VPS35 (Q96QK1) Curation Notes

Overview & Complex Architecture

• VPS35 (Q96QK1, ~92 kDa, 796 aa) is the central alpha-helical solenoid scaffold of the mammalian retromer cargo-selective complex (CSC) (GO:0030906), a conserved heterotrimer composed of VPS35, VPS29, and either VPS26A or VPS26B ([PMID:11102511, "The data suggest a model in which hVps35 serves as the core of a multimeric complex by binding directly to hVps26, hVps29, and SNX1."]; PMID:17891154; PMID:27889239; PMID:30224749; PMID:37172566).
• VPS35 forms an elongated right-handed alpha-helical solenoid containing 17 HEAT-like repeats (~34 alpha-helices):
• Its N-terminal region (residues 1–172, notably the evolutionarily conserved PRLYL motif at residues 104–108) directly binds the C-terminal arrestin-like subdomain of VPS26A or VPS26B (PMID:11102511; PMID:16732284; PMID:27889239).
• Its C-terminal half (residues 476–780) wraps around the metallophosphoesterase-fold scaffold subunit VPS29 ([PMID:17891154, "Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35."]).
• On endosomal membranes, retromer dimers assemble into arch-like oligomers over membrane-bound sorting nexins, with antiparallel homodimerization of the VPS35 C-terminal domain forming the apex of the arch while VPS26 dimers dock onto membrane-associated SNX3 or SNX-BAR subunits (PMID:30224749).
• Unlike VPS29 (which is shared with the Retriever complex VPS26C:VPS35L:VPS29), VPS35 is exclusive to the retromer CSC; Retriever uses the distant paralog VPS35L (C16orf62) (PMID:28892079; PMID:37172566).

Core Biological Functions

1. Endosome-to-Trans-Golgi Network (TGN) Retrograde Transport (GO:0042147):
2. Retromer retrieves acid hydrolase sorting receptors—most prominently the cation-independent mannose 6-phosphate receptor (CI-MPR / IGF2R) and sortilin (SORT1)—from early/maturing endosomes back to the TGN, preventing their delivery to and degradation in lysosomes ([PMID:15078903, "The hVps35 subunit of retromer interacts with the cytosolic domain of the CI-MPR. This interaction probably occurs in an endosomal compartment, where most of the retromer is localized."]; [PMID:15078903, "Depletion of retromer by RNA interference increases the lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal hydrolases, and causes swelling of lysosomes."]; PMID:22431521).
3. In conjunction with SNX3 (GO:0042147), retromer mediates retrograde endosome-to-TGN retrieval of the Wnt sorting receptor Wntless (WLS/Evi), which is required for secretion of Wnt morphogens ([PMID:18193037, "Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner."]; PMID:21725319; PMID:27889239).
4. Endocytic Recycling (GO:0032456), D1 Dopamine Receptor Binding (GO:0031748), and Transcytosis (GO:0045056):
5. Coupled with the endosomal sorting nexin SNX27 (which binds VPS26A via its PDZ domain) and the actin-nucleating WASH complex (which binds the VPS35 C-terminal tail via FAM21/WASHC2C), retromer mediates direct endosome-to-plasma membrane recycling of numerous cell-surface cargoes, including the beta-2 adrenergic receptor (ADRB2), dopamine receptor D1 (DRD1, via direct binding GO:0031748), glucose transporter GLUT1 (SLC2A1), divalent metal transporter DMT1-II (SLC11A2), and AMPA/NMDA glutamate receptors (PMID:20164305; PMID:20923837; [PMID:21602791, "β2AR recycling, as measured by antibody efflux following agonist removal, was strongly inhibited by multiple siRNA sequences targeting either VPS26 or VPS35."]; PMID:23563491; PMID:24705354; PMID:27460146).
6. In polarized epithelial cells, retromer promotes basolateral-to-apical transcytosis (GO:0045056) of the polymeric immunoglobulin receptor (pIgR-pIgA) ([PMID:15247922, "Here, we show a function for the mammalian Vps35-Vps29-Vps26 retromer subcomplex in promoting pIgR-pIgA transcytosis."]).
7. Mitochondria-Derived Vesicle (MDV) Trafficking & Mitochondrial Dynamics (GO:0099073, GO:0099074):
8. VPS35 also localizes to mitochondria-derived vesicles (GO:0099073), mediating delivery of MAPL/MUL1-containing MDVs to peroxisomes and facilitating turnover of mitochondrial dynamin-like protein 1 (DLP1 / DNM1L) complexes via MDV-mediated transport to lysosomes (GO:0099074) ([PMID:26618722, "VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation."]).

Disease Genetics & Parkinson Disease (PARK17)

• Heterozygous missense mutations in VPS35, most notably p.Asp620Asn (D620N) and p.Arg524Trp (R524W), cause autosomal-dominant late-onset Parkinson disease (PARK17, MIM:614203) (PMID:24705354; PMID:25533483; PMID:26618722; PMID:27385586; PMID:27460146).
• The D620N mutation resides in the C-terminal region of VPS35 and does not disrupt assembly of the VPS35-VPS29-VPS26A trimer; instead, it decreases affinity for the WASH complex subunit FAM21 (WASHC2C), impairing WASH recruitment, ATG9A trafficking, autophagosome maturation, DRD1 surface recycling, and AMPA receptor trafficking, while enhancing interaction with mitochondrial DLP1 (DNM1L) and causing excessive mitochondrial fragmentation (PMID:24705354; PMID:26618722; PMID:27460146).

Key Curation & GO Annotation Decisions

• GOA Row Count Note: VPS35-goa.tsv contains 183 raw annotation rows; because ('GO:0005515', 'IPI', 'PMID:11102511', 'enables', 'UniProtKB:O75436') is duplicated identically in VPS35-goa.tsv (differing only in ASSIGNED_BY), VPS35-ai-review.yaml contains 182 unique existing_annotations entries.
• Core MF (ACCEPT):
• GO:0140312 (cargo adaptor activity, contributes_to): VPS35, together with VPS26A/B and VPS29 in the retromer CSC (GO:0030906), forms the cooperative cargo-recognition platform that binds sorting nexins (SNX3, SNX27, SNX-BARs) and transmembrane cargo sorting signals (PMID:27889239; PMID:30224749). Modeled via contributes_to_molecular_function in core_functions.
• GO:0031748 (D1 dopamine receptor binding, enables, IPI PMID:27460146 and ISS GO_REF:0000024): Direct binding of VPS35 to the cytoplasmic tail of DRD1 to promote its cell-surface recycling (PMID:27460146).
• Core BP (ACCEPT):
• GO:0042147 (retrograde transport, endosome to Golgi, 8 rows)
• GO:0032456 (endocytic recycling, 3 rows)
• Core CC (ACCEPT):
• GO:0030904 (retromer complex, 7 rows) and GO:0030906 (retromer, cargo-selective complex, 5 rows)
• GO:0005768 (endosome, 5 rows), GO:0005769 (early endosome, 4 rows), GO:0010008 (endosome membrane, 2 rows), GO:0097422 (tubular endosome, 1 row), and GO:0005829 (cytosol, 4 rows)
• Broad Terms Refined (MODIFY):
• GO:0015031 (protein transport), GO:0051049 (regulation of transport), GO:0099638 (obsolete endosome to plasma membrane protein transport), GO:1903828 (negative regulation of protein localization), GO:1903829 (positive regulation of protein localization), GO:0009967 (positive regulation of signal transduction), GO:0031647 (regulation of protein stability), GO:0042176 (regulation of protein catabolic process), and GO:0051246 (regulation of protein metabolic process): MODIFY to GO:0042147 (retrograde transport, endosome to Golgi) and GO:0032456 (endocytic recycling).
• GO:0005737 (cytoplasm) and GO:0016020 (membrane): MODIFY to GO:0005829 (cytosol) and GO:0010008 (endosome membrane).
• Specialized, Neuronal, Mitochondrial, and Downstream Roles (KEEP_AS_NON_CORE):
• Endolysosomal/perinuclear/exosomal CC and homeostasis terms (GO:0005770 late endosome, GO:0005765 lysosomal membrane, GO:0048471 perinuclear region of cytoplasm, GO:0070062 extracellular exosome, GO:0007040 lysosome organization, GO:0016241 regulation of macroautophagy, GO:0036010 protein localization to endosome, GO:1902823 negative regulation of late endosome to lysosome transport, GO:1904377 positive regulation of protein localization to cell periphery, GO:1905166 negative regulation of lysosomal protein catabolic process, GO:0031648 protein destabilization, GO:0045732 positive regulation of protein catabolic process, GO:0032463 negative regulation of protein homooligomerization, GO:0045056 transcytosis).
• Mitochondrial MDV/DLP1 turnover terms (GO:0005739 mitochondrion, GO:0099073 mitochondrion-derived vesicle, GO:0099074 mitochondrion to lysosome vesicle-mediated transport, GO:0010821 regulation of mitochondrion organization, GO:0090141 positive regulation of mitochondrial fission, GO:0043653 mitochondrial fragmentation involved in apoptotic process).
• Wntless-dependent Wnt secretion terms (GO:0016055 Wnt signaling pathway, GO:0061357 positive regulation of Wnt protein secretion, GO:0090263 positive regulation of canonical Wnt signaling pathway) and anti-inflammatory signaling (GO:0050728 negative regulation of inflammatory response).
• Neuronal/synaptic localization and receptor recycling terms (GO:0014069 postsynaptic density, GO:0043005 neuron projection, GO:0043025 neuronal cell body, GO:0045202 synapse, GO:0098691 dopaminergic synapse, GO:0098793 presynapse, GO:0098794 postsynapse, GO:0098978 glutamatergic synapse, GO:0098887 neurotransmitter receptor transport, endosome to postsynaptic membrane, GO:0099639 neurotransmitter receptor transport, endosome to plasma membrane, GO:0060161 positive regulation of dopamine receptor signaling pathway, GO:0050804 modulation of chemical synaptic transmission, GO:0090128 regulation of synapse maturation, GO:0099175 regulation of postsynapse organization, GO:0150052 regulation of postsynapse assembly, GO:1902950 regulation of dendritic spine maintenance, GO:1905606 regulation of presynapse assembly, GO:2000331 regulation of terminal button organization).
• Distant Transcriptional / Behavioral Over-Annotations (MARK_AS_OVER_ANNOTATED):
• GO:0010628 (positive regulation of gene expression), GO:0010629 (negative regulation of gene expression), GO:0050793 (regulation of developmental process), GO:0050882 (voluntary musculoskeletal movement), GO:0090326 (positive regulation of locomotion involved in locomotory behavior), and GO:1903181 (positive regulation of dopamine biosynthetic process): indirect organismal/transcriptional readouts of altered receptor and mitochondrial trafficking.
• Uninformative Generic Protein Binding (REMOVE):
• GO:0005515 (protein binding, 75 IPI rows) — removed per standard GO protein-binding policy.