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Protein

Vacuolar protein sorting-associated protein 35

Gene

VPS35

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The CSC seems to associate with the cytoplasmic domain of cargo proteins predominantly via VPS35; however, these interactions seem to be of low affinity and retromer SNX proteins may also contribute to cargo selectivity thus questioning the classical function of the CSC. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5 (Probable). Required for retrograde transport of lysosomal enzyme receptor IGF2R and SLC11A2. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15078903, PubMed:15247922, PubMed:20164305). Required for endosomal localization of WASHC2C (PubMed:22070227). Mediates the association of the CSC with the WASH complex via WASHC2 (PubMed:22070227, PubMed:24980502, PubMed:24819384). Required for the endosomal localization of TBC1D5 (PubMed:20923837).4 Publications8 Publications
(Microbial infection) The heterotrimeric retromer cargo-selective complex (CSC) mediates the exit of human papillomavirus from the early endosome and the delivery to the Golgi apparatus.2 Publications

GO - Molecular functioni

  • D1 dopamine receptor binding Source: ParkinsonsUK-UCL
  • protein transporter activity Source: GO_Central

GO - Biological processi

Keywordsi

Biological processHost-virus interaction, Protein transport, Transport

Enzyme and pathway databases

ReactomeiR-HSA-3238698 WNT ligand biogenesis and trafficking

Protein family/group databases

TCDBi9.A.3.1.1 the sorting nexin27 (snx27)-retromer assembly apparatus for recycling integral membrane proteins (snx27-retromeraa) family

Names & Taxonomyi

Protein namesi
Recommended name:
Vacuolar protein sorting-associated protein 35
Short name:
hVPS35
Alternative name(s):
Maternal-embryonic 3
Vesicle protein sorting 35
Gene namesi
Name:VPS351 PublicationImported
Synonyms:MEM3
ORF Names:TCCCTA00141
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

EuPathDBiHostDB:ENSG00000069329.15
HGNCiHGNC:13487 VPS35
MIMi601501 gene
neXtProtiNX_Q96QK1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endosome, Membrane

Pathology & Biotechi

Involvement in diseasei

Parkinson disease 17 (PARK17)6 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant, adult-onset form of Parkinson disease. Parkinson disease is a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain.
See also OMIM:614203
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_066659620D → N in PARK17; decreases interaction with WASHC2C, FKBP15 and the WASH complex; impairs recruitment of the WASH complex to endosomes; shows reduced retrograde transport of selective cargo between lysosomes and the Golgi apparatus; shows a progressive reduction in neurite length and branching. 6 PublicationsCorresponds to variant dbSNP:rs188286943EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi108L → P: Disrupts interaction with VPS26; no effect on interaction with VPS29. 1 Publication1
Mutagenesisi675H → R: Disrupts interaction with VPS29. Does not effect interaction with VPS26. 1 Publication1

Keywords - Diseasei

Neurodegeneration, Parkinson disease, Parkinsonism

Organism-specific databases

DisGeNETi55737
GeneReviewsiVPS35
MalaCardsiVPS35
MIMi614203 phenotype
OpenTargetsiENSG00000069329
Orphaneti411602 Hereditary late-onset Parkinson disease
PharmGKBiPA37783

Chemistry databases

ChEMBLiCHEMBL2216744

Polymorphism and mutation databases

BioMutaiVPS35
DMDMi25453321

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000658961 – 796Vacuolar protein sorting-associated protein 35Add BLAST796

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei7PhosphoserineCombined sources1
Modified residuei783PhosphoserineBy similarity1
Modified residuei791PhosphotyrosineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ96QK1
MaxQBiQ96QK1
PaxDbiQ96QK1
PeptideAtlasiQ96QK1
PRIDEiQ96QK1
ProteomicsDBi77884

PTM databases

iPTMnetiQ96QK1
PhosphoSitePlusiQ96QK1
SwissPalmiQ96QK1

Expressioni

Tissue specificityi

Ubiquitous. Highly expressed in heart, brain, placenta, skeletal muscle, spleen, thymus, testis, ovary, small intestine, kidney and colon.

Gene expression databases

BgeeiENSG00000069329 Expressed in 98 organ(s), highest expression level in intestine
ExpressionAtlasiQ96QK1 baseline and differential
GenevisibleiQ96QK1 HS

Organism-specific databases

HPAiHPA040802

Interactioni

Subunit structurei

Component of the heterotrimeric retromer cargo-selective complex (CSC), also decribed as vacuolar protein sorting subcomplex (VPS), formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35 (PubMed:11102511). The CSC has a highly elongated structure with VPS26 and VPS29 binding independently at opposite distal ends of VPS35 as central platform (By similarity). The CSC is believed to associate with variable sorting nexins to form functionally distinct retromer complex variants. The originally described retromer complex (also called SNX-BAR retromer) is a pentamer containing the CSC and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity. The CSC associates with SNX3 to form a SNX3-retromer complex. The CSC associates with SNX27, the WASH complex and the SNX-BAR subcomplex to form the SNX27-retromer complex (Probable). Interacts with VPS26A, VPS26B, VPS29, SNX1, SNX2, IGF2R, SNX3, GOLPH3, LRRK2, SLC11A2, WASHC2A, WASHC2C, FKBP15, WASHC1, RAB7A, SNX27, WASHC5, EHD1 (PubMed:11102511, PubMed:15078903, PubMed:17868075PubMed:22070227, PubMed:19553991, PubMed:21725319, PubMed:22070227, PubMed:22513087, PubMed:23331060, PubMed:23563491, PubMed:23395371, PubMed:24344282, PubMed:24980502, PubMed:17891154, PubMed:19531583). Interacts with MAGEL2; leading to recruitment of the TRIM27:MAGEL2 E3 ubiquitin ligase complex retromer-containing endosomes (PubMed:23452853).2 PublicationsBy similarity14 Publications
(Microbial infection) Interacts with human papillomavirus 16 minor capsid protein L2 (via C-terminus); this interaction mediates the transport of the capsid from the early endosome to the Golgi apparatus.1 Publication

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi120855, 83 interactors
CORUMiQ96QK1
DIPiDIP-29076N
IntActiQ96QK1, 35 interactors
MINTiQ96QK1
STRINGi9606.ENSP00000299138

Structurei

Secondary structure

1796
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ96QK1
SMRiQ96QK1
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ96QK1

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni25 – 44Interaction with SNX31 PublicationAdd BLAST20
Regioni205 – 215Interaction with SNX31 PublicationAdd BLAST11
Regioni438 – 796Interaction with SLC11A21 PublicationAdd BLAST359
Regioni500 – 693Interaction with IGF2R cytoplasmic domain1 PublicationAdd BLAST194

Sequence similaritiesi

Belongs to the VPS35 family.Curated

Phylogenomic databases

eggNOGiKOG1107 Eukaryota
ENOG410XNXC LUCA
GeneTreeiENSGT00390000007315
HOVERGENiHBG054277
InParanoidiQ96QK1
KOiK18468
OMAiHLWWATP
OrthoDBiEOG091G0OHF
PhylomeDBiQ96QK1
TreeFamiTF105659

Family and domain databases

InterProiView protein in InterPro
IPR016024 ARM-type_fold
IPR005378 Vps35
PANTHERiPTHR11099 PTHR11099, 1 hit
PfamiView protein in Pfam
PF03635 Vps35, 1 hit
PIRSFiPIRSF009375 Retromer_Vps35, 1 hit
SUPFAMiSSF48371 SSF48371, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 4 potential isoforms that are computationally mapped.Show allAlign All

Q96QK1-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MPTTQQSPQD EQEKLLDEAI QAVKVQSFQM KRCLDKNKLM DALKHASNML
60 70 80 90 100
GELRTSMLSP KSYYELYMAI SDELHYLEVY LTDEFAKGRK VADLYELVQY
110 120 130 140 150
AGNIIPRLYL LITVGVVYVK SFPQSRKDIL KDLVEMCRGV QHPLRGLFLR
160 170 180 190 200
NYLLQCTRNI LPDEGEPTDE ETTGDISDSM DFVLLNFAEM NKLWVRMQHQ
210 220 230 240 250
GHSRDREKRE RERQELRILV GTNLVRLSQL EGVNVERYKQ IVLTGILEQV
260 270 280 290 300
VNCRDALAQE YLMECIIQVF PDEFHLQTLN PFLRACAELH QNVNVKNIII
310 320 330 340 350
ALIDRLALFA HREDGPGIPA DIKLFDIFSQ QVATVIQSRQ DMPSEDVVSL
360 370 380 390 400
QVSLINLAMK CYPDRVDYVD KVLETTVEIF NKLNLEHIAT SSAVSKELTR
410 420 430 440 450
LLKIPVDTYN NILTVLKLKH FHPLFEYFDY ESRKSMSCYV LSNVLDYNTE
460 470 480 490 500
IVSQDQVDSI MNLVSTLIQD QPDQPVEDPD PEDFADEQSL VGRFIHLLRS
510 520 530 540 550
EDPDQQYLIL NTARKHFGAG GNQRIRFTLP PLVFAAYQLA FRYKENSKVD
560 570 580 590 600
DKWEKKCQKI FSFAHQTISA LIKAELAELP LRLFLQGALA AGEIGFENHE
610 620 630 640 650
TVAYEFMSQA FSLYEDEISD SKAQLAAITL IIGTFERMKC FSEENHEPLR
660 670 680 690 700
TQCALAASKL LKKPDQGRAV STCAHLFWSG RNTDKNGEEL HGGKRVMECL
710 720 730 740 750
KKALKIANQC MDPSLQVQLF IEILNRYIYF YEKENDAVTI QVLNQLIQKI
760 770 780 790
REDLPNLESS EETEQINKHF HNTLEHLRLR RESPESEGPI YEGLIL
Length:796
Mass (Da):91,707
Last modified:November 25, 2002 - v2
Checksum:i28D2DD1C6B920A0A
GO

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
I3L4P4I3L4P4_HUMAN
Vacuolar protein sorting-associated...
VPS35
47Annotation score:
I3L4S0I3L4S0_HUMAN
Vacuolar protein sorting-associated...
VPS35
41Annotation score:
H3BRJ7H3BRJ7_HUMAN
Vacuolar protein sorting-associated...
VPS35
48Annotation score:
A0A1W2PP10A0A1W2PP10_HUMAN
Vacuolar protein sorting-associated...
VPS35
46Annotation score:

Sequence cautioni

The sequence AAG01989 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAA91137 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAB14626 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti42A → S in CAB66822 (PubMed:11230166).Curated1
Sequence conflicti160I → T in BAB14626 (PubMed:14702039).Curated1
Sequence conflicti168T → P in AAF89953 (PubMed:11102511).Curated1
Sequence conflicti453S → F in AAH10362 (PubMed:15489334).Curated1
Sequence conflicti526R → G in BAA91790 (PubMed:14702039).Curated1
Sequence conflicti694K → E in BAA91790 (PubMed:14702039).Curated1
Sequence conflicti796L → H in BAA91137 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06665351G → S1 PublicationCorresponds to variant dbSNP:rs193077277EnsemblClinVar.1
Natural variantiVAR_06665457M → I1 PublicationCorresponds to variant dbSNP:rs183554824EnsemblClinVar.1
Natural variantiVAR_06665582T → R1 PublicationCorresponds to variant dbSNP:rs188245364Ensembl.1
Natural variantiVAR_066656241I → M Found in a patient with Parkinson disease. 1 PublicationCorresponds to variant dbSNP:rs192783364EnsemblClinVar.1
Natural variantiVAR_066657316P → S Found in a patient with Parkinson disease. 1 PublicationCorresponds to variant dbSNP:rs770029606EnsemblClinVar.1
Natural variantiVAR_080769469Q → P Found in a consanguineous family with intellectual disability; unknown pathological significance. 1 Publication1
Natural variantiVAR_066658524R → W Found in a patient with Parkinson disease. 1 PublicationCorresponds to variant dbSNP:rs184277092EnsemblClinVar.1
Natural variantiVAR_054046602V → D. Corresponds to variant dbSNP:rs34687100Ensembl.1
Natural variantiVAR_066659620D → N in PARK17; decreases interaction with WASHC2C, FKBP15 and the WASH complex; impairs recruitment of the WASH complex to endosomes; shows reduced retrograde transport of selective cargo between lysosomes and the Golgi apparatus; shows a progressive reduction in neurite length and branching. 6 PublicationsCorresponds to variant dbSNP:rs188286943EnsemblClinVar.1
Natural variantiVAR_066660737A → V1 PublicationCorresponds to variant dbSNP:rs749516404EnsemblClinVar.1
Natural variantiVAR_066661774L → M1 PublicationCorresponds to variant dbSNP:rs192419029EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF191298 mRNA Translation: AAF02778.2
AF186382 mRNA Translation: AAG40619.1
AF175265 mRNA Translation: AAF89953.1
AF183418 mRNA Translation: AAG09687.1
AK001614 mRNA Translation: BAA91790.1
AK023650 mRNA Translation: BAB14626.1 Different initiation.
AK000395 mRNA Translation: BAA91137.1 Different initiation.
AL136888 mRNA Translation: CAB66822.1
AL512769 mRNA Translation: CAC21686.1
BC002414 mRNA Translation: AAH02414.1
BC010362 mRNA Translation: AAH10362.1
BC093036 mRNA Translation: AAH93036.1
AY007112 mRNA Translation: AAG01989.1 Different initiation.
CCDSiCCDS10721.1
PIRiJC7516
RefSeqiNP_060676.2, NM_018206.5
UniGeneiHs.454528
Hs.595143

Genome annotation databases

EnsembliENST00000299138; ENSP00000299138; ENSG00000069329
GeneIDi55737
KEGGihsa:55737
UCSCiuc002eef.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF191298 mRNA Translation: AAF02778.2
AF186382 mRNA Translation: AAG40619.1
AF175265 mRNA Translation: AAF89953.1
AF183418 mRNA Translation: AAG09687.1
AK001614 mRNA Translation: BAA91790.1
AK023650 mRNA Translation: BAB14626.1 Different initiation.
AK000395 mRNA Translation: BAA91137.1 Different initiation.
AL136888 mRNA Translation: CAB66822.1
AL512769 mRNA Translation: CAC21686.1
BC002414 mRNA Translation: AAH02414.1
BC010362 mRNA Translation: AAH10362.1
BC093036 mRNA Translation: AAH93036.1
AY007112 mRNA Translation: AAG01989.1 Different initiation.
CCDSiCCDS10721.1
PIRiJC7516
RefSeqiNP_060676.2, NM_018206.5
UniGeneiHs.454528
Hs.595143

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2R17X-ray2.80C/D483-780[»]
5F0JX-ray2.70A14-470[»]
5F0KX-ray3.07A/B/C/D/E14-470[»]
5F0LX-ray3.20A14-470[»]
5F0MX-ray3.10A14-470[»]
5F0PX-ray2.78A14-470[»]
5OSHX-ray4.30B/E/H/K482-780[»]
5OSIX-ray2.52B/E/H/K471-781[»]
ProteinModelPortaliQ96QK1
SMRiQ96QK1
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi120855, 83 interactors
CORUMiQ96QK1
DIPiDIP-29076N
IntActiQ96QK1, 35 interactors
MINTiQ96QK1
STRINGi9606.ENSP00000299138

Chemistry databases

ChEMBLiCHEMBL2216744

Protein family/group databases

TCDBi9.A.3.1.1 the sorting nexin27 (snx27)-retromer assembly apparatus for recycling integral membrane proteins (snx27-retromeraa) family

PTM databases

iPTMnetiQ96QK1
PhosphoSitePlusiQ96QK1
SwissPalmiQ96QK1

Polymorphism and mutation databases

BioMutaiVPS35
DMDMi25453321

Proteomic databases

EPDiQ96QK1
MaxQBiQ96QK1
PaxDbiQ96QK1
PeptideAtlasiQ96QK1
PRIDEiQ96QK1
ProteomicsDBi77884

Protocols and materials databases

DNASUi55737
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000299138; ENSP00000299138; ENSG00000069329
GeneIDi55737
KEGGihsa:55737
UCSCiuc002eef.5 human

Organism-specific databases

CTDi55737
DisGeNETi55737
EuPathDBiHostDB:ENSG00000069329.15
GeneCardsiVPS35
GeneReviewsiVPS35
HGNCiHGNC:13487 VPS35
HPAiHPA040802
MalaCardsiVPS35
MIMi601501 gene
614203 phenotype
neXtProtiNX_Q96QK1
OpenTargetsiENSG00000069329
Orphaneti411602 Hereditary late-onset Parkinson disease
PharmGKBiPA37783
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1107 Eukaryota
ENOG410XNXC LUCA
GeneTreeiENSGT00390000007315
HOVERGENiHBG054277
InParanoidiQ96QK1
KOiK18468
OMAiHLWWATP
OrthoDBiEOG091G0OHF
PhylomeDBiQ96QK1
TreeFamiTF105659

Enzyme and pathway databases

ReactomeiR-HSA-3238698 WNT ligand biogenesis and trafficking

Miscellaneous databases

ChiTaRSiVPS35 human
EvolutionaryTraceiQ96QK1
GeneWikiiVPS35
GenomeRNAii55737
PROiPR:Q96QK1
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000069329 Expressed in 98 organ(s), highest expression level in intestine
ExpressionAtlasiQ96QK1 baseline and differential
GenevisibleiQ96QK1 HS

Family and domain databases

InterProiView protein in InterPro
IPR016024 ARM-type_fold
IPR005378 Vps35
PANTHERiPTHR11099 PTHR11099, 1 hit
PfamiView protein in Pfam
PF03635 Vps35, 1 hit
PIRSFiPIRSF009375 Retromer_Vps35, 1 hit
SUPFAMiSSF48371 SSF48371, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiVPS35_HUMAN
AccessioniPrimary (citable) accession number: Q96QK1
Secondary accession number(s): Q561W2
, Q9H016, Q9H096, Q9H4P3, Q9H8J0, Q9NRS7, Q9NVG2, Q9NX80, Q9NZK2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 25, 2002
Last sequence update: November 25, 2002
Last modified: November 7, 2018
This is version 175 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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