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PreprintCited by 51Cellular transport and secretionAutophagy in Disease and TherapyExtracellular vesicles in disease

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Structural Organization of the Retriever-CCC Endosomal Recycling Complex

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Boesch, Daniel J., Singla, Amika, Han, Yan, Kramer, Daniel A., Liu, Qi, Suzuki, Kohei, Juneja, Puneet, Zhao, Xuefeng, Long, Xin, Medlyn, Michael J., Billadeau, Daniel D., Chen, Zhe, Chen, Baoyu, Burstein, Ezra·2023·Nature Structural & Molecular Biology
DOI 10.1101/2023.06.06.543888PMC PMC11260360

Preprint — published as 10.1038/s41594-023-01184-4 · Paper page

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Abstract

The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

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  1. Uhlen, M. , et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
  2. 10.1038/nbt1210-1248 · DOI · Paper page
  3. 10.1083/jcb.142.3.665 · DOI · Paper page
  4. 10.1091/mbc.11.12.4105 · DOI · Paper page
  5. 10.1006/bbrc.2000.3727 · DOI
  6. 10.1038/ncb2721 · DOI · Paper page
  7. 10.1073/pnas.1316482111 · DOI
  8. Yong, X. et al. SNX27-FERM-SNX1 complex structure rationalizes divergent trafficking pathways by SNX17 and SNX27. Proc Natl Acad Sci U S A 118(2021). · DOI
  9. Simonetti, B. et al. SNX27-Retromer directly binds ESCPE-1 to transfer cargo proteins during endosomal recycling. PLoS Biol 20, e3001601 (2022). · DOI · Paper page
  10. 10.1016/j.devcel.2009.09.009 · DOI · Paper page
  11. 10.1091/mbc.E12-02-0101 · DOI · Paper page
  12. 10.1091/mbc.E11-12-1059 · DOI · Paper page
  13. 10.1016/j.devcel.2009.09.010 · DOI · Paper page
  14. 10.1091/mbc.E14-06-1073 · DOI · Paper page
  15. 10.1074/jbc.M501928200 · DOI · Paper page
  16. 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 (2013). · DOI
  17. Healy, M.D. et al. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins. Elife 7(2018). · DOI · Paper page
  18. 10.1016/j.jmb.2006.10.030 · DOI
  19. 10.1093/hmg/11.2.165 · DOI · Paper page
  20. 10.1016/S0168-8278(03)00380-5 · DOI
  21. Stewart, D.J. , Short, K.K. , Maniaci, B.N. & Burkhead, J.L . COMMD1 and PtdIns(4,5)P2 interaction maintain ATP7B copper transporter trafficking fidelity in HepG2 cells. J Cell Sci 132(2019). · DOI
  22. 2019, Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling, Nat Commun, 10, 4271, 10.1038/s41467-019-12221-6 · DOI · Paper page
  23. 10.1038/ncb3610 · DOI · Paper page
  24. Bartuzi, P. et al. CCC-and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat Commun 7, 10961 (2016). · DOI · Paper page
  25. Singla, A. et al. Regulation of murine copper homeostasis by members of the COMMD protein family. Dis Model Mech 14(2021). · DOI
  26. 10.1016/j.bbamcr.2019.02.006 · DOI · Paper page
  27. Borchers, A.C. , Langemeyer, L. & Ungermann, C . Who’s in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond. J Cell Biol 220(2021). · DOI · Paper page
  28. 10.1038/nature14877 · DOI
  29. 2017, Systems-wide Studies Uncover Commander, a Multiprotein Complex Essential to Human Development, Cell Syst, 4, 483, 10.1016/j.cels.2017.04.006 · DOI · Paper page
  30. 10.1038/nsmb954 · DOI
  31. 10.1002/hep.26540 · DOI
  32. Hecht, M. , Bromberg, Y. & Rost, B . Better prediction of functional effects for sequence variants. BMC Genomics 16 Suppl 8, S1 (2015). · DOI · Paper page
  33. Evans;, R. , et al. Protein complex prediction with AlphaFold-Multimer. BioRxiv Preprint, https://doi.org/10.1101/2021.10.04.463034 (2022). · DOI · Paper page
  34. 10.1073/pnas.1110415108 · DOI · Paper page
  35. 10.1038/mp.2011.95 · DOI · Paper page
  36. Kolanczyk, M. et al. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome. Eur J Hum Genet (2014). · DOI · Paper page
  37. 10.1136/jmedgenet-2019-106213 · DOI · Paper page
  38. Otsuji, S. et al. Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome. J Med Genet (2022). · DOI · Paper page
  39. 10.1128/MCB.01932-06 · DOI · Paper page
  40. 10.1083/jcb.201505108 · DOI · Paper page
  41. 10.1093/jhered/esg030 · DOI
  42. Vonk, W.I. et al. Liver-specific Commd1 knockout mice are susceptible to hepatic copper accumulation. PLoS One 6, e29183 (2011). · DOI
  43. 10.1093/hmg/11.2.165 · DOI · Paper page
  44. Vos, D.Y. et al. Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins. Arterioscler Thromb Vasc Biol (2022). · DOI · Paper page
  45. 10.1161/CIRCRESAHA.117.312004 · DOI · Paper page
  46. 10.1038/sj.emboj.7601489 · DOI
  47. 10.1038/embor.2009.10 · DOI
  48. 10.1172/JCI66466 · DOI · Paper page
  49. 2017, Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis, Immunity, 47, 66, 10.1016/j.immuni.2017.06.018 · DOI
  50. 10.1053/j.gastro.2014.04.007 · DOI
  51. 10.1084/jem.20181494 · DOI
  52. 2023, Celastrol suppresses humoral immune responses and autoimmunity by targeting the COMMD3/8 complex, Sci Immunol, 8, eadc9324, 10.1126/sciimmunol.adc9324 · DOI
  53. 10.1038/s41586-018-0526-z · DOI · Paper page
  54. 2023, Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome, Cell, 186, 2219, 10.1016/j.cell.2023.04.003 · DOI · Paper page
  55. Laulumaa, S. , Kumpula, E.-P. , Huiskonen, J.T. & Varjosalo, M. Structure and Interactions of the Endogenous Human Commander Complex BioRxiv Preprint https://doi.org/10.1101/2023.04.03.535349 (2023). · DOI · Paper page
  56. Giridharan, S.S.P. et al. Lipid kinases VPS34 and PIKfyve coordinate a phosphoinositide cascade to regulate retriever-mediated recycling on endosomes. Elife 11(2022). · DOI · Paper page
  57. 10.1038/nsmb.1587 · DOI
  58. 10.1016/B978-0-12-397924-7.00004-2 · DOI
  59. Chen, B. et al. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. Elife 6(2017). · DOI · Paper page
  60. 10.1016/j.jsb.2005.07.007 · DOI
  61. 10.1038/nmeth.4169 · DOI · Paper page
  62. Sanchez-Garcia, R. et al. DeepEMhancer: a deep learning solution for cryo-EM volume post-processing. Commun Biol 4, 874 (2021). · DOI
  63. 10.1002/jcc.20084 · DOI
  64. 10.1016/j.str.2011.12.014 · DOI · Paper page
  65. 10.1107/S0907444910007493 · DOI · Paper page
  66. 10.1107/S2059798319011471 · DOI · Paper page
  67. 10.1107/S0907444909042073 · DOI · Paper page
  68. 10.1007/978-1-4939-7000-1_26 · DOI · Paper page
  69. 10.1002/PRO.3943 · DOI
  70. 10.1093/nar/gkw408 · DOI · Paper page

Metadata

Authors
Boesch, D. J., Singla, A., Han, Y., Kramer, D. A., Liu, Q., Suzuki, K., Juneja, P., Zhao, X., Long, X., Medlyn, M. J., Billadeau, D. D., Chen, Z., Chen, B., & Burstein, E.
Affiliations
  • Iowa State University (US)
  • The University of Texas Southwestern Medical Center (US)
  • Mayo Clinic (US)
Corresponding author
  • Chen, Zhe
  • Chen, Baoyu
  • Burstein, Ezra
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2023-06-07
Volume
31
Issue
6
Pages
910-924
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2023.06.06.543888
PMC
PMC11260360
OpenAlex
W4389440027
Cited by
51
References
1
Citations by year
2026: 8 · 2025: 26 · 2024: 16 · 2023: 1
FWCI
7.64
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by)
  • Iowa State University Digital Repository (Iowa State University) (submittedVersion)
Funders
  • National Science Foundation (CAREER, 2047640)
  • Roy J. Carver Charitable Trust
  • Cancer Prevention and Research Institute of Texas (RP220582)
  • University of Texas Southwestern Medical Center
  • Iowa State University
  • National Institutes of Health
  • National Institute of General Medical Sciences (R35GM128786)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107733, P30DK127984)
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 › Molecular Biology › Extracellular vesicles in disease
Keywords
endosomal recycling, membrane protein recycling, VPS29, protein complex structure, retromer, cancer-associated mutations

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