Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation
Open accessPublished version of a preprint
Abstract
Endosomal retrieval and recycling of integral cargo proteins is essential for cell and organism development and homeostasis and is orchestrated through a specialised endosomal nanodomain, the retrieval sub-domain. Sub-domain dysfunction is associated with human disease, but our mechanistic understanding of its function remains poorly described. Here, using proximity proteomics of retrieval sub-domain components Retromer and Retriever we identify mechanistic details of retrieval sub-domain composition and organization, including an unrecognised complexity in the interface with RAB GTPase switching. Combining X-ray crystallography and in silico predictions with biochemical and cellular analysis, we reveal that Retromer directly associates and recruits the RAB10 regulators DENND4A, DENND4C, TBC1D1, and TBC1D4, and the RAB35 regulator TBC1D13 to regulate retrieval sub-domain function. The retrieval sub-domain therefore constitutes a hub for integrating cargo recycling with the regulated switching of selected RAB GTPases. We propose this constitutes a major component of the neuroprotective role of the retrieval sub-domain.
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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
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · see citing works
Fast and accurate protein structure search with Foldseek
van Kempen, M., Kim, S. S., Tumescheit, C., Mirdita, M., Lee, J., Gilchrist, C. L. M., Söding, J., & Steinegger, M. (2022) · doi:10.1101/2022.02.07.479398 · Cited by 2,598 · see citing works
Fast and accurate protein structure search with Foldseek
van Kempen, M., Kim, S. S., Tumescheit, C., Mirdita, M., Lee, J., Gilchrist, C. L. M., Söding, J., & Steinegger, M. (2024) · Nature Biotechnology · doi:10.1038/s41587-023-01773-0 · Cited by 2,596 · see citing works
Improved prediction of protein-protein interactions using AlphaFold2
Bryant, P., Pozzati, G., & Elofsson, A. (2021) · doi:10.1101/2021.09.15.460468 · Cited by 1,025 · see citing works
Vietri, M., Radulovic, M., & Stenmark, H. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0177-4 · Cited by 962 · 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-citationPredictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions
Schmid, E. W., & Walter, J. C. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.01.034 · Cited by 120 · see citing works
LET-413/Erbin acts as a RAB-5 effector to promote RAB-10 activation during endocytic recycling
Liu, H., Wang, S., Hang, W., Gao, J., Zhang, W., Cheng, Z., Yang, C., He, J., Zhou, J., Chen, J., et al. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201705136 · Cited by 38 · see citing works
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- Authors
- Antón-Plágaro, C., Chen, K.-E., Guo, Q., Liu, M., Evans, A. J., Lewis, P. A., Heesom, K. J., Wilkinson, K. A., Collins, B. M., & Cullen, P. J.
- Affiliations
- University of Bristol (GB)
- The University of Queensland (AU)
- Corresponding author
- Antón-Plágaro, Carlos
- Collins, Brett M.
- Cullen, Peter J.
- ORCID
- Venue
- Nature Communications
- Published
- 2025-07-30
- Volume
- 16
- Issue
- 1
- Pages
- 6990-6990
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12311110
- OpenAlex
- W4412739843
- Cited by
- 14
- References
- 9
- Citations by year
- 2026: 12 · 2025: 2
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (104568/Z/14/Z, 220260/Z/20/Z)
- RCUK | Medical Research Council (MR/L007363/1, MR/P018807/1)
- Royal Society (RSRP/R1/211004)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- retromer, proximity proteomics, TBC1D1, TBC1D4, Rab10, Rab35, neuroprotection
- MeSH terms
- HeLa Cells, Humans, Protein Binding, Endosomes, Crystallography, X-Ray, Proteome, GTPase-Activating Proteins, rab GTP-Binding Proteins, Proteomics, HEK293 Cells
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