PXD064959-1

PXD064959 is an original dataset announced via ProteomeXchange.

Title	Identification of a VPS29 isoform with restricted association to Retriever and Retromer accessory proteins through autoinhibition
Description	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 harbours an extended amino-terminal sequence compared to VPS29A and VPS29B. Through a combination of AlphaFold predictive modelling, 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 characterisation 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.
HostingRepository	PRIDE
AnnounceDate	2025-07-21
AnnouncementXML	Submission_2025-07-20_16:17:19.093.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	James Daly
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-12 14:51:45	ID requested
⏵ 1	2025-07-20 16:17:19	announced

10.1073/pnas.2501111122;

Daly JL, Chen KE, Butkovi, č R, Guo Q, Healy MD, Pennink E, Gamble-Strutt G, Higham Z, Moody ERR, Lewis PA, Heesom KJ, Williams TA, McMillan KJ, Collins BM, Cullen PJ, Identification of a VPS29 isoform with restricted association to Retriever and Retromer accessory proteins through autoinhibition. Proc Natl Acad Sci U S A, 122(27):e2501111122(2025) [pubmed]

submitter keyword: Commander, Retriever, endosomes, lysosomes,Retromer

Peter J. Cullen
contact affiliation	School of Biochemistry, Biomedical Sciences Building, University Walk, University of Bristol, BS8 1TD, U.K.
contact email	pete.cullen@bristol.ac.uk
lab head
James Daly
contact affiliation	King's College London
contact email	james.l.daly@kcl.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD064959
     1. Label: PRIDE project
     2. Name: Identification of a VPS29 isoform with restricted association to Retriever and Retromer accessory proteins through autoinhibition