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PreprintCited by 14Cellular transport and secretionAutophagy in Disease and TherapyUbiquitin and proteasome pathways

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Mapping the endosomal proximity proteome reveals Retromer as a hub for RAB GTPase regulation

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Antón-Plágaro, Carlos, Chen, Kai-en, Guo, Qian, Liu, Meihan, Evans, Ashley J., Lewis, Philip A., Heesom, Kate J, Wilkinson, Kevin A., Collins, Brett M., Cullen, Peter J.·2024·Nature Communications
DOI 10.1101/2024.11.22.622898PMC PMC12311110

Preprint — published as 10.1038/s41467-025-61802-1 · Paper page

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Abstract

Endosomal retrieval and recycling of integral cargo proteins is essential for cell, tissue and organism-level development and homeostasis and is orchestrated through a specialised retrieval sub-domain on the endosomal vacuole. However, although sub-domain dysfunction is associated with human disease our appreciation of the molecular details and functional components of the retrieval sub-domain(s) remains poorly described. Here, using comparative proximity proteomics of critical retrieval sub-domain components Retromer and Retriever, their cargo adaptors, and a component of the opposing ESCRT-degradative sub-domain, we provide a data-rich resource that identifies new molecular details of retrieval sub-domain composition and organization, including an unrecognised complexity in the interface of Retromer with RAB GTPases. Combining X-ray crystallography and in silico predictions with extensive biochemical and cellular analysis, we dissect the direct association of Retromer with RAB10 regulators DENND4A, DENND4C, TBC1D1, and TBC1D4, and the RAB35 regulator TBC1D13. Overall, we conclude that the Retromer retrieval sub-domain constitutes a major hub for the regulated switching of selected RAB GTPases and propose that this constitutes a major component of the role of Retromer in neuroprotection.

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Metadata

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
Publisher
openRxiv
Published
2024-11-22
Volume
16
Issue
1
Pages
6990-6990
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.11.22.622898
PMC
PMC12311110
OpenAlex
W4412739843
Cited by
14
References
1
Citations by year
2026: 12 · 2025: 2
FWCI
6.95
Type
journal article
Language
en
Open access
Licence
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 (220260/Z/20/Z, 104568/Z/14/Z)
  • Royal Society (RSRP/R1/211004)
  • Medical Research Council (MR/P018807/1, MR/L007363/1)
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 › 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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