Structural organization of the retriever–CCC endosomal recycling complex
Open accessPublished version of a preprint
Abstract
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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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Protein complex prediction with AlphaFold-Multimer
Evans, R., O’Neill, M., Pritzel, A., Antropova, N., Senior, A., Green, T., Žídek, A., Bates, R., Blackwell, S., Yim, J., et al. (2021) · doi:10.1101/2021.10.04.463034 · Cited by 3,808 · see citing works
Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling
McNally, K. E., Faulkner, R., Steinberg, F., Gallon, M., Ghai, R., Pim, D., Langton, P., Pearson, N., Danson, C. M., Nägele, H., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3610 · Cited by 346 · see citing works
Self-citationCCDC22: a novel candidate gene for syndromic X-linked intellectual disability
Voineagu, I., Huang, L., Winden, K., Lazaro, M., Haan, E., Nelson, J., McGaughran, J., Nguyen, L. S., Friend, K., Hackett, A., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.95 · Cited by 61 · see citing works
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- 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
- Published
- 2023-12-07
- Volume
- 31
- Issue
- 6
- Pages
- 910-924
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC11260360
- OpenAlex
- W4389440027
- Cited by
- 52
- References
- 4
- Citations by year
- 2026: 9 · 2025: 29 · 2024: 13 · 2023: 1
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- 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
- Health Sciences › Medicine › Epidemiology › 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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