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Identification of a VPS29 isoform with restricted association to Retriever and Retromer accessory proteins through autoinhibition

Daly, James L., Chen, Kai-en, Butkovič, Rebeka, Guo, Qian, Healy, Michael D., Pennink, Eva, Gamble-Strutt, Georgia, Higham, Zara, Moody, Edmund R. R., Lewis, Philip A., Heesom, Kate J., Williams, Tom A., McMillan, Kirsty J., Collins, Brett M., Cullen, Peter J.·2025·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2501111122PMC PMC12260524
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Abstract

The endosomal–lysosomal network is a hub of organelles that orchestrate the dynamic sorting of hundreds of integral membrane proteins to maintain cellular homeostasis. VPS29 is a central conductor of this network through its assembly into Retromer, Retriever, and Commander endosomal sorting complexes, and its role in regulating RAB GTPase activity. Two VPS29 isoforms have been described, VPS29A and VPS29B, that differ solely in their amino-terminal sequences. Here, we identify a third VPS29 isoform, which we term VPS29C, that harbors an extended amino-terminal sequence compared to VPS29A and VPS29B. Through a combination of AlphaFold predictive modeling, in vitro complex reconstitution, mass spectrometry, and molecular cell biology, we find that the amino-terminal VPS29C extension constitutes an autoinhibitory sequence that limits access to a hydrophobic groove necessary for effector protein recruitment to Retromer, and association with Retriever and Commander. VPS29C is therefore unique in its ability to uncouple Retromer-dependent cargo sorting from the broader roles of VPS29A and VPS29B in regulating the endosomal–lysosomal network through accessory protein recruitment. Our identification and characterization of VPS29C points to additional complexity in the differential subunit assembly of Retromer, an important consideration given the increasing interest in Retromer as a potential therapeutic target in neurodegenerative diseases.

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  • Human Retromer is a stable heterotrimer of VPS35, either VPS26A or VPS26B, and one of three VPS29 isoforms, and regulates endosomal retrieval and trafficking of numerous cargoes away from the degradative pathway.

    “Human Retromer is a stable heterotrimer of vacuolar protein sorting protein 35 (VPS35), either VPS26A or VPS26B [20,21], and one of three VPS29 isoforms [22,23], and regulates the endosomal retrieval and trafficking of numerous cargoes away from the degradative pathway [23].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [22]

  • The full binding affinity for TBC1D13 will require the canonical VPS29 isoform 1, and splice variants 2 and 3 with longer amino-terminal sequences could be compromised for TBC1D13 binding.

    “This suggests that the full binding affinity for TBC1D13 will require the canonical VPS29 isoform 1, and that the splice variants 2 and 3 with longer amino-terminal sequences109 could be compromised for TBC1D13 binding.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [109]

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Metadata

Authors
Daly, J. L., Chen, K.-E., Butkovič, R., Guo, Q., Healy, M. D., Pennink, E., Gamble-Strutt, G., Higham, Z., Moody, E. R. R., Lewis, P. A., Heesom, K. J., Williams, T. A., McMillan, K. J., Collins, B. M., & Cullen, P. J.
Affiliations
  • School of Biochemistry, Faculty of Health and Life Sciences, University of Bristol
  • Institute for Molecular Bioscience, The University of Queensland
  • School of Biological Sciences, University of Bristol
  • Bristol Proteomics Facility, School of Biochemistry, Faculty of Life Sciences, University of Bristol
  • Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2025-06-30
Volume
122
Issue
27
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.2501111122
PMC
PMC12260524
Cited by
5
References
8
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Wellcome Trust (104568/Z/14/Z, 220260/Z/20/Z, 225128/Z/22/Z)
  • UKRI | Medical Research Council (MR/L007363/1, MR/P018807/1)
  • Royal Society (RSRP/R1/211004)
  • Federal Government | DHAC | National Health and Medical Research Council (APP2016410, APP1136021, APP1156493)
  • EC | European Research Council (953489)

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