Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway

The carboxy-terminal sequence of SNX17 is essential for binding to Commander.

“The same sequence is essential for binding to Commander”

• cites [9] McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. cell Biol. 19, 1214–1225 (2017). sourcePartly supported

  The Results section, “Retriever interacts with the evolutionary conserved carboxy-tail of SNX17” (page unavailable), shows that SNX17’s carboxy-terminal tail is necessary for binding to retriever. It does not establish binding to Commander as stated; the paper instead distinguishes SNX17’s association with retriever from association through the CCC complex. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [26] Healy, M. D. et al. Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins. Structure 30, 1590–1602.e1596 (2022). sourceSupported

In the Commander trafficking pathway, sequence-dependent integral protein recognition is principally mediated by the cargo adaptor sorting nexin-17 (SNX17).

“In the Commander trafficking pathway sequence-dependent integral protein recognition is principally mediated by the cargo adaptor sorting nexin-17 (SNX17)9”

• cites [9] McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. cell Biol. 19, 1214–1225 (2017). sourceSupported

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”

• cites [7] Phillips-Krawczak, C. A. et al. COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A. Mol. Biol. Cell 26, 91–103 (2015). sourcePartly supported

  The Results section, “Identification of the CCC complex” (page unavailable), supports a CCC complex involving CCDC22, CCDC93 and COMMD proteins, including interactions with all 10 human COMMD family members. The copy does not establish that this is a dodecameric complex or that it joins Retriever and DENND10 in a 16-subunit Commander super-assembly; it instead names C16orf62 among the CCC components. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [8] Mallam, A. L. & Marcotte, E. M. Systems-wide studies uncover commander, a multiprotein complex essential to human development. Cell Syst. 4, 483–494 (2017). sourcePartly supported

  In “Discovery of the 14-subunit Commander complex” (page unavailable), the paper identifies a Commander complex containing the COMMD proteins, CCDC22, CCDC93, DSCR3, and C16orf62, and describes CCC as a subcomplex. It calls Commander putatively 14-member, not 16-subunit, and the passages do not establish the claimed Retriever–DENND10 assembly. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [9] McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. cell Biol. 19, 1214–1225 (2017). sourcePartly supported

  The Abstract says retriever associates with the CCC complex, and the Results identify retriever as a heterotrimer and CCC as containing CCDC22, CCDC93 and COMMD proteins. Our copy does not establish that CCC is dodecameric or that DENND10 joins these complexes in a 16-subunit Commander super-assembly. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [10] Boesch, D. J. et al. Structural organization of the retriever-CCC endosomal recycling complex. Nat. Struct. Mol. Biol. 31, 910–924 (2024). sourceSupported
• cites [11] Healy, M. D. et al. Structure of the endosomal commander complex linked to ritscher-schinzel syndrome. Cell 186, 2219–2237.e2229 (2023). sourceSupported
• cites [12] Laulumaa, S., Kumpula, E. P., Huiskonen, J. T. & Varjosalo, M. Structure and interactions of the endogenous human Commander complex. Nat. Struct. Mol. Biol. 31, 925–938 (2024). sourceSupported

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”

• cites [7] Phillips-Krawczak, C. A. et al. COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A. Mol. Biol. Cell 26, 91–103 (2015). sourceCould not verify

  The Introduction describes retromer as a VPS26–VPS29–VPS35 cargo-selection trimer, not Retriever. Searches for Retriever, VPS26C, and VPS35L found no passage in our copy addressing Retriever’s composition or stability. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [8] Mallam, A. L. & Marcotte, E. M. Systems-wide studies uncover commander, a multiprotein complex essential to human development. Cell Syst. 4, 483–494 (2017). sourceCould not verify

  The section ‘Commander’s role in trafficking and transport’ describes a three-protein retromer cargo-recognition complex containing VPS26, VPS29 and VPS35, not the claimed Retriever complex. Searches for Retriever and for VPS26C, VPS35L and VPS29 together found no passage in our copy establishing Retriever’s composition or stability. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites [9] McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. cell Biol. 19, 1214–1225 (2017). sourceSupported
• cites [10] Boesch, D. J. et al. Structural organization of the retriever-CCC endosomal recycling complex. Nat. Struct. Mol. Biol. 31, 910–924 (2024). sourceSupported
• cites [11] Healy, M. D. et al. Structure of the endosomal commander complex linked to ritscher-schinzel syndrome. Cell 186, 2219–2237.e2229 (2023). sourceSupported
• cites [12] Laulumaa, S., Kumpula, E. P., Huiskonen, J. T. & Varjosalo, M. Structure and interactions of the endogenous human Commander complex. Nat. Struct. Mol. Biol. 31, 925–938 (2024). sourceSupported

Over 100 integral proteins require SNX17 and Retriever for their endosomal sorting through the Commander axis, including members of the integrin and lipoprotein receptor families.

“Over 100 integral proteins require SNX17 and Retriever for their endosomal sorting through the Commander axis including members of the integrin and lipoprotein receptor families9.”

• cites [9] McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. cell Biol. 19, 1214–1225 (2017). sourcePartly supported

  The Results section on cell-surface cargo proteins reports that 225 membrane proteins decreased at the surface after SNX17 depletion, including integrins and lipoprotein receptor family members. It validates Retriever dependence for LRP1, but does not establish that all 225—or more than 100—require both SNX17 and Retriever for endosomal sorting. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

The FERM domain of SNX17 binds to a ØxNxx[Y/F] sorting motif presented in the cytoplasmic facing domains of integral proteins.

“the FERM domain of which binds to a ØxNxx[Y/F] sorting motif presented in the cytoplasmic facing domains of integral proteins (where Ø is a hydrophobic residue and x is any residue)22–25”

• cites [22] van Kerkhof, P. et al. Sorting nexin 17 facilitates LRP recycling in the early endosome. Embo j. 24, 2851–2861 (2005). sourcePartly supported

  The Introduction identifies a FERM domain in SNX17, and the LRP-binding results show that the SNX17 region containing that domain contributes to binding the LRP cytoplasmic tail. The results identify an essential IxNPxY motif in LRP, not the broader ØxNxx[Y/F] motif: proline was required, and the paper does not establish that a terminal phenylalanine can substitute for tyrosine or that the motif generally applies to integral proteins (pages unavailable in our copy). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [23] Böttcher, R. T. et al. Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β1-integrin tail. Nat. Cell Biol. 14, 584–592 (2012). sourceNot checked — no full text of the source
• cites [24] 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, 219–230 (2012). sourcePartly supported

  The Results and discussion section shows that SNX17’s FERM-like domain directly binds the membrane-distal NPXY motif in integrin β-subunit cytoplasmic tails. Our copy does not establish the more specific ØxNxx[Y/F] consensus motif or show that binding extends generally to integral proteins. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [25] Ghai, R. et al. Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins. Proc. Natl Acad. Sci. 110, E643–E652 (2013). sourceSupported

These foci represent previously described retrieval sub-domains from where cargo-enriched transport carriers exit the endosome.

“These foci therefore represent the previously described retrieval sub-domains from where cargo-enriched transport carriers exit the endosome for transport to their destination9,34,35,39,41,49.”

• cites [9] McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. cell Biol. 19, 1214–1225 (2017). sourceSupported
• cites [34] Puthenveedu, M. A. et al. Sequence-dependent sorting of recycling proteins by actin-stabilized endosomal microdomains. Cell 143, 761–773 (2010). sourceSupported
• cites [35] Temkin, P. et al. SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors. Nat. Cell Biol. 13, 715–721 (2011). sourceSupported
• cites [39] Bowman, S. L., Shiwarski, D. J. & Puthenveedu, M. A. Distinct G protein-coupled receptor recycling pathways allow spatial control of downstream G protein signaling. J. Cell Biol. 214, 797–806 (2016). sourcePartly supported

  The Introduction and Results and discussion (page unavailable) describe endosomal microdomains that sort B2AR into tubular domains for recycling to the cell surface. They do not establish that the citing paper’s foci are those domains or show cargo-enriched transport carriers exiting from them. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [41] Varandas, K. C., Irannejad, R. & von Zastrow, M. Retromer endosome exit domains serve multiple trafficking destinations and regulate local G protein activation by GPCRs. Curr. Biol. 26, 3129–3142 (2016). sourceSupported
• cites [49] Liu, N., Liu, K. & Yang, C. WDR91 specifies the endosomal retrieval subdomain for retromer-dependent recycling. J. Cell Biol. 221, E202203013 (2022). sourceSupported

The interface between SNX17 and Retriever extends to include upstream residues 459NFAF462 in the SNX17 tail engaging primarily with VPS26C.

“The interface between SNX17 and Retriever extended to include upstream residues 459NFAF462 in the SNX17 tail engaging primarily with VPS26C.”

GFP-SNX17(I465A), -(D467A) and -(L470G) mutants lead to near-complete loss of Retriever binding.

“GFP-SNX17(I465A), -(D467A) and -(L470G) mutants led to near-complete loss of Retriever binding (Fig. 2C).”

AlphaFold2 predicts a high-confidence interaction between the unstructured carboxy-terminal region of SNX17 and Retriever.

“AlphaFold2 predictions show a high confidence interaction between the unstructured carboxy-terminal region of SNX17 and Retriever (Fig S5A).”

Retriever coupling of SNX17 is mediated by motifs within its unstructured carboxy termini binding to surfaces at the VPS26C:VPS35L interface of Retriever.

“Collectively these data show that Retriever coupling of SNX17 is mediated by motifs within its unstructured carboxy termini binding to surfaces at the VPS26C:VPS35L interface of Retriever.”

VPS35L(R293E), which disrupts binding to VPS26C, fails to associate with SNX17 in cell-based immunoprecipitations.

“a VPS35L mutant that specifically disrupted binding to VPS26C, VPS35L(R293E)11, failed to associate with SNX17 in quantitative cell-based immunoprecipitations”

SNX17(D469A) and more modestly SNX17(E468A) impact Retriever association.

“SNX17(D469A) and, more modestly SNX17(E468A) also impacted on the Retriever association (Fig. 2C)”

VPS35L(R248A), -(W280A), and -(K283E) mutations all cause pronounced loss of SNX17 association.

“VPS35L(R248A), -(W280A), and -(K283E) all showed a pronounced loss of SNX17 association (Fig. 2B).”

The SNX17-binding pocket in VPS35L is highly conserved across eukaryotic Retriever.

“this pocket is highly conserved across eukaryotic Retriever (Fig. 1B).”

The extreme carboxy-terminal Leu470 residue of SNX17 makes extensive contact with VPS35L through hydrophobic interaction with Trp280 and electrostatic interaction of the carboxy-terminal carboxyl group with Arg248.

“One striking feature of the predicted complex is that the extreme carboxy-terminal Leu470 residue of SNX17 makes extensive contact with VPS35L through hydrophobic interaction with Trp280 and via an electrostatic interaction of the carboxy-terminal carboxyl group with Arg248 (Fig. 1B).”

VPS35L(L35D), which disrupts VPS29 binding, has no effect on SNX17 association.

“In contrast a mutant that selectively disrupted VPS29 binding to VPS35L, VPS35L(L35D)11, had no effect on SNX17 association (Fig. 2A).”

Recombinant SNX17(L470G) binds to Retriever at significantly lower levels than wild-type SNX17.

“recombinant SNX17(L470G) bound to Retriever at significantly lower levels (Fig. 1A, Supplementary Fig. 1B).”

SNX17(NFAF-AAAA), SNX17(F462A) and SNX17(F462E) mutants display reduced Retriever and CCC complex association.

“SNX17(NFAF-AAAA) and the more conservative SNX17(F462A) and -(F462E) mutants also displayed reduced Retriever and CCC complex association (Fig. 2D).”

AlphaFold2 modelling predicts that the 465IGDEDL470 motif of SNX17 binds to a pocket in VPS35L defined by Arg248, Trp280, and Lys283, close to the VPS35L:VPS26C interface.

“This predicted a high confidence model where the 465IGDEDL470 motif of SNX17 bound to a pocket in VPS35L defined by Arg248, Trp280, and Lys283, that resided close to the VPS35L:VPS26C interface”

SNX17 directly binds to Retriever through a mechanism involving its unstructured carboxy-terminal tail.

“Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander.”

Association of SNX17 (and cargo) with Retriever is not a pre-requisite for sub-domain organization, as VPS35L(R248A)-GFP retains localization to the retrieval sub-domain.

“Our data shows that the association of SNX17 (and cargo) with Retriever was not a pre-requisite for sub-domain organization, as VPS35L(R248A)-GFP retained localization to the retrieval sub-domain.”

Endogenous SNX17 displays a general distribution over the bulk of EEA1-positive endosomal membranes.

“Endogenous SNX17 displayed a general distribution over the bulk of EEA1-positive endosomal membranes (Fig. 6A).”

SNX17 association with Retriever-coated beads is enhanced in a dose-dependent manner by inclusion of the LRP1 peptide.

“SNX17 associated with Retriever coated beads, and this association was enhanced in a dose-dependent manner by inclusion of the LRP1 peptide (Fig. 5D, Supplementary Fig. 3B).”

In models of apo SNX17 from various species, the carboxy-terminal 459NFAF462 sequence invariably forms an intramolecular association with the F3 groove, mimicking cargo sequences in an autoinhibitory conformation.

“In models of apo SNX17 from various species (data not shown), the carboxy-terminal 459NFAF462 sequence (human numbering) invariably formed an intramolecular association with the F3 groove, mimicking cargo sequences in what would be an autoinhibitory conformation (Fig. 4B).”

There is clear spatial separation of SNX17 from the Retriever and Retromer labelled retrieval sub-domain.

“Together these data confirm the clear spatial separation of SNX17 from the Retriever and Retromer labelled retrieval sub-domain.”

These FERM domain mutants also show reduced binding to LRP1 cargo.

“These mutants also showed a reduced binding to the LRP1 cargo, consistent with binding being mediated through the same groove.”

VPS35L KO cells display a partial perturbation in the sub-domain organization of FAM21, SNX1 and VPS35.

“VPS35L KO cells displayed a partial perturbation in the sub-domain organization of FAM21, SNX1 and VPS35 (Fig. 6C, and Supplementary Fig. 4A, B).”

AlphaFold2 modelling suggests that cargo proteins carrying the ØxNxx[Y/F] sorting motif, including β1-integrin and LRP1, bind through β-sheet augmentation in a complementary groove of the F3 module.

“Alphafold2 modelling suggested that cargo proteins carrying the conserved ØxNxx[Y/F] sorting motif, including β1-integrin and LRP1, bind through β-sheet augmentation in a complementary groove of the F3 module, in agreement with previous X-ray crystallographic structures”

LRP1 and APP cargo peptides display approximately 2-fold lower affinity for full-length SNX17 compared with SNX17ΔC.

“both LRP1 and APP peptides displayed an approximate 2-fold lower affinity for binding to full-length SNX17 when compared with SNX17ΔC (Fig. 5B, Supplementary Table 1).”

On the same endosome, endogenous SNX17 is enriched predominantly on the vacuolar region.

“On the same individual endosome, endogenous SNX17 was enriched predominantly on the vacuolar region (Fig. 7A).”

In VPS35L KO RPE1 cells, VPS35 loses spatial restriction to the tubular sub-domain and localizes alongside SNX17 on the vacuolar region of the endosomal limiting membrane.

“in the VPS35L KO RPE1 cell line (not rescued by VPS35L-GFP re-expression) we observed the loss of spatial restriction of VPS35 to the tubular sub-domain, rather it localized alongside SNX17 on the vacuolar region of the endosomal limiting membrane (Fig. 7B iii–iv).”

The carboxy-terminal 465IGDEDL470 of SNX17 adopts an intramolecular conformation mutually exclusive of Retriever binding.

“The carboxy-terminal 465IGDEDL470 also adopted an intramolecular conformation that would be mutually exclusive of Retriever binding (Fig. 4B).”

A corresponding LRP1 peptide carrying a Y4473A mutation in the ØxNxx[Y/F] motif fails to enhance SNX17 association to Retriever.

“a corresponding LRP1 peptide carrying a Y4473A mutation in the ØxNxx[Y/F] motif failed to enhance SNX17 association to Retriever (Fig. 5D, Supplementary Fig. 3B).”

SNX17(NFAF-AAAA), SNX17(F462A) and SNX17(F462E) mutants show robust enhancement of LRP1, LRP2, and APP binding compared to wild-type SNX17.

“immuno-isolation of GFP-tagged SNX17 mutants from HEK293T cells revealed a robust enhancement of LRP1, LRP2, and APP binding compared to the wild-type protein (Fig. 4C).”

In VPS35L KO cells, FAM21, SNX1 and VPS35 occupy multiple, less well-defined foci on the EEA1 and SNX17 endosomal membrane with greater localization overlap with EEA1 or SNX17.

“in VPS35L KO cells, these markers occupied multiple, less well-defined foci on the EEA1 and SNX17 endosomal membrane with greater localization overlap with EEA1 or SNX17 (Fig. 6C, and Supplementary Fig. 4A, B).”

Retriever, CCC and WASH complex markers co-localize with core Retromer component VPS35 and SNX1.

“Retriever, CCC and WASH complex markers also co-localized with the core Retromer component VPS35 and SNX1, an ESCPE-1 subunit that drives endosomal tubulation during the biogenesis of transport carriers46–48 (Fig. 6C, and Supplementary Fig. 4B).”

Whilst present, SNX17 is not enriched in these retrieval sub-domains.

“whilst present, SNX17 is not enriched in these retrieval sub-domains.”

GFP-SNX17(V380D), which exhibits decreased cargo-binding, fails to localize to the endosomal network when transiently transfected into RPE1 cells.

“the FERM-domain mutant GFP-SNX17(V380D) that exhibited decreased cargo-binding failed to localize to the endosomal network when transiently transfected into RPE1 cells (Fig. 5E).”

GFP-SNX17(F462A), which has enhanced cargo-binding, displays increased co-localisation with EEA1 compared with wild-type GFP-SNX17.

“the enhanced cargo-binding GFP-SNX17(F462A) mutant displayed an even more pronounced endosomal association, as evidenced by increased co-localisation with the endosomal marker EEA1 compared with wild-type GFP-SNX17 (Fig. 5E).”

Cargo binding facilitates SNX17 endosomal association.

“Importantly, we establish that cargo binding facilitates SNX17 endosomal association”

• AssumptionRests on an assumption: SNX17 associates with endosomal membranes enriched for phosphatidylinositol 3-monophosphate (PI3P).

VPS35L-GFP is enriched on a tubular-vesicular sub-domain extending from the vacuolar endosomal limiting membrane.

“immunogold staining of the VPS35L KO RPE1 cell line engineered to stably re-express VPS35L-GFP revealed enrichment of Retriever on a tubular-vesicular sub-domain extending from the vacuolar endosomal limiting membrane (Fig. 7A).”

GFP-SNX17(W321A), -(V380D) and -(M384E) mutants display a modest but significant increase in binding to Retriever and the Commander super-assembly.

“the GFP-tagged SNX17(W321A), -(V380D) and -(M384E) mutants all displayed a modest but significant increase in binding to Retriever and the Commander super-assembly (Fig. 4D).”

When AlphaFold2 modelling incorporates full-length SNX17, only two of five predicted structures display the same mechanism of SNX17 binding to the VPS26C:VPS35L interface.

“when we expanded the AlphaFold2 modelling to incorporate full-length SNX17 only two of the five predicted structures displayed the same mechanism of SNX17 binding to the VPS26C:VPS35L interface (Supplementary Fig. 3A).”

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.”

• cites [11] Healy, M. D. et al. Structure of the endosomal commander complex linked to ritscher-schinzel syndrome. Cell 186, 2219–2237.e2229 (2023). sourceNot checked yet

Weakening or ablating the intramolecular interaction of the 459NFAF462 sequence allows increased intermolecular binding of ØxNxx[Y/F]-containing cargo to the FERM domain.

“This suggests that weakening or ablating the intramolecular interaction of the 459NFAF462 sequence allows for increased intermolecular binding of ØxNxx[Y/F]-containing cargo to the FERM domain.”

The endosomal localization of SNX17 requires avidity-based co-incident sensing of PI(3)P and ØxNxx[Y/F]-containing cargo proteins.

“the endosomal localization of SNX17 requires avidity-based co-incident sensing of phosphoinositides, specifically phosphatidylinositol 3-monophosphate (PI(3)P) and ØxNxx[Y/F]-containing cargo proteins25.”

• cites [25] Ghai, R. et al. Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins. Proc. Natl Acad. Sci. 110, E643–E652 (2013). sourceNot checked yet

Transient coupling of cargo-bound SNX17 to Retriever and Commander may serve to handover cargo into a pre-existing retrieval sub-domain for endosomal exit and recycling to the cell surface.

“Rather it appears that the transient coupling of cargo bound SNX17 to Retriever and Commander may serve to handover cargo into a pre-existing retrieval sub-domain for endosomal exit and recycling to the cell surface (Fig. 8).”

The study provides fundamental mechanistic and regulatory insight into the role of the SNX17-dependent Commander retrieval and recycling pathway during essential cellular processes ranging from directed cell migration through to cholesterol homeostasis.

“Overall, our study provides fundamental mechanistic and regulatory insight into the role of the SNX17-dependent Commander retrieval and recycling pathway during essential cellular processes ranging from directed cell migration through to cholesterol homeostasis.”

• AssumptionRests on an assumption: SNX17 associates with endosomal membranes enriched for phosphatidylinositol 3-monophosphate (PI3P).

Cargo enters a pre-existing retrieval sub-domain for the promotion of Commander mediated cell surface recycling.

“and the entry of cargo into a pre-existing retrieval sub-domain for the promotion of Commander mediated cell surface recycling.”

• AssumptionRests on an assumption: SNX17 associates with endosomal membranes enriched for phosphatidylinositol 3-monophosphate (PI3P).

Cargo occupancy relieves an autoinhibited SNX17 conformation to promote Retriever association.

“and that cargo occupancy relieves an autoinhibited SNX17 conformation to promote Retriever association”

• AssumptionRests on an assumption: SNX17 associates with endosomal membranes enriched for phosphatidylinositol 3-monophosphate (PI3P).

By identifying the molecular details of SNX17 coupling to Retriever, the study revealed the evolutionarily conserved mechanism through which hundreds of integral membrane proteins, including integrins and lipoprotein receptors, enter the Commander retrieval and recycling pathway.

“In summary, by identifying the molecular details of SNX17 coupling to Retriever we have revealed the evolutionarily conserved mechanism through which hundreds of integral membrane proteins, including integrins and lipoprotein receptors, enter the Commander retrieval and recycling pathway.”

• AssumptionRests on an assumption: SNX17 associates with endosomal membranes enriched for phosphatidylinositol 3-monophosphate (PI3P).

VPS35L and the Retriever complex play a role in organizing endosomal retrieval sub-domains.

“that VPS35L and the Retriever complex play a role in organizing endosomal retrieval sub-domains”