoning
When associated with Commander, DENND10 would be unable to engage a RAB GTPase in the same way as DENND1B with RAB35.
“Thus, when associated with Commander, DENND10 would be unable to engage a RAB GTPase in the same way as DENND1B with RAB35 (Figure S6D).”
Quote in the paperSubstantial claim - Interpretationown data
The intramolecular association of VPS35L N- and C-terminal regions serves to tether and orient two PL motifs, 26PL27 and 34PL35, for binding to a hydrophobic surface on VPS29.
“The intramolecular association of VPS35L N- and C-terminal regions serves to tether and orient two Pro-Leu (PL) motifs, 26PL27 and 34PL35 of VPS35L, for binding to a hydrophobic surface on VPS29 (see inset (v) in Figure 1B).”
Quote in the paperSubstantial claim - Interpretationown data
This work provides a molecular explanation for the coupling of the CCC and Retriever assemblies into the holo-Commander complex.
“This work provides a molecular explanation for the coupling of the CCC and Retriever assemblies into the holo-Commander complex.”
Quote in the paperSubstantial claim - Interpretationreasoning
This reaffirms the important role that VPS29 plays in Commander function.
“and reaffirms the important role that VPS29 plays in Commander function.”
Quote in the paperSubstantial claim - Interpretationown data
The Retriever map is insufficient for model building and refinement.
“The map is therefore insufficient for model building and refinement.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Incorporation of VPS29 into Retriever is mutually exclusive with its ability to function in canonical Retromer-mediated transport.
“Incorporation of VPS29 into Retriever is therefore mutually exclusive with its ability to function in canonical Retromer-mediated transport”
Quote in the paperSubstantial claim - Premisecitation
The proteins must form obligate dimers due to the distinct structure of their C-terminal COMM domains.
“The proteins must form obligate dimers due to the distinct structure of their C-terminal COMM domains.42”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
- It may state two separate claims as one. 75
- Probably not a substantial claim. 56
- The quote only partly states this claim. 6
It may state two separate claims as one.
PremisecitationApart from COMMD9 and VPS29, the structure of Commander is almost completely uncharacterized, and the stoichiometry of the different subunits remains unclear.
“Apart from COMMD942 and VPS29,44,45,46,47,48,49,50,51 the structure of Commander is almost completely uncharacterized, and the stoichiometry of the different subunits remain unclear.”
Quote in the paperSubstantial claim1 of 9 sources checked- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
- cites [44] Chen K.E. Guo Q. Hill T.A. Cui Y. Kendall A.K. Yang Z. Hall R.J. Healy M.D. Sacharz J. Norwood S.J. De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex Sci. Adv. 7 2021 eabg4007 10.1126/sciadv.abg4007 34851660 PMC8635440
- cites [45] Collins B.M. Skinner C.F. Watson P.J. Seaman M.N.J. Owen D.J. Vps29 has a phosphoesterase fold that acts as a protein interaction scaffold for retromer assembly Nat. Struct. Mol. Biol. 12 2005 594 602 10.1038/nsmb954 15965486
- cites [46] Crawley-Snowdon H. Yang J.C. Zaccai N.R. Davis L.J. Wartosch L. Herman E.K. Bright N.A. Swarbrick J.S. Collins B.M. Jackson L.P. Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29 Nat. Commun. 11 2020 5031 10.1038/s41467-020-18773-2 33024112 PMC7539009
- cites [47] Jia D. Zhang J.S. Li F. Wang J. Deng Z. White M.A. Osborne D.G. Phillips-Krawczak C. Gomez T.S. Li H. Structural and mechanistic insights into regulation of the retromer coat by TBC1d5 Nat. Commun. 7 2016 13305 10.1038/ncomms13305 27827364 PMC5105194
- cites [48] Bärlocher K. Hutter C.A.J. Swart A.L. Steiner B. Welin A. Hohl M. Letourneur F. Seeger M.A. Hilbi H. Structural insights into Legionella RidL-Vps29 retromer subunit interaction reveal displacement of the regulator TBC1D5 Nat. Commun. 8 2017 1543 10.1038/s41467-017-01512-5 29146912 PMC5691146
- cites [49] Damen E. Krieger E. Nielsen J.E. Eygensteyn J. van Leeuwen J.E.M. The human Vps29 retromer component is a metallo-phosphoesterase for a cation-independent mannose 6-phosphate receptor substrate peptide Biochem. J. 398 2006 399 409 10.1042/BJ20060033 16737443 PMC1559457
- cites [50] Romano-Moreno M. Rojas A.L. Williamson C.D. Gershlick D.C. Lucas M. Isupov M.N. Bonifacino J.S. Machner M.P. Hierro A. Molecular mechanism for the subversion of the retromer coat by the Legionella effector RidL Proc. Natl. Acad. Sci. USA 114 2017 E11151 E11160 10.1073/pnas.1715361115 29229824 PMC5748213
- cites [51] Yao J. Yang F. Sun X. Wang S. Gan N. Liu Q. Liu D. Zhang X. Niu D. Wei Y. Mechanism of inhibition of retromer transport by the bacterial effector RidL Proc. Natl. Acad. Sci. USA 115 2018 E1446 E1454 10.1073/pnas.1717383115 29386389 PMC5816186
It may state two separate claims as one.
PremisecitationMutations in Commander subunits are causative for X-linked intellectual disability (XLID) and Ritscher-Schinzel syndrome (RSS).
“mutations in its subunits are causative for X-linked intellectual disability (XLID) and Ritscher-Schinzel syndrome (RSS), a multi-system developmental disorder characterised by abnormal craniofacial features, cerebellar hypoplasia, and stunted cardiovascular development.7,8,9,10,11,12,13,14”
Quote in the paperSubstantial claim4 of 8 sources checked- cites [7] Gjerulfsen C.E. Møller R.S. Fenger C.D. Hammer T.B. Bayat A. Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised? Eur. J. Med. Genet. 64 2021 104246 10.1016/j.ejmg.2021.104246 34020006
- cites [8] Kato K. Oka Y. Muramatsu H. Vasilev F.F. Otomo T. Oishi H. Kawano Y. Kidokoro H. Nakazawa Y. Ogi T. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex J. Med. Genet. 57 2020 245 253 10.1136/jmedgenet-2019-106213 31712251 source
- cites [9] Kolanczyk M. Krawitz P. Hecht J. Hupalowska A. Miaczynska M. Marschner K. Schlack C. Emmerich D. Kobus K. Kornak U. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome Eur. J. Hum. Genet. 23 2015 720 10.1038/ejhg.2014.278 25880334 PMC4402643 source
- cites [10] Neri S. Maia N. Fortuna A.M. Damasio J. Coale E. Willis M. Jorge P. Højte A.F. Fenger C.D. Møller R.S. Bayat A. Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes Eur. J. Med. Genet. 65 2022 104624 10.1016/j.ejmg.2022.104624 36130690
- cites [11] Otsuji S. Nishio Y. Tsujita M. Rio M. Huber C. Antón-Plágaro C. Mizuno S. Kawano Y. Miyatake S. Simon M. Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome J. Med. Genet. 60 2023 359 367 10.1136/jmg-2022-108602 36113987 PMC10086474 source
The Introduction identifies CCDC22 as a gene responsible for Ritscher-Schinzel syndrome and describes the syndrome’s craniofacial, cerebellar and cardiac features. The References include a study titled “Missense variant in CCDC22 causes X-linked recessive intellectual disability,” but the paper’s main text does not directly make the XLID claim; its explicit discussion of intellectual disability here concerns an autosomal recessive condition linked to WASHC4. (LLM, conf=0.79)
Experimental — accuracy not yet measured - cites [12] Starokadomskyy P. Gluck N. Li H. Chen B. Wallis M. Maine G.N. Mao X. Zaidi I.W. Hein M.Y. McDonald F.J. CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappaB signaling J. Clin. Invest. 123 2013 2244 2256 10.1172/JCI66466 23563313 PMC3635737 source
The section on CCDC22 and COMMD proteins (page unavailable) reports a CCDC22 mutation in a family with XLID and shows that the mutation impairs COMMD1 binding. Our copy does not identify these patients as having Ritscher-Schinzel syndrome or support the cited syndrome description, so it supports only the XLID part of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [13] Bartuzi P. Billadeau D.D. Favier R. Rong S. Dekker D. Fedoseienko A. Fieten H. Wijers M. Levels J.H. Huijkman N. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL Nat. Commun. 7 2016 10961 10.1038/ncomms10961 26965651 PMC4792963 source
The Abstract states that CCDC22 mutations cause X-linked intellectual disability, and the Results identify CCDC22 as a CCC-complex component. The Results section on LDLR trafficking attributes Ritscher–Schinzel syndrome to a mutation in KIAA0196, which it identifies as a WASH-complex component, not a CCC/Commander subunit. Thus this paper does not support the claim that mutations in Commander subunits cause both conditions. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [14] Voineagu I. Huang L. Winden K. Lazaro M. Haan E. Nelson J. McGaughran J. Nguyen L.S. Friend K. Hackett A. CCDC22: a novel candidate gene for syndromic X-linked intellectual disability Mol. Psych. 17 2012 4 7 10.1038/mp.2011.95 PMC3586744 21826058 source
The paper’s main text says a CCDC22 mutation in one family suggests that CCDC22 mutations are a rare cause of XLID, but calls CCDC22 a candidate gene rather than establishing causation. It does not identify CCDC22 as a Commander subunit or address Ritscher–Schinzel syndrome. Its account of the family’s cardiac and facial abnormalities does not establish the syndrome description in the citing sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe COMM domain has high sequence similarity across the ten COMMD proteins and is composed of three anti-parallel β-strands and a C-terminal α-helix.
“The COMM domain has high sequence similarity across the ten proteins and is composed of three anti-parallel β-strands, β1-β3, and a C-terminal α-helix α7.42”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
The Results section on the Commd9 crystal structure describes each COMM-domain monomer as an N-terminal three-stranded β-sheet capped by an α-helix. The Results section on the conserved dimerization interface reports that COMM domains are highly conserved across the COMMD family. Our copy does not explicitly establish that the three β-strands are antiparallel. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationCommander is required for cellular infection by human papilloma virus (HPV) and SARS-CoV-2.
“Commander is also required for cellular infection by human papilloma virus (HPV)6 and SARS-CoV-2.30,31,32,33”
Quote in the paperNot a substantial claim1 of 5 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
- cites [30] Daniloski Z. Jordan T.X. Wessels H.H. Hoagland D.A. Kasela S. Legut M. Maniatis S. Mimitou E.P. Lu L. Geller E. Identification of required host factors for SARS-CoV-2 infection in human cells Cell 184 2021 92 105.e16 10.1016/j.cell.2020.10.030 33147445 PMC7584921
- cites [31] Ugalde A.P. Bretones G. Rodríguez D. Quesada V. Llorente F. Fernández-Delgado R. Jiménez-Clavero M.Á. Vázquez J. Calvo E. Tamargo-Gómez I. Autophagy-linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS-CoV-2 entry into human cells EMBO J. 41 2022 e110727 10.15252/embj.2022110727 36124427 PMC9627672
- cites [32] Zhu Y. Feng F. Hu G. Wang Y. Yu Y. Zhu Y. Xu W. Cai X. Sun Z. Han W. A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry Nat. Commun. 12 2021 961 10.1038/s41467-021-21213-4 33574281 PMC7878750
- cites [33] Lu A. Hsieh F. Sharma B.R. Vaughn S.R. Enrich C. Pfeffer S.R. CRISPR screens for lipid regulators reveal a role for ER-bound SNX13 in lysosomal cholesterol export J. Cell Biol. 221 2022 e202105060 10.1083/jcb.202105060 34936700 PMC8704955
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationEarly studies implicated COMMD1 and COMMD7 in regulating NF-κB levels and transcriptional pathways through interactions with cullin-containing ubiquitin ligases.
“early studies of individual Commander subunits (COMMD1 and COMMD7) implicated these proteins in regulating NF-κB levels and transcriptional pathways through interactions with cullin-containing ubiquitin ligases.12,34,35,36,37,38,39,40”
Quote in the paperNot a substantial claim1 of 8 sources checked- cites [12] Starokadomskyy P. Gluck N. Li H. Chen B. Wallis M. Maine G.N. Mao X. Zaidi I.W. Hein M.Y. McDonald F.J. CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappaB signaling J. Clin. Invest. 123 2013 2244 2256 10.1172/JCI66466 23563313 PMC3635737 source
The Introduction links COMMD1 and other COMMD family members to Cullin-RING ligases, and describes a COMMD1-dependent ligase step in NF-κB regulation. The paper does not specifically link COMMD7 to NF-κB regulation through those ligases; a search for COMMD7 found only statements about the COMMD family as a whole. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [34] Bartuzi P. Hofker M.H. van de Sluis B. Tuning NF-kappaB activity: a touch of COMMD proteins Biochim. Biophys. Acta 1832 2013 2315 2321 10.1016/j.bbadis.2013.09.014 24080195
- cites [35] Esposito E. Napolitano G. Pescatore A. Calculli G. Incoronato M.R. Leonardi A. Ursini M.V. COMMD7 as a novel NEMO interacting protein involved in the termination of NF-kappaB signaling J. Cell. Physiol. 231 2016 152 161 10.1002/jcp.25066 26060140
- cites [36] O'Hara A. Simpson J. Morin P. Loveridge C.J. Williams A.C. Novo S.M. Stark L.A. p300-mediated acetylation of COMMD1 regulates its stability, and the ubiquitylation and nucleolar translocation of the RelA NF-kappaB subunit J. Cell Sci. 127 2014 3659 3665 10.1242/jcs.149328 25074812 PMC4150058
- cites [37] Riera-Romo M. COMMD1: a multifunctional regulatory protein J. Cell. Biochem. 119 2018 34 51 10.1002/jcb.26151 28543362
- cites [38] Zheng L. You N. Huang X. Gu H. Wu K. Mi N. Li J. COMMD7 regulates NF-kappaB signaling pathway in hepatocellular carcinoma stem-like cells Mol. Ther. Oncolytics 12 2019 112 123 10.1016/j.omto.2018.12.006 30719501 PMC6350112
- cites [39] Mao X. Gluck N. Chen B. Starokadomskyy P. Li H. Maine G.N. Burstein E. COMMD1 (copper metabolism MURR1 domain-containing protein 1) regulates Cullin RING ligases by preventing CAND1 (Cullin-associated Nedd8-dissociated protein 1) binding J. Biol. Chem. 286 2011 32355 32365 10.1074/jbc.M111.278408 21778237 PMC3173175
- cites [40] de Bie P. van de Sluis B. Burstein E. Duran K.J. Berger R. Duckett C.S. Wijmenga C. Klomp L.W.J. Characterization of COMMD protein-protein interactions in NF-kappaB signalling Biochem. J. 398 2006 63 71 10.1042/BJ20051664 16573520 PMC1525016
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe HN domain has a conserved globular structure of six α-helices α1-α6.
“The HN domain, while relatively divergent in sequence, has a conserved globular structure of six α-helices α1-α6.42,43”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
The Results section, “Crystal structure of the Commd9 N-terminal HN domain,” describes Commd9’s HN domain as a globular six-helix bundle and says HN domains are broadly conserved despite sequence variation. But it also states that Commd1 lacks α1 and shares only helices α2–α6, so six helices are not established as a conserved feature of every HN domain. (LLM, conf=0.89)
Experimental — accuracy not yet measured - cites [43] Sommerhalter M. Zhang Y. Rosenzweig A.C. Solution structure of the COMMD1 N-terminal domain J. Mol. Biol. 365 2007 715 721 10.1016/j.jmb.2006.10.030 17097678 PMC2706016
It may state two separate claims as one.
FindingcitationThe interfaces are centered around Trp157 of COMMD5 and Trp139 of COMMD7, which are strictly conserved across all homologues and species of every COMMD protein.
“For clarity, we describe these two interfaces as centered around Trp157 of COMMD5 and Trp139 of COMMD7 (Figures 3F and 3H), as these Trp residues are the only residues that are strictly conserved across all homologues and species of every COMMD protein.42”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
The Results section on CCDC22 and CCDC93 binding says that Trp128 of COMMD9 is strictly conserved across the COMMD family, supporting conservation of a corresponding tryptophan. It does not establish that Trp157 of COMMD5 and Trp139 of COMMD7 are the only residues strictly conserved across every homologue and species. The description of the interfaces as ‘centered around’ those residues is the citing authors’ own framing. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationVPS26C was shown to be required for coupling to the SNX17 cargo adaptor.
“Previously, VPS26C was shown to be required for coupling to the SNX17 cargo adaptor,6”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
It may state two separate claims as one.
PremisecitationEvidence that CCDC22(T17A), CCDC22(Y557C), and VPS35L(A830T) perturb endosomal recycling of LRP1 and LDLR and lead to hypercholesterolemia.
“Taken alongside evidence that CCDC22(T17A), CCDC22(Y557C), and VPS35L(A830T) perturb endosomal recycling of LRP1 and LDLR and lead to hypercholesterolemia,11,65”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [11] Otsuji S. Nishio Y. Tsujita M. Rio M. Huber C. Antón-Plágaro C. Mizuno S. Kawano Y. Miyatake S. Simon M. Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome J. Med. Genet. 60 2023 359 367 10.1136/jmg-2022-108602 36113987 PMC10086474 source
The Results section (‘VPS35L is essential for lipid metabolism’; page unavailable) reports that VPS35L depletion reduced cell-surface LRP1 and LDLR and impaired LDL uptake. The Discussion links this mechanism to hypercholesterolaemia in patients with VPS35L-associated RSS. Our copy does not establish these effects for the specified VPS35L(A830T) variant or for CCDC22(T17A) and CCDC22(Y557C). (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [65] Phillips-Krawczak C.A. Singla A. Starokadomskyy P. Deng Z. Osborne D.G. Li H. Dick C.J. Gomez T.S. Koenecke M. Zhang J.S. COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A Mol. Biol. Cell 26 2015 91 103 10.1091/mbc.E14-06-1073 25355947 PMC4279232 source
The Results section (no page number available in our copy) shows that CCDC22(T17A) fibroblasts have altered ATP7A trafficking and loss of endosomal COMMD1 localization. It does not establish that CCDC22(T17A), CCDC22(Y557C), or VPS35L(A830T) disrupt recycling of LRP1 or LDLR or lead to hypercholesterolemia; the trafficking results here concern ATP7A and TGN46. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
FindingcitationThe first conserved patch is on the CCDC22-CCDC93 coiled-coil structure, lying adjacent to DENND10, aligning closely with a region required for interacting with FAM21 of the WASH complex.
“The first is a patch on the CCDC22-CCDC93 coiled-coil structure, lying adjacent to DENND10 (Figure S7B) aligning closely with a region required for interacting with FAM21 of the WASH complex.65”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [65] Phillips-Krawczak C.A. Singla A. Starokadomskyy P. Deng Z. Osborne D.G. Li H. Dick C.J. Gomez T.S. Koenecke M. Zhang J.S. COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A Mol. Biol. Cell 26 2015 91 103 10.1091/mbc.E14-06-1073 25355947 PMC4279232 source
The Results section, “The carboxy-terminal ends of CCDC22/CCDC93 are responsible for FAM21 binding” (page unavailable), maps regions of both proteins that interact with FAM21. It does not identify a conserved patch on their coiled-coil structure, place that patch adjacent to DENND10, or establish that it aligns with the FAM21-interacting region. (LLM, conf=0.87)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Interpretationown dataVPS26C plays a central role in the endosomal association and function of Commander through a mechanism that may include association with the cargo adaptor SNX17, the WASH complex, and/or an inherent ability of VPS26C to associate with membranes.
“VPS26C therefore plays a central role in the endosomal association and function of Commander through a mechanism that may include association with the cargo adaptor SNX17,6 the WASH complex,65 and/or an inherent ability of VPS26C to associate with membranes.60”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
The Results section on endosomal targeting reports that suppressing DSCR3 (renamed VPS26C) partially reduces retriever’s endosomal association, supporting a role in its localisation. It does not establish an inherent membrane-binding ability for VPS26C, the mechanism to which citation 60 is attached. The paper instead proposes recruitment through the WASH and CCC complexes (Results, ‘Retriever and retromer utilise distinct targeting mechanisms’; page unavailable). (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [65] Phillips-Krawczak C.A. Singla A. Starokadomskyy P. Deng Z. Osborne D.G. Li H. Dick C.J. Gomez T.S. Koenecke M. Zhang J.S. COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A Mol. Biol. Cell 26 2015 91 103 10.1091/mbc.E14-06-1073 25355947 PMC4279232 source
- cites [60] Leneva N. Kovtun O. Morado D.R. Briggs J.A.G. Owen D.J. Architecture and mechanism of metazoan retromer:SNX3 tubular coat assembly Sci. Adv. 7 2021 eabf8598 10.1126/sciadv.abf8598 33762348 PMC7990337
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe only structure of a DENN domain-RAB complex is of DENND1B and RAB35.
“the only structure of a DENN domain-RAB complex is of DENND1B and RAB35.70”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [70] Wu X. Bradley M.J. Cai Y. Kümmel D. De La Cruz E.M. Barr F.A. Reinisch K.M. Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate Proc. Natl. Acad. Sci. USA 108 2011 18672 18677 10.1073/pnas.1110415108 22065758 PMC3219131 source
The Abstract describes a structure of DENND1B-S complexed with Rab35 and calls it the first structure of a DENN-domain protein bound to its substrate. It does not establish the citing sentence’s stronger claim that this is the only DENN-domain–Rab complex structure. (LLM, conf=0.85)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataThe VPS35L(M931Wfs∗2) and VPS35L(Del437-461) mutants retained CCC complex association but had reduced VPS29 binding.
“In contrast, the VPS35L(M931Wfs∗2) and VPS35L(Del437-461) mutants11 retained CCC complex association but had reduced VPS29 binding (Figure 7B).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] Otsuji S. Nishio Y. Tsujita M. Rio M. Huber C. Antón-Plágaro C. Mizuno S. Kawano Y. Miyatake S. Simon M. Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome J. Med. Genet. 60 2023 359 367 10.1136/jmg-2022-108602 36113987 PMC10086474 source
The Results section, “Functional analysis of identified variant proteins” (page unavailable), reports reduced VPS29 binding for several other VPS35L variants, but does not identify M931Wfs*2 or Del437-461 or test their CCC-complex association. Searches for both variant names and CCC association found no passage addressing the claimed pair of mutants. (LLM, conf=0.74)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataKnockout of VPS35L resulted in increased colocalization of α5β1-integrin with the LAMP1-positive late endosome/lysosome and a corresponding reduction in surface α5β1-integrin.
“and an increased colocalization of α5β1-integrin with the LAMP1-positive late endosome/lysosome (Figures 2D–2F) with a corresponding reduction in surface α5β1-integrin6 (Figure 2E).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
The Results section (page unavailable) reports that siRNA suppression of C16orf62 caused α5β1-integrin enrichment in LAMP1-positive late endosomes/lysosomes and reduced its cell-surface level. The Discussion identifies C16orf62 as VPS35L. However, the paper reports C16orf62 knockdown, not VPS35L knockout, for these effects. (LLM, conf=0.88)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationRetriever shares similarities with Retromer, composed of related VPS35L and VPS26C subunits and the shared VPS29 protein, and associates with one divergent adaptor SNX17.
“Although Retriever shares similarities with Retromer, composed of related VPS35L and VPS26C subunits and the shared VPS29 protein, and associates with one divergent adaptor SNX17,2,3,6,15”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [2] Mallam A.L. Marcotte E.M. Systems-wide studies uncover commander, a multiprotein complex essential to human development Cell Syst. 4 2017 483 494 10.1016/j.cels.2017.04.006 28544880 PMC5541947
- cites [3] McNally K.E. Cullen P.J. Endosomal retrieval of cargo: retromer is not alone Trends Cell Biol. 28 2018 807 822 10.1016/j.tcb.2018.06.005 30072228 source
- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOnly one crystal structure of a DENN domain in complex with a RAB GEF substrate has been determined.
“Only one crystal structure of a DENN domain in complex with a RAB GEF substrate has been determined,70”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [70] Wu X. Bradley M.J. Cai Y. Kümmel D. De La Cruz E.M. Barr F.A. Reinisch K.M. Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate Proc. Natl. Acad. Sci. USA 108 2011 18672 18677 10.1073/pnas.1110415108 22065758 PMC3219131 source
The Abstract calls the DENND1B-S–Rab35 complex the first structure of a DENN-domain protein bound to its Rab substrate, and Results and Discussion describes the crystals obtained. That supports the existence of the structure and its priority in 2011, but does not establish that it remained the only such structure when the citing sentence was written. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim. It may be too vague to check against evidence.
InterpretationreasoningPrevious studies examining individual components of the complex may need to be re-interpreted.
“and implies that previous studies examining individual components of the complex, including our own,42 may need to be re-interpreted.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
It may state two separate claims as one.
PremisecitationEndosome-associated branched actin is nucleated by Arp2/3 following activation by the WASH complex, which interacts with Commander subunits.
“Endosome-associated branched actin is nucleated by Arp2/3 following activation by the WASH complex, which interacts with Commander subunits.4,6,13,21,65,78”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [4] Simonetti B. Cullen P.J. Actin-dependent endosomal receptor recycling Curr. Opin. Cell Biol. 56 2019 22 33 10.1016/j.ceb.2018.08.006 30227382 source
- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
- cites [13] Bartuzi P. Billadeau D.D. Favier R. Rong S. Dekker D. Fedoseienko A. Fieten H. Wijers M. Levels J.H. Huijkman N. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL Nat. Commun. 7 2016 10961 10.1038/ncomms10961 26965651 PMC4792963 source
The Results section ('COMMD1 and WASH facilitate LDLR trafficking'; page unavailable) says WASH-mediated actin polymerization occurs on endosomes and identifies a WASH1 mutant that cannot activate Arp2/3. The Abstract (page unavailable) says the CCC complex interacts with WASH. Our copy does not specify that the actin is branched or identify the CCC complex as Commander, so those parts of the claim are not established by this source. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim.
Study design and conductcitationSignificance in the mass spectrometry analysis was determined by permutation-based FDR statistics with the s0 factor iteratively modified to exclude all identifications enriched in the control experiment, yielding an s0 of 1 at 1% FDR.
“Significance was determined by permutation-based FDR statistics122 where the s0 factor was iteratively modified to exclude all identifications enriched in the control experiment, yielding an s0 of 1 at 1% FDR.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [122] Tyanova S. Temu T. Sinitcyn P. Carlson A. Hein M.Y. Geiger T. Mann M. Cox J. The Perseus computational platform for comprehensive analysis of (prote)omics data Nat. Methods 13 2016 731 740 10.1038/nmeth.3901 27348712 source
It may state two separate claims as one.
PremisecitationDENND10 localizes to late endosomes, and its knockdown perturbs aspects of endosomal morphology and function, although it appears dispensable for assembly of Commander.
“DENND10 localizes to late endosomes, and its knockdown perturbs aspects of endosomal morphology and function,21,69 although it appears dispensable for assembly of Commander.21”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [21] Singla A. Fedoseienko A. Giridharan S.S.P. Overlee B.L. Lopez A. Jia D. Song J. Huff-Hardy K. Weisman L. Burstein E. Billadeau D.D. Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling Nat. Commun. 10 2019 4271 10.1038/s41467-019-12221-6 31537807 PMC6753146 source
The Results report that deleting FAM45A perturbed GLUT1 trafficking but had minimal impact on CCC or retriever subunit expression, supporting the functional and assembly portions of the claim. The Discussion says altered endosomal morphology was not seen in FAM45A-deleted cells. Our copy calls the protein FAM45A rather than DENND10, does not establish late-endosome localization, and reports deletion rather than knockdown. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [69] Zhang J. Zhang K. Qi L. Hu Q. Shen Z. Liu B. Deng J. Zhang C. Zhang Y. DENN domain-containing protein FAM45A regulates the homeostasis of late/multivesicular endosomes Biochim. Biophys. Acta. Mol. Cell Res. 1866 2019 916 929 10.1016/j.bbamcr.2019.02.006 30771381 source
It may state two separate claims as one.
Findingown dataVPS35L has little sequence similarity to VPS35 (<21% identity), but both are comprised of sixteen HEAT-like α-helical repeat structures.
“VPS35L has little sequence similarity to the Retromer subunit VPS35 (<21% identity), but both are comprised of sixteen HEAT-like α-helical repeat structures.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataVPS35L(R293E) induced a >95% decrease in VPS26C binding but retained binding to VPS29 and the CCC complex.
“VPS35L(R293E) (see inset (i) in Figure 1B) induced a >95% decrease in VPS26C binding but retained binding to VPS29 and the CCC complex (Figure 1C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.
“The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataUnlike VPS35, VPS35L has an additional conserved N-terminal sequence (~180 residues) that is mostly unstructured apart from elements predicted to engage both the last three α-helical repeats of VPS35L and VPS29.
“Unlike VPS35, VPS35L has an additional conserved N-terminal sequence (∼180 residues) that is mostly unstructured apart from elements that are predicted to engage both the last three α-helical repeats of VPS35L as well as VPS29 (discussed below).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataVPS35L is an extended α-solenoid that binds VPS26C and VPS29 at its amino- and carboxy-terminal ends respectively.
“Analogous to Retromer,57,58,59,60,61,62 VPS35L is an extended α-solenoid that binds VPS26C and VPS29 at its amino- and carboxy-terminal ends respectively (Figures 1B and S1A).”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [57] Hierro A. Rojas A.L. Rojas R. Murthy N. Effantin G. Kajava A.V. Steven A.C. Bonifacino J.S. Hurley J.H. Functional architecture of the retromer cargo-recognition complex Nature 449 2007 1063 1067 10.1038/nature06216 17891154 PMC2377034 source
- cites [58] Kendall A.K. Xie B. Xu P. Wang J. Burcham R. Frazier M.N. Binshtein E. Wei H. Graham T.R. Nakagawa T. Jackson L.P. Mammalian retromer is an adaptable scaffold for cargo sorting from endosomes Structure 28 2020 393 405.e4 10.1016/j.str.2020.01.009 32027819 PMC7145723
- cites [59] Kovtun O. Leneva N. Bykov Y.S. Ariotti N. Teasdale R.D. Schaffer M. Engel B.D. Owen D.J. Briggs J.A.G. Collins B.M. Structure of the membrane-assembled retromer coat determined by cryo-electron tomography Nature 561 2018 561 564 10.1038/s41586-018-0526-z 30224749 PMC6173284
- cites [60] Leneva N. Kovtun O. Morado D.R. Briggs J.A.G. Owen D.J. Architecture and mechanism of metazoan retromer:SNX3 tubular coat assembly Sci. Adv. 7 2021 eabf8598 10.1126/sciadv.abf8598 33762348 PMC7990337
- cites [61] Lucas M. Gershlick D.C. Vidaurrazaga A. Rojas A.L. Bonifacino J.S. Hierro A. Structural mechanism for cargo recognition by the retromer complex Cell 167 2016 1623 1635.e14 10.1016/j.cell.2016.10.056 27889239 PMC5147500
- cites [62] Norwood S.J. Shaw D.J. Cowieson N.P. Owen D.J. Teasdale R.D. Collins B.M. Assembly and solution structure of the core retromer protein complex Traffic 12 2011 56 71 10.1111/j.1600-0854.2010.01124.x 20875039
It may state two separate claims as one.
Findingown dataAlthough the complex studied by cryoEM includes the full-length CCDC proteins, no density is observed for the CH domain of CCDC22 or the C-terminal coiled-coil domains of either protein, indicating significant flexibility in their relative orientation to the COMMD ring.
“Although the complex studied by cryoEM includes the full-length CCDC proteins, no density is observed for the CH domain of CCDC22 or the C-terminal coiled-coil domains of either protein, indicating significant flexibility in their relative orientation to the COMMD ring.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataKnockout of VPS35L resulted in a loss of CCC complex association with endosomes, demonstrating a requirement of Retriever for CCC endosome recruitment.
“Knockout of VPS35L also resulted in a loss of CCC complex association with endosomes, demonstrating a requirement of Retriever for CCC endosome recruitment”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThese losses continued following the diversification of the major eukaryotic lineages; for example, within embryophytes, Arabidopsis thaliana appears to have lost Commander entirely, while Physcomitrium patens has retained four of the ancestral subunits.
“These losses continued following the diversification of the major eukaryotic lineages; for example, within embryophytes (land plants), the model tracheophyte Arabidopsis thaliana appears to have lost Commander entirely, while the bryophyte Physcomitrium patens has retained four of the ancestral subunits (Figure S5B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataTwo critical contacts involve Leu129 in COMMD10 and the analogous Ile118 in COMMD9, which lie within the respective linkers between the HN and COMM domains.
“Two critical contacts involve Leu129 in COMMD10 and the analogous Ile118 in COMMD9; these lie within the respective linkers between the HN and COMM domains (Figures 3D and 3E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe decameric COMMD ring and trimeric Retriever are tethered by the heterodimeric CCDC22 and CCDC93 proteins, with DENND10 associated at the apex of the structure.
“The decameric COMMD ring and trimeric Retriever are tethered by the heterodimeric CCDC22 and CCDC93 proteins, with DENND10 associated at the apex of the structure.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe phenotypes of VPS35L knockout were rescued by wild-type VPS35L, but not the VPS26C-binding mutant VPS35L(R293E).
“These phenotypes were all rescued by wild-type VPS35L, but not the VPS26C-binding mutant VPS35L(R293E) (Figures 2D–2F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataFull-length CCDC22 and CCDC93 are predicted to form a heterodimer with four coiled-coil regions (CC1-CC4) in two V-shaped structures, the first of which interacts with DENND10.
“Full-length CCDC22 and CCDC93 are predicted to form a heterodimer with four coiled-coil regions (CC1-CC4) in two V-shaped structures, the first of which interacts with DENND10 (Figure 5).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
FindingcitationDENND10 deletion does not affect recycling of α5 integrin.
“its deletion does not affect recycling of α5 integrin.21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Singla A. Fedoseienko A. Giridharan S.S.P. Overlee B.L. Lopez A. Jia D. Song J. Huff-Hardy K. Weisman L. Burstein E. Billadeau D.D. Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling Nat. Commun. 10 2019 4271 10.1038/s41467-019-12221-6 31537807 PMC6753146 source
It may state two separate claims as one.
Findingown dataTwo PxxR sequences in CCDC22 that form similar turn structures, 145PHLR148 and 199PVGR202, bind the HN domains of COMMD5 and COMMD3, respectively.
“Two PxxR sequences in CCDC22 that form similar turn structures, 145PHLR148 (Figure 4F) and 199PVGR202 (Figure 4G), bind the HN domains of COMMD5 and COMMD3, respectively.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataOne surface of the COMMD ring is decorated by the HN domains of COMMD1, 4, 2, 10, and 7, while the other consists of COMMD8, 3, 5, and 9.
“One surface of the ring is decorated by the HN domains of COMMD1, 4, 2, 10, and 7, while the other consists of COMMD8, 3, 5, and 9 (human COMMD6 lacks the HN domain, although it is present in other species) (Figure 4B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDeleting the first 17 residues of VPS35L leads to a near complete loss of VPS29 and CCC complex binding without affecting VPS26C association.
“Deleting these residues leads to a near complete loss of VPS29 and CCC complex binding without affecting VPS26C association, which is replicated with VPS35L(R9D/R11D) and VPS35L(L825K) mutants (Figure 1G).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataHuman COMMD6 lacks the HN domain, although it is present in other species.
“human COMMD6 lacks the HN domain, although it is present in other species”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataWestern analysis confirmed a complex of all twelve proteins, with native PAGE and mass spectrometry consistent with a 1:1 stoichiometry assembly.
“Western analysis confirmed a complex of all twelve proteins, with native PAGE and mass spectrometry consistent with a 1:1 stoichiometry assembly (Methods S1).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCo-expression of all ten human COMMD proteins in E. coli followed by affinity purification resulted in isolation of three homogeneous and stable tetrameric sub-complexes: COMMD1-4-6-8 (subcomplex A), COMMD2-3-4-8 (subcomplex B), and COMMD5-7-9-10 (subcomplex C).
“affinity purification of these four tagged-proteins followed by gel filtration and peptide mass spectrometry resulted in the isolation of three homogeneous and stable tetrameric sub-complexes: COMMD1-4-6-8 (isolated by COMMD1-His), COMMD2-3-4-8 (isolated by COMMD2-His), and COMMD5-7-9-10 (isolated by COMMD5-His or COMMD10-His), which we referred to as subcomplex A, B, and C, respectively (Figure 3”
Quote in the paperSubstantial claimIt may state two separate claims as one.
FindingcitationPhylogenetic analysis demonstrated that all twelve proteins (COMMD subunits, CCDC22, CCDC93) were present in the last eukaryotic common ancestor (LECA), with no sequence homologues identified in Archaea or Bacteria.
“Phylogenetic analysis of the COMMD subunits CCDC22 and CCDC93 demonstrated that all twelve proteins were present in the last eukaryotic common ancestor (LECA),2 with no sequence homologues identified in Archaea or Bacteria (Figures S5A and S5B).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Mallam A.L. Marcotte E.M. Systems-wide studies uncover commander, a multiprotein complex essential to human development Cell Syst. 4 2017 483 494 10.1016/j.cels.2017.04.006 28544880 PMC5541947
It may state two separate claims as one.
Findingown dataIn the complex, the HN domain of COMMD10 enfolds the loop of the COMMD5 COMM domain, while the HN domain of COMMD9 enfolds the corresponding loop of COMMD7.
“In this complex, the HN domain of COMMD10 enfolds the loop of the COMMD5 COMM domain, while the HN domain of COMMD9 enfolds the corresponding loop of COMMD7.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataRetriever did not regulate the RAB7 GAP activity of endosomal TBC1D5, as VPS35L KO HeLa cells did not phenocopy the defect in endosomal maturation and accumulation of hyperactivated RAB7-GTP observed in Retromer KO cells.
“Retriever did not regulate the RAB7 GAP activity of endosomal TBC1D5, as CRISPR/Cas9 knockout VPS35L HeLa cells did not phenocopy the defect in endosomal maturation and accumulation of hyperactivated RAB7-GTP observed in Retromer KO cells64 (Figures S1F and S1G).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Jimenez-Orgaz A. Kvainickas A. Nägele H. Denner J. Eimer S. Dengjel J. Steinberg F. Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy EMBO J. 37 2018 235 254 10.15252/embj.201797128 29158324 PMC5770787
It may state two separate claims as one.
Findingown dataEach COMMD forms a strongly supported (>90% bootstrap) clan in the unrooted phylogeny, and each clan contains representatives from all major lineages of eukaryotes.
“Each COMMD forms a strongly supported (>90% bootstrap) clan in the unrooted phylogeny, and each clan contains representatives from all major lineages (supergroups) of eukaryotes”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataVPS35L(R661A) or VPS35L(I710D) and CCDC22(V501D) or CCDC93(E503R) all specifically perturbed Retriever and CCC complex association without affecting assembly of either subcomplex.
“We validated the major interface by mutagenesis of key residues, with VPS35L(R661A) or VPS35L(I710D) and CCDC22(V501D) or CCDC93(E503R) all specifically perturbing Retriever and CCC complex association without affecting assembly of either subcomplex (Figures 6B and 6C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataStrepTactin-affinity isolation of the twelve-subunit CCC complex revealed that CCDC93-Strep and all other proteins were enriched in the desthiobiotin eluate, with size-exclusion chromatography revealing a single homogeneous peak.
“StrepTactin-affinity isolation revealed that CCDC93-Strep and all other proteins were enriched in the desthiobiotin eluate, with size-exclusion chromatography revealing a single homogeneous peak (Methods S1).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe CC1-CC2 coiled-coil regions of CCDC22 and CCDC93 formed a stable dimer, which bound to recombinant DENND10 with an affinity of 28 ± 6 nM.
“Consistent with this, the CC1-CC2 coiled-coil regions of CCDC22 and CCDC93 formed a stable dimer, which bound to recombinant DENND10 with an affinity of 28 ± 6 nM (Figure 5B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataVPS29(L152E) and VPS29(V174D) retained Retromer association but displayed a >95% decrease in binding to VPS35L and CCDC proteins.
“Moreover, VPS29(L152E) and VPS29(V174D) retained Retromer association but displayed a >95% decrease in binding to VPS35L (and CCDC proteins), confirming the central importance of the 34PL35-VPS29 association for Retriever assembly (Figure 1E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataLoss of VPS35L in HeLa cells induced a reduction in VPS26C levels, indicating their reciprocal requirement for Retriever stability.
“In VPS35L KO HeLa cells, loss of VPS35L induced a reduction in VPS26C levels, indicating their reciprocal requirement for Retriever stability.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe cryoEM structure is consistent with the COMMD10-5-COMMD7-9 crystal structure, the tetrameric sub-assemblies observed in bacterial expression, and the complex predicted with AlphaFold2 across diverse species.
“This cryoEM structure is consistent with (i) the COMMD10-5-COMMD7-9 crystal structure, (ii) the tetrameric sub-assemblies observed in bacterial expression, and (iii) the complex predicted with AlphaFold2 across diverse species (Figures S3C–S3E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCCDC22(Y557C) is a highly conserved sidechain and lies directly within the interface with VPS35L.
“CCDC22(Y557C) is a highly conserved sidechain and lies directly within the interface with VPS35L.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataOnly subcomplex C produced an X-ray crystal structure (3.3 Å resolution), revealing a 1:1:1:1 heterotetrameric assembly formed by COMMD5-COMMD10 and COMMD7-COMMD9 heterodimers.
“only subcomplex C produced an X-ray crystal structure (3.3 Å resolution), revealing a 1:1:1:1 heterotetrameric assembly formed by COMMD5-COMMD10 and COMMD7-COMMD9 heterodimers (Figure 3B, Table S2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
FindingcitationNo putative RAB effector protein(s) have yet been identified, although there is evidence for an association with RAB27.
“no putative RAB effector protein(s) have yet been identified, although there is evidence for an association with RAB27.69”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Zhang J. Zhang K. Qi L. Hu Q. Shen Z. Liu B. Deng J. Zhang C. Zhang Y. DENN domain-containing protein FAM45A regulates the homeostasis of late/multivesicular endosomes Biochim. Biophys. Acta. Mol. Cell Res. 1866 2019 916 929 10.1016/j.bbamcr.2019.02.006 30771381 source
It may state two separate claims as one.
Findingown dataOur data define precisely how COMMD family members interact with each other in preferred heterodimers and provide a detailed understanding of their complete assembly into a heterodecameric ring, the stability of which is dependent on interaction with CCDC22 and CCDC93.
“Our data define precisely how COMMD family members interact with each other in preferred heterodimers and provide a detailed understanding of their complete assembly into a heterodecameric ring, the stability of which is dependent on interaction with CCDC22 and CCDC93.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataSeveral methods of data processing in RELION/CryoSPARC to recover less frequent orientations were unsuccessful at improving the distribution of views and the overall final map.
“We also tried several methods of data processing in RELION/CryoSPARC to recover less frequent orientations. However, these were unsuccessful at improving the distribution of views and the overall final map (data not shown).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataIn general, the β1-β2 loop within the COMM domain of each COMMD subunit docks closely into a complementary pocket formed by the HN domain and linker of its cognate dimeric partner, and these interactions involve a strictly conserved tryptophan within the C-terminal α7-helix of the neighboring subunit.
“Although there are many individual requirements for precise COMMD interactions, in general the β1-β2 loop within the COMM domain of each COMMD subunit docks closely into a complementary pocket formed by the HN domain and linker of its cognate dimeric partner, and these interactions involve a strictly conserved tryptophan within the C-terminal α7-helix of the neighboring subunit.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingnone givenCryoEM maps of Retriever have revealed its overall architecture but not its entire atomic structure.
“cryoEM maps of Retriever have revealed its overall architecture but not its entire atomic structure.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataElectron density for the two HN domains positioned by PHASER was relatively poor, but they could be identified confidently as belonging to COMMD9 and COMMD10 based on their connectivity to the core COMM domains of these two subunits.
“Electron density for the two HN domains positioned by PHASER was relatively poor but they could be identified confidently as belonging to COMMD9 and COMMD10 based on their connectivity to the core COMM domains of these two subunits.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
FindingreasoningThe VPS35L sequence binds VPS29 with high affinity, which is enhanced by intramolecular tethering and thus blocks Retriever-bound VPS29 from participating in these regulatory interactions.
“The VPS35L sequence binds VPS29 with high affinity, which is enhanced by intramolecular tethering and thus blocks Retriever-bound VPS29 from participating in these regulatory interactions.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataAlphaFold2 models of Danio rerio and Salpingoeca rosetta complexes were entirely consistent with the predicted human complex.
“These were entirely consistent with the predicted human complex.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingnone givenA tilted dataset was collected but data processing with it was unsuccessful.
“We also collected a tilted dataset but data processing with this dataset was unsuccessful (data not shown).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataMost missense mutations map to key structural elements or inter-subunit interfaces, and those tested all result in significant loss in overall Commander protein levels.
“Most missense mutations map to key structural elements or inter-subunit interfaces, and those tested all result in significant loss in overall Commander protein levels.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe final CryoSPARC refined Retriever map does not contain particles observed from all angles, has a large deviation from the directional FSC and displays low sphericity (0.715 out of 1).
“The final CryoSPARC refined map does not contain particles observed from all angles, has a large deviation from the directional FSC and displays low sphericity (0.715 out of 1) (Methods S1).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataPHASER successfully placed four copies of the COMMD9 COMM domain, one copy of the COMMD9 HN domain, and one copy of the COMMD10 HN domain.
“PHASER was able to successfully place four copies of the COMMD9 COMM domain, one copy of the COMMD9 HN domain and one copy of the COMMD10 HN domain.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataAttempts to overcome Retriever preferential orientation issues by changing sample preparation were unsuccessful.
“We tried unsuccessfully to overcome these preferential orientation issues by changing the sample prep”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataOur studies have shown an analogous architecture; however, Retriever is more compact and has distinct conserved surfaces that mediate specific interactions with the CCC machinery and an intrinsically unstructured N-terminal region that binds and regulates VPS29.
“Our studies have shown an analogous architecture; however, Retriever is more compact and has distinct conserved surfaces that mediate specific interactions with the CCC machinery and an intrinsically unstructured N-terminal region that binds and regulates VPS29.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingnone givenInteractions of the CCC complex with DENND10 and with Retriever have been mapped and experimentally validated in vitro and in situ.
“while interactions of the CCC complex with DENND10 and with Retriever have been mapped and experimentally validated in vitro and in situ”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Findingown dataThe combined CCC complex particles refined to 4.2 Å.
“combined to give a total of 166,533 particles which were then refined to 4.2 Å.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAlignment-free 3D classification selected a class (20,034 particles) containing densities for all HN domains and the CH domain of CCDC93, resulting in a 3.8 Å reconstruction, which was further improved to 3.5 Å after final CTF refinement and 3D refinement.
“The best 3D class (20,034 particles), which contained densities for all the HN domains as well as the CH domain of CCDC93, was selected for a further round of 3D refinement, resulting in a 3.8 Å reconstruction, which was further improved to 3.5 Å following a final round of CTF refinement and 3D refinement.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingown dataThe best-fitting phylogenetic models were Q.yeast+R5 for the COMMD1-10 tree, LG + C20 + F+G for CCD22, and Q.insect+F+I + G4 for CCD93.
“The best-fitting models were Q.yeast+R5 for the COMMD1-10 tree, LG + C20 + F+G for CCD22, and Q.insect+F+I + G4 for CCD93.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Findingnone givenCore structures of the CCC complex and the interaction of VPS29 with the N-terminal tail of VPS35L have been determined at high resolution using X-ray crystallography and cryoEM.
“while core structures of the CCC complex and the interaction of VPS29 with the N-terminal tail of VPS35L have been determined at high resolution using X-ray crystallography and cryoEM”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataCCDC22 and CCDC93 adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits DENND10 to form the complete Commander complex.
“These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationRetriever shares distant homology to Retromer.
“Retriever, a VPS26C:VPS35L:VPS29 trimer, shares distant homology to Retromer, itself a trimer of VPS29, VPS35, and either VPS26A or VPS26B (paralogues with VPS26C).2,15”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Mallam A.L. Marcotte E.M. Systems-wide studies uncover commander, a multiprotein complex essential to human development Cell Syst. 4 2017 483 494 10.1016/j.cels.2017.04.006 28544880 PMC5541947
- cites [15] Chen K.E. Healy M.D. Collins B.M. Towards a molecular understanding of endosomal trafficking by Retromer and Retriever Traffic 20 2019 465 478 10.1111/tra.12649 30993794 source
Probably not a substantial claim.
PremisecitationRetriever is a VPS26C:VPS35L:VPS29 trimer.
“Retriever, a VPS26C:VPS35L:VPS29 trimer, shares distant homology to Retromer, itself a trimer of VPS29, VPS35, and either VPS26A or VPS26B (paralogues with VPS26C).2,15”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Mallam A.L. Marcotte E.M. Systems-wide studies uncover commander, a multiprotein complex essential to human development Cell Syst. 4 2017 483 494 10.1016/j.cels.2017.04.006 28544880 PMC5541947
- cites [15] Chen K.E. Healy M.D. Collins B.M. Towards a molecular understanding of endosomal trafficking by Retromer and Retriever Traffic 20 2019 465 478 10.1111/tra.12649 30993794 source
It may state two separate claims as one.
Interpretationown dataReduced VPS29 interaction correlates with a decrease in CCC complex association, suggesting that VPS29 binding to VPS35L is important to stabilize Retriever and CCC assembly.
“Interestingly, reduced VPS29 interaction correlated with a decrease in CCC complex association, suggesting that its binding to VPS35L is important to stabilize Retriever and CCC assembly.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataRetriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors.
“Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationCOMMD proteins possess a C-terminal COMM domain approximately 70-80 residues in length and an α-helical N-terminal (HN) domain.
“The COMMD proteins possess a C-terminal COMM domain approximately 70–80 residues in length, as well as an α-helical N-terminal (HN) domain.41,42”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [41] Burstein E. Hoberg J.E. Wilkinson A.S. Rumble J.M. Csomos R.A. Komarck C.M. Maine G.N. Wilkinson J.C. Mayo M.W. Duckett C.S. COMMD proteins, a novel family of structural and functional homologs of MURR1 J. Biol. Chem. 280 2005 22222 22232 10.1074/jbc.M501928200 15799966 source
- cites [42] Healy M.D. Hospenthal M.K. Hall R.J. Chandra M. Chilton M. Tillu V. Chen K.E. Celligoi D.J. McDonald F.J. Cullen P.J. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins Elife 7 2018 e35898 10.7554/eLife.35898 30067224 PMC6089597 source
It may state two separate claims as one.
Interpretationown dataVPS35L pathogenic mutations A830T, Del906, and P787L cluster toward the VPS29 interface and are anticipated to disrupt the C-terminal structure of the VPS35L solenoid.
“VPS35L pathogenic mutations A830T, Del906, and P787L cluster toward the VPS29 interface and are anticipated to disrupt the C-terminal structure of the VPS35L solenoid.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataOur studies provide a comprehensive understanding of how Retriever and CCC complexes are assembled and how they combine to form the Commander super-complex.
“Our studies provide a comprehensive understanding of how Retriever and CCC complexes are assembled and how they combine to form the Commander super-complex.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Study design and conductown dataThe threshold of significant enrichment was determined to be 2-fold (log2 fold change = 1) based on the distribution of unenriched proteins.
“The threshold of significant enrichment was determined to be 2-fold (log2 fold change = 1) based on the distribution of unenriched proteins.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningThe extensive interactions mediated by the linker regions of the CCDC proteins appear to enhance the stability of the COMMD ring and likely explain why only tetrameric sub-complexes are isolated when expressing the COMMD proteins alone in E. coli.
“The extensive interactions mediated by the linker regions of the CCDC proteins appears to enhance the stability of the COMMD ring and likely explains why only tetrameric sub-complexes are isolated when expressing the COMMD proteins alone in E. coli (Figure 3).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataIn Retriever, the VPS29 binding site for Retromer accessory proteins is occluded, and VPS29 serves to facilitate association with the CCC complex.
“These results establish that while Retromer-assembled VPS29 provides a docking site for accessory proteins that regulate RAB GTPases;46,47,63 in Retriever, this binding site is occluded, and VPS29 serves to facilitate association with the CCC complex.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [46] Crawley-Snowdon H. Yang J.C. Zaccai N.R. Davis L.J. Wartosch L. Herman E.K. Bright N.A. Swarbrick J.S. Collins B.M. Jackson L.P. Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29 Nat. Commun. 11 2020 5031 10.1038/s41467-020-18773-2 33024112 PMC7539009
- cites [47] Jia D. Zhang J.S. Li F. Wang J. Deng Z. White M.A. Osborne D.G. Phillips-Krawczak C. Gomez T.S. Li H. Structural and mechanistic insights into regulation of the retromer coat by TBC1d5 Nat. Commun. 7 2016 13305 10.1038/ncomms13305 27827364 PMC5105194
- cites [63] Hesketh G.G. Pérez-Dorado I. Jackson L.P. Wartosch L. Schäfer I.B. Gray S.R. McCoy A.J. Zeldin O.B. Garman E.F. Harbour M.E. VARP is recruited on to endosomes by direct interaction with retromer, where together they function in export to the cell surface Dev. Cell 29 2014 591 606 10.1016/j.devcel.2014.04.010 24856514 PMC4059916
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenParental and stable cell lines were negative for mycoplasma by DAPI staining.
“Parental and stable cells lines were negative for mycoplasma by DAPI staining.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataThe final model has excellent refinement statistics and stereochemistry based on Molprobity scores.
“resulting in a final model with excellent refinement statistics and stereochemistry based on Molprobity scores.”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may be too vague to check against evidence.
Interpretationnone givenOur work provides the overall structural framework for analyzing Commander function in a wide array of cellular and disease-associated processes.
“Our work provides the overall structural framework for analyzing Commander function in a wide array of cellular and disease-associated processes.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductown dataeHAP COMMD knockout clonal populations were screened by SDS-PAGE, immunoblotting, and Sanger sequencing of genomic PCR products.
“Clonal populations were expanded and screen by a combination of SDS-PAGE and immunoblotting and Sanger sequencing of genomic PCR products cloned into pGEM4Z.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningThe HN domains are positioned peripherally and appear to be primed for mediating specific intermolecular interactions.
“One functional implication of the COMMD assembly is that the HN domains are positioned peripherally and appear to be primed for mediating specific intermolecular interactions.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataEach phylogenetic tree was inferred with 10,000 ultrafast bootstrap replicates.
“Each tree was inferred with 10,000 ultrafast bootstrap replicates.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataAll maximum likelihood phylogenetic trees were inferred under the best-fitting model according to the Bayesian Information Criterion implemented in ModelFinder.
“All maximum likelihood trees were inferred under the best-fitting model according to the Bayesian Information Criterion implemented in ModelFinder (part of IQTree2.1.3112)”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningXLID/RSS mutations can lead to either overall Commander instability or loss of specific interactions within the complex.
“This shows that XLID/RSS mutations can lead to either overall Commander instability or loss of specific interactions within the complex”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataOur data support the idea that while the CCC and Retriever assemblies are distinct structures, the function of these proteins likely depends on their incorporation into the Commander holo-assembly.
“Our data thus support the idea that while the CCC and Retriever assemblies are distinct structures, the function of these proteins likely depends on their incorporation into the Commander holo-assembly.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
InterpretationreasoningThe absence of electron density for the N-terminal HN domains of COMMD5 and COMMD7 is likely due to flexibility in the orientation of these domains.
“This is likely due to flexibility in the orientation of these domains.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenFalse discovery rates in affinity enrichment mass spectrometry were determined through the target-decoy approach set to 1% for both peptides and proteins.
“False discovery rates (FDR) were determined through the target-decoy approach set to 1% for both peptides and proteins.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductnone givenSequencing of purified plasmid DNA established whether the desired mutation had been introduced in site-directed mutagenesis.
“Sequencing of purified plasmid DNA established whether the desired mutation had been introduced.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationRetromer is a well-characterized complex that works with different cargo adaptors including SNX3 and SNX27 to facilitate endosomal sorting.
“Retromer is a well-characterized complex that works with different cargo adaptors including SNX3 and SNX27 to facilitate endosomal sorting.5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Weeratunga S. Paul B. Collins B.M. Recognising the signals for endosomal trafficking Curr. Opin. Cell Biol. 65 2020 17 27 10.1016/j.ceb.2020.02.005 32155566
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductown dataFLAG-tagged cell lines were verified by SDS-PAGE and immunoblotting after puromycin selection.
“Infected cells were selected using 2 μg mL−1 puromycin, and transduction verified by SDS-PAGE and immunoblotting.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataData collection of the CCC complex was performed from 2 independently prepared grids, in 2 separate sessions.
“Data was collected from 2 independently prepared grids, in 2 separate sessions.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningDENND10 is distinct from these, lacking key residues found in DENND1B required for GEF activity, and the interface with CCDC22-CCDC93 would preclude RAB binding in the same region.
“DENND10 is distinct from these, lacking key residues found in DENND1B required for GEF activity, and the interface with CCDC22-CCDC93 would preclude RAB binding in the same region.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataColocalisation analysis of fluorescently labeled proteins was performed with automatic Costes background thresholding.
“Colocalisation analysis of fluorescently labeled proteins was performed in Volocity 6.3.1 software (PerkinElmer) with automatic Costes background thresholding.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe two movie datasets from the two independent grids were processed independently until indicated.
“The two movie datasets from the two independent grids were processed independently until indicated.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Study design and conductown dataThe threshold of significant enrichment in affinity enrichment mass spectrometry was set to 2-fold (log2 fold change = 1) based on the distribution of unenriched proteins quantified.
“The threshold of significant enrichment was set to 2-fold (log2 fold change = 1) based on the distribution of unenriched proteins quantified.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenValues listed as 'Only identified by site,' 'Reverse,' or 'Contaminants' were removed from the affinity enrichment mass spectrometry dataset.
“Values listed as being “Only identified by site,” “Reverse,” or “Contaminants” were removed from the dataset.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationVPS35 knock-out HeLa cells were previously generated.
“VPS35 knock-out HeLa cells were previously generated.97”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [97] Simonetti B. Danson C.M. Heesom K.J. Cullen P.J. Sequence-dependent cargo recognition by SNX-BARs mediates retromer-independent transport of CI-MPR J. Cell Biol. 216 2017 3695 3712 10.1083/jcb.201703015 28935633 PMC5674890
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenPeptides labeled by MaxQuant as 'only identified by site', 'reverse' or 'potential contaminant' were removed from the mass spectrometry data analysis.
“Peptides labeled by MaxQuant as ‘only identified by site’, ‘reverse’ or ‘potential contaminant’ were removed”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenIn proteomic data analysis, the reverse database search option was enabled and all data were filtered to satisfy a false discovery rate of 5%.
“The reverse database search option was enabled and all data was filtered to satisfy false discovery rate (FDR) of 5%.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductown dataAll isothermal titration calorimetry experiments were performed at least in triplicate to check reproducibility.
“All experiments were performed at least in triplicate to check for reproducibility of the data.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenAll quantified western blots are the mean of at least 3 independent experimental repeats, with statistical analysis performed using Prism 7.
“All quantified western blots are the mean of at least 3 independent experimental repeats, with statistical analysis performed using Prism 7 (GraphPad Software, USA).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenRows having less than 3 valid values in the enrichment group were removed from the mass spectrometry data analysis.
“rows having less than 3 valid values in the enrichment group were removed”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCH domains are often involved in direct interactions with both actin and microtubule filaments.
“and CH domains are often involved in direct interactions with both actin and microtubule filaments.93,94,95,96”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [93] Galkin V.E. Orlova A. Salmazo A. Djinovic-Carugo K. Egelman E.H. Opening of tandem calponin homology domains regulates their affinity for F-actin Nat. Struct. Mol. Biol. 17 2010 614 616 10.1038/nsmb.1789 20383143 PMC2921939
- cites [94] Palani S. Ghosh S. Ivorra-Molla E. Clarke S. Suchenko A. Balasubramanian M.K. Köster D.V. Calponin-homology domain mediated bending of membrane-associated actin filaments Elife 10 2021 e61078 10.7554/eLife.61078 34269679 PMC8315802
- cites [95] Slep K.C. Vale R.D. Structural basis of microtubule plus end tracking by XMAP215, CLIP-170, and EB1 Mol. Cell 27 2007 976 991 10.1016/j.molcel.2007.07.023 17889670 PMC2052927
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll quantified western blots are the mean of at least 3 independent experimental repeats.
“All quantified western blots are the mean of at least 3 independent experimental repeats”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe COMMD proteins have been shown to undergo homo- and heteromeric interactions using co-immunoprecipitation from cells or following pairwise co-expression in bacterial systems.
“The COMMD proteins have been shown to undergo homo- and heteromeric interactions using co-immunoprecipitation from cells,6,16,17,19,21,28,40,41,42,68,77 or following pairwise co-expression in bacterial systems.42,77”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [6] McNally K.E. Faulkner R. Steinberg F. Gallon M. Ghai R. Pim D. Langton P. Pearson N. Danson C.M. Nägele H. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling Nat. Cell Biol. 19 2017 1214 1225 10.1038/ncb3610 28892079 PMC5790113 source
- cites [16] Hein M.Y. Hubner N.C. Poser I. Cox J. Nagaraj N. Toyoda Y. Gak I.A. Weisswange I. Mansfeld J. Buchholz F. A human interactome in three quantitative dimensions organized by stoichiometries and abundances Cell 163 2015 712 723 10.1016/j.cell.2015.09.053 26496610 source
- cites [17] Wan C. Borgeson B. Phanse S. Tu F. Drew K. Clark G. Xiong X. Kagan O. Kwan J. Bezginov A. Panorama of ancient metazoan macromolecular complexes Nature 525 2015 339 344 10.1038/nature14877 26344197 PMC5036527
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataTypically, three independent AlphaFold2 models were generated for each complex, and their quality was assessed by iPTM scores, PAE plots, and visual inspection of structural alignment.
“Typically, three independent models were generated for each complex and the quality of the predicted complexes was assessed by examining multiple outputs including the iPTM scores (confidence scores for interfacial residues), predicted alignment error (PAE) plots, and finally a visual inspection of how well the resulting structures aligned with each other in PyMol.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe only other structures known are Longin and DENN domain-containing dimers of C9orf72/SMCR8 and Folliculin/FNIP2 that act as RAB GAP complexes.
“while the only other structures known are Longin and DENN domain-containing dimers of C9orf72/SMCR8 and Folliculin/FNIP2 that act as RAB GAP complexes.83,84,85,86,87”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [83] Jansen R.M. Peruzzo R. Fromm S.A. Yokom A.L. Zoncu R. Hurley J.H. Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation Sci. Adv. 8 2022 eadd2926 10.1126/sciadv.add2926 36103527 PMC9473554
- cites [84] Nörpel J. Cavadini S. Schenk A.D. Graff-Meyer A. Hess D. Seebacher J. Chao J.A. Bhaskar V. Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture PLoS Biol. 19 2021 e3001344 10.1371/journal.pbio.3001344 34297726 PMC8336837
- cites [85] Shen K. Rogala K.B. Chou H.T. Huang R.K. Yu Z. Sabatini D.M. Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex Cell 179 2019 1319 1329.e8 10.1016/j.cell.2019.10.036 31704029 PMC7008705
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductown dataHeLa VPS29 or VPS35L knockout single cell clones were screened for gene knockout by lysis and Western blotting.
“Single cell clones were expanded and screened for gene KO by lysis and Western blotting.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationIn human cells, VPS29 is highly abundant, typically present at up to twice the level of other Retromer subunits, and more than twenty times the concentration of other Commander subunits.
“In human cells, VPS29 is highly abundant, typically present at up to twice the level of other Retromer subunits, and more than twenty times the concentration of other Commander subunits.75,76”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [75] Cho N.H. Cheveralls K.C. Brunner A.D. Kim K. Michaelis A.C. Raghavan P. Kobayashi H. Savy L. Li J.Y. Canaj H. OpenCell: Endogenous tagging for the cartography of human cellular organization Science 375 2022 eabi6983 10.1126/science.abi6983 35271311 PMC9119736 source
- cites [76] Itzhak D.N. Tyanova S. Cox J. Borner G.H. Global, quantitative and dynamic mapping of protein subcellular localization Elife 5 2016 e16950 10.7554/eLife.16950 27278775 PMC4959882
Probably not a substantial claim.
Study design and conductnone givenOnly proteins quantified based on more than one unique peptide were considered for further analysis in the mass spectrometry data analysis.
“only those proteins quantified based on >1 unique peptide were considered for further analysis”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenColocalisation analysis was performed in Volocity 6.3.1 with automatic Costes background thresholding.
“Colocalisation analysis was performed in Volocity 6.3.1 software (PerkinElmer) with automatic Costes background thresholding.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe CCDC proteins share some structural similarity with other CH domain-containing and coiled-coil heterodimers, predominantly involved in regulating cytoskeletal interactions such as with ciliary microtubules, within dynein-adaptor assemblies, or at the kinetochore.
“The CCDC proteins share some structural similarity with other CH domain-containing and coiled-coil heterodimers,88 predominantly involved in regulating cytoskeletal interactions such as with ciliary microtubules,66,71,72 within dynein-adaptor assemblies,89,90,91 or at the kinetochore,92”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [88] Schou K.B. Andersen J.S. Pedersen L.B. A divergent calponin homology (NN-CH) domain defines a novel family: implications for evolution of ciliary IFT complex B proteins Bioinformatics 30 2014 899 902 10.1093/bioinformatics/btt661 24257188
- cites [66] Lacey S.E. Foster H.E. Pigino G. The molecular structure of IFT-A and IFT-B in anterograde intraflagellar transport trains Nat. Struct. Mol. Biol. 2023 10.1038/s41594-022-00905-5 PMC10191852 36593313
- cites [71] Petriman N.A. Loureiro-López M. Taschner M. Zacharia N.K. Georgieva M.M. Boegholm N. Wang J. Mourão A. Russell R.B. Andersen J.S. Lorentzen E. Biochemically validated structural model of the 15-subunit intraflagellar transport complex IFT-B EMBO J. 41 2022 e112440 10.15252/embj.2022112440 36354106 PMC9753473
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
Study design and conductown dataThe final crystallographic model for subcomplex C had excellent refinement statistics and stereochemistry based on Molprobity scores.
“resulted in a final model with excellent refinement statistics and stereochemistry based on Molprobity scores.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The molecular structure of Commander has been mostly unexplored.
“Despite its essential role in membrane trafficking and importance in disease, the molecular structure of Commander has been mostly unexplored.”
The paper relies on this without support.
Whether Retriever assembled or functioned in a similar manner to Retromer was unclear.
“whether it assembled or functioned in a similar manner was unclear.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CCC subunits form a large conserved protein assembly renamed Commander.
“Other studies examining protein assemblies across distinct organisms confirmed that CCC subunits (CCDC22, CCDC93 and 10 COMMD proteins) form a large conserved protein assembly as had been originally described14 and renamed the assembly as Commander28.”
From Structural organization of the retriever–CCC endosomal recycling complex (2024) · cites this paper as [28]
The Results section, “Structure of the twelve-subunit core CCC complex” (page not provided), confirms that CCDC22, CCDC93 and ten COMMD proteins form a conserved twelve-protein assembly. But the Introduction distinguishes that CCC assembly from Commander, which it defines as a sixteen-subunit complex that also includes Retriever and DENND10. The source therefore does not support saying that the CCC assembly itself was renamed Commander. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe structural model does not identify critical protein-protein interactions mediated by R234, which is in an extended surface loop that is unresolved in recent cryo-EM models but predicted not to contact the COMMD ring according to recent highly concordant AlphaFold2-based models.
“However, the structural model does not identify critical protein-protein interactions mediated by R234, which is in an extended surface loop that is unresolved in recent cryo-EM models but predicted not to contact the COMMD ring according to recent highly concordant AlphaFold2-based models (Fig. 3A) [16–18].”
From CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome (2025) · cites this paper as [17]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredRetriever is assembled around a central VPS35L subunit to which VPS26C and VPS29 associate at spatially distant amino- and carboxy-terminal regions of the VPS35L α-solenoid.
“Retriever is assembled around a central VPS35L subunit to which VPS26C and VPS29 associate at spatially distant amino- and carboxy-terminal regions of the VPS35L α-solenoid (Fig. 1B)10–12.”
From Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway (2024) · cites this paper as [11]
Retriever, together with the dodecameric CCDC22, CCDC93, COMMD (CCC) complex and DENND10, forms the 16-subunit Commander super-assembly.
“that together with the dodecameric CCDC22, CCDC93, COMMD (CCC) complex and DENND10, forms the 16-subunit Commander super-assembly7–12”
From Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway (2024) · cites this paper as [11]
Retriever is a stable heterotrimer of VPS26C, VPS35L and VPS29.
“Retriever is an essential cargo sorting complex and is a stable heterotrimer of VPS26C, VPS35L and VPS29”
From Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway (2024) · cites this paper as [11]
E208 is specifically located in the interface between CCDC22 and COMMD4, where it establishes a critical point of contact with K180 in COMMD4.
“Overlaying these mutations onto the recently derived models of the CCC complex [16–18], we identified that E208 is specifically located in the interface between CCDC22 and COMMD4, where it establishes a critical point of contact with K180 in COMMD4 (Fig. 3A).”
From CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome (2025) · cites this paper as [17]
SNX17-Retriever assembles into a larger complex, Commander, with perturbation of this complex implicated in neurodevelopmental disorders.
“SNX17-Retriever assembles into a larger complex, Commander, with perturbation of this complex implicated in neurodevelopmental disorders [111-114, 148-150].”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [148]
The putative Rab binding surface of DENND10 seems to overlap with its binding surface for CCDC22/CCDC93.
“Notably, the putative Rab binding surface of DENND10 seems to overlap with its binding surface for CCDC22/CCDC93,25,26,27 suggesting potential competition or a “hand-over” mechanism.”
From Endosomal protein DENND10 promotes developmental competence of neurite extension (2025) · cites this paper as [27]
DENND10 associates specifically and reproducibly with the CCC/Retriever endosomal complexes.
“These findings demonstrate that DENND10 associates specifically and reproducibly with the CCC/Retriever endosomal complexes.”
From Endosomal protein DENND10 promotes developmental competence of neurite extension (2025) · cites this paper as [27]
DENND10 interacts with the CCC/Retriever endosomal complex.
“DENND10 is a potential regulator of Rab GTPase signaling and interacts with the CCC/Retriever endosomal complex.”
From Endosomal protein DENND10 promotes developmental competence of neurite extension (2025) · cites this paper as [27]
The lack of VPS29 enrichment in either VPS35L proximity proteomes may reflect a technical caveat or arise from a restricted capacity for biotinylation due to the distinct mechanism for VPS29 association within the Retriever assembly.
“The lack of VPS29 enrichment in either VPS35L proximity proteomes may reflect a technical caveat or arise from a restricted capacity for biotinylation due to the distinct mechanism for VPS29 association within the Retriever assembly20–22.”
From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [20]
This feature of Retromer appears to be specific in that Retriever is unable to associate with any of these RAB regulators because of its structural architecture.
“This feature of Retromer appears to be specific in that, because of its structural architecture20–22, Retriever is unable to associate with any of these RAB regulators.”
From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [20]
Loss of VPS35L expression leads to Commander dysfunction including a reduction in association of endogenous COMMD1 to Retromer-labelled endosomes.
“Previous studies have shown that loss of VPS35L expression leads to Commander dysfunction including a reduction in the association of endogenous COMMD1, a marker of the CCC complex and Commander assembly to Retromer labelled endosomes11.”
From Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway (2024) · cites this paper as [11]
Retriever (and the larger Commander assembly) may adopt a completely different membrane-proximal orientation to Retromer, or the distinct organisation of the Retriever heterotrimer may result in less spatial segregation of amino- and carboxy-termini.
“One likely reason is that Retriever (and the larger Commander assembly) may adopt a completely different membrane-proximal orientation to Retromer. It may also reflect the distinct organisation of the Retriever heterotrimer where the amino- and carboxy-termini are less spatially segregated due to its more compact structure20–22 (Supplementary Fig. 4C).”
From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [20]
This provides in cellulo evidence in support of the proposed structural organisation of the Commander super-assembly.
“This provides in cellulo evidence in support of the proposed structural organisation of the Commander super-assembly20–22.”
From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [20]
VPS35KO, SNX27KO, SNX17KO, and VPS35LKO clonal cell lines used in this study were previously characterised.
“VPS35KO, SNX27KO, SNX17KO, and VPS35LKO clonal cell lines used in this study were previously characterised19,20,31.”
From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [20]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
DENND10 binding affinity differs between text and figure
MajorThe text reports a 28 ± 6 nM affinity for DENND10 binding the CCDC22-CCDC93 coiled-coil dimer, whereas Figure 5B gives 34 ± 0.5 nM for the wild-type complex.
“bound to recombinant DENND10 with an affinity of 28 ± 6 nM (Figure 5B)”
“The binding affinities were as follows: WT, 34 nM ± 0.5 nM;”
Listed gradient segments total 130 minutes, not 150
MinorThe seven stated segments last 1 + 58 + 58 + 5 + 1 + 6 + 1 = 130 minutes, rather than the reported 150 minutes.
Reported 150 · recomputed 130
“over a 150 min organic gradient, using 7 gradient segments (1–6% solvent B over 1 min, 6–15% B over 58 min, 15–32% B over 58 min, 32–40% B over 5 min, 40–90% B over 1 min, held at 90% B for 6 min and then reduced to 1% B over 1min)”
Figure 6 names CCDC92 instead of CCDC93
MinorThe Figure 6 caption identifies CCDC92 as a protein coupling Retriever and CCC, while the paper consistently identifies the relevant coiled-coil pair as CCDC22 and CCDC93.
“the C-terminal coiled-coil regions of CCDC22 and CCDC92”
“The decameric COMMD ring and trimeric Retriever are tethered by the heterodimeric CCDC22 and CCDC93 proteins”
CCC dataset counts and order disagree
MinorData collection assigns 2,871 movies to the first dataset and 2,779 to the second. Processing instead assigns 2,779 micrographs to the first and 2,872 to the second; the stated second-dataset micrograph count also exceeds its movie count.
“The first dataset consisting of 2871 movies was collected with a total dose 43.55 e−/Å2 over a total exposure time of 9.01 s. The second dataset, consisting of 2779 movies”
“For the first dataset, consisting of 2,779 micrographs, 198,705 particles were used to generate 2 ab inito reconstructions. For the second dataset, consisting of 2,872 micrographs”
Citations
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COMMD10 inhibited DNA damage to promote the progression of gastric cancer
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Disruption of Retriever Function Impacts Retrograde Trafficking From Endosomes
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A Commander-independent function of COMMD3 in endosomal traffickingPreprint
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VPS29C: Adding complexity to the Retromer complex
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Self-citation
Metadata
- Authors
- Healy, M. D., McNally, K. E., Butkovič, R., Chilton, M., Kato, K., Sacharz, J., McConville, C., Moody, E. R. R., Shaw, S., Planelles-Herrero, V. J., Yadav, S. K. N., Ross, J., Borucu, U., Palmer, C. S., Chen, K.-E., Croll, T. I., Hall, R. J., Caruana, N. J., Ghai, R., Nguyen, T. H. D., Heesom, K. J., Saitoh, S., Berger, I., Schaffitzel, C., Williams, T. A., Stroud, D. A., Derivery, E., Collins, B. M., & Cullen, P. J.
- Affiliations
- The University of Queensland (AU)
- MRC Laboratory of Molecular Biology (GB)
- University of Bristol (GB)
- The University of Melbourne (AU)
- University of Cambridge (GB)
- Nagoya City University (JP)
- Royal Children's Hospital (AU)
- Corresponding author
- McNally, Kerrie E.
- Collins, Brett M.
- Cullen, Peter J.
- ORCID
- Healy, Michael D.
- McNally, Kerrie E.
- Butkovič, Rebeka
- Chilton, Molly
- Kato, Kohji
- Sacharz, Joanna
- Moody, Edmund R.R.
- Shaw, Shrestha
- Planelles-Herrero, Vicente J.
- Yadav, Sathish K.N.
- Borucu, Ufuk
- Palmer, Catherine S.
- Chen, Kai-En
- Croll, Tristan I.
- Hall, Ryan J.
- Caruana, Nikeisha J.
- Ghai, Rajesh
- Heesom, Kate J.
- Saitoh, Shinji
- Berger, Imre
- Schaffitzel, Christiane
- Williams, Tom A.
- Stroud, David A.
- Derivery, Emmanuel
- Collins, Brett M.
- Cullen, Peter J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 186
- Issue
- 10
- Pages
- 2219-2237.e29
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC10187114
- OpenAlex
- W4376126637
- Cited by
- 91
- References
- 151
- Citations by year
- 2026: 17 · 2025: 42 · 2024: 28 · 2023: 4
- FWCI
- 9.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- SSRN Electronic Journal (acceptedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- Explore Bristol Research (publishedVersion, cc-by)
- Funders
- Gordon and Betty Moore Foundation
- Wellcome Trust (210701/Z/18/Z, 206181/Z/17/Z, Z/17/Z, 220480/Z/20/Z, 106115/Z/14/Z, 220260/Z/20/Z, 202904/Z/16/Z, 104568/Z/14/Z)
- University of Bristol
- Australian Institute of Nuclear Science and Engineering
- Australian Synchrotron
- Lister Institute of Preventive Medicine
- University of Queensland
- Medical Research Council (MC_UP_1201/13, MR/P018807/1, MR/L007363/1)
- Biotechnology and Biological Sciences Research Council (BB/R000484/1)
- Japan Society for the Promotion of Science (23K14945, 23KJ1817, 20K16897)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- endosomal recycling, VPS29, retromer complex, protein complex structure, pathogenic variants, cargo trafficking
- MeSH terms
- Abnormalities, Multiple, Dandy-Walker Syndrome, Heart Septal Defects, Atrial, Humans, Proteins, Endosomes, Craniofacial Abnormalities, Protein Transport, Multiprotein Complexes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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