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Protein

Vacuolar protein sorting-associated protein 4A

Gene

VPS4A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses). Involved in cytokinesis: retained at the midbody by ZFYVE19/ANCHR and CHMP4C until abscission checkpoint signaling is terminated at late cytokinesis. It is then released following dephosphorylation of CHMP4C, leading to abscission (PubMed:24814515). VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).5 Publications

Catalytic activityi

ATP + H2O = ADP + phosphate.

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi167 – 1748ATPCurated

GO - Molecular functioni

  • ATPase activity Source: UniProtKB
  • ATPase activity, coupled Source: UniProtKB
  • ATP binding Source: UniProtKB
  • protein C-terminus binding Source: UniProtKB
  • protein domain specific binding Source: UniProtKB

GO - Biological processi

  • abscission Source: UniProtKB
  • autophagy Source: ParkinsonsUK-UCL
  • cell division Source: UniProtKB
  • cell separation after cytokinesis Source: UniProtKB
  • endosomal transport Source: UniProtKB
  • endosomal vesicle fusion Source: UniProtKB
  • ESCRT complex disassembly Source: ParkinsonsUK-UCL
  • ESCRT III complex disassembly Source: ParkinsonsUK-UCL
  • intracellular cholesterol transport Source: UniProtKB
  • late endosomal microautophagy Source: ParkinsonsUK-UCL
  • membrane budding Source: UniProtKB
  • mitotic metaphase plate congression Source: UniProtKB
  • multivesicular body assembly Source: ParkinsonsUK-UCL
  • negative regulation of cytokinesis Source: UniProtKB
  • nucleus organization Source: UniProtKB
  • positive regulation of exosomal secretion Source: UniProtKB
  • positive regulation of viral budding via host ESCRT complex Source: UniProtKB
  • positive regulation of viral life cycle Source: UniProtKB
  • positive regulation of viral release from host cell Source: UniProtKB
  • protein transport Source: UniProtKB-KW
  • regulation of protein localization Source: UniProtKB
  • regulation of protein localization to plasma membrane Source: UniProtKB
  • ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway Source: UniProtKB
  • ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway Source: UniProtKB
  • vacuole organization Source: GO_Central
  • vesicle-mediated transport Source: UniProtKB
  • vesicle uncoating Source: UniProtKB
  • viral budding via host ESCRT complex Source: UniProtKB
  • viral life cycle Source: Reactome
  • viral release from host cell Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Biological processi

Cell cycle, Cell division, Protein transport, Transport

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-162588. Budding and maturation of HIV virion.
R-HSA-917729. Endosomal Sorting Complex Required For Transport (ESCRT).

Names & Taxonomyi

Protein namesi
Recommended name:
Vacuolar protein sorting-associated protein 4A (EC:3.6.4.6)
Alternative name(s):
Protein SKD2
VPS4-1
Short name:
hVPS4
Gene namesi
Name:VPS4AImported
Synonyms:VPS4Imported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

HGNCiHGNC:13488. VPS4A.

Subcellular locationi

GO - Cellular componenti

  • centrosome Source: UniProtKB
  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • early endosome Source: UniProtKB
  • endosome Source: UniProtKB
  • extracellular exosome Source: UniProtKB
  • Flemming body Source: UniProtKB
  • late endosome Source: UniProtKB
  • late endosome membrane Source: UniProtKB-SubCell
  • lysosome Source: UniProtKB
  • midbody Source: UniProtKB
  • nucleus Source: UniProtKB
  • perinuclear region of cytoplasm Source: UniProtKB
  • plasma membrane Source: UniProtKB
  • spindle pole Source: UniProtKB
  • vacuolar membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Endosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi13 – 131V → A or D: Diminishes interaction with IST1. 2 Publications
Mutagenesisi13 – 131V → D: Abolishes interaction with CHMP6, no effect on interaction with CHMP1A. 2 Publications
Mutagenesisi13 – 131V → D: Greatly diminishes localization to punctate class E compartments; when associated with Q-173. 2 Publications
Mutagenesisi64 – 641L → A or D: Abolishes interaction with CHMP1B; diminishes interaction with IST1. 5 Publications
Mutagenesisi64 – 641L → D: Greatly diminishes localization to punctate class E compartments and partially restores HIV-1 release; when associated with Q-173. 5 Publications
Mutagenesisi64 – 641L → D: Modestly reduces interaction with CHMP6. 5 Publications
Mutagenesisi68 – 681E → D: Diminishes interaction with CHMP1B. 1 Publication
Mutagenesisi173 – 1731K → Q: Defective in ATP-binding. Causes membrane association. Induces vacuolation of endosomal compartments and impairs cholesterol sorting. Inhibits HIV-1 release. Greatly diminishes localization to punctate class E compartments and partially restores HIV-1 release; when associated with D-64. Greatly diminishes localization to punctate class E compartments; when associated with D-173. 4 Publications
Mutagenesisi201 – 2022WL → AA: Strongly impairs HIV-1 release. 1 Publication
Mutagenesisi203 – 2031G → A: Impairs HIV-1 release. 1 Publication
Mutagenesisi228 – 2281E → Q: Defective in ATP-hydrolysis. Causes membrane association. Induces vacuolation of endosomal compartments and impairs cholesterol and protein sorting. Inhibits HIV-1 release. Increases binding to CHMP1. 5 Publications

Organism-specific databases

PharmGKBiPA38362.

Polymorphism and mutation databases

BioMutaiVPS4A.
DMDMi62511240.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 437437Vacuolar protein sorting-associated protein 4APRO_0000084765Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei8 – 81N6-acetyllysineCombined sources
Modified residuei95 – 951PhosphoserineBy similarity
Modified residuei97 – 971PhosphoserineBy similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ9UN37.
MaxQBiQ9UN37.
PaxDbiQ9UN37.
PeptideAtlasiQ9UN37.
PRIDEiQ9UN37.

PTM databases

iPTMnetiQ9UN37.
PhosphoSiteiQ9UN37.

Expressioni

Tissue specificityi

Ubiquitously expressed.2 Publications

Gene expression databases

BgeeiENSG00000132612.
CleanExiHS_VPS4A.
ExpressionAtlasiQ9UN37. baseline and differential.
GenevisibleiQ9UN37. HS.

Organism-specific databases

HPAiCAB018751.
CAB034411.

Interactioni

Subunit structurei

Proposed to be monomeric or homodimeric in nucleotide-free form and to oligomerize upon binding to ATP to form two stacked hexameric or heptameric rings with a central pore through which ESCRT-III substrates are translocated in an ATP-dependent manner (By similarity). Interacts with CHMP1A, CHMP1B, CHMP2A, CHMP2B, CHMP3, CHMP4A, CHMP4B, CHMP4C and CHMP6. Interacts with VPS4B; the interaction suggests a heteromeric assembly with VPS4B. Interacts with SPAST. Interacts with IST1. Interacts with ZFYVE19/ANCHR; leading to retain it at midbody.By similarity12 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CHMP1AQ9HD426EBI-1171942,EBI-1057156
CHMP1BQ7LBR13EBI-1171942,EBI-2118090
CHMP2AO436333EBI-1171942,EBI-2692789

GO - Molecular functioni

  • protein C-terminus binding Source: UniProtKB
  • protein domain specific binding Source: UniProtKB

Protein-protein interaction databases

BioGridi118059. 28 interactions.
DIPiDIP-44585N.
IntActiQ9UN37. 15 interactions.
STRINGi9606.ENSP00000254950.

Structurei

Secondary structure

1
437
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi5 – 2117Combined sources
Helixi25 – 4521Combined sources
Helixi50 – 7627Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1YXRNMR-A1-77[»]
2JQ9NMR-A1-84[»]
2K3WNMR-A1-84[»]
ProteinModelPortaliQ9UN37.
SMRiQ9UN37. Positions 1-77, 116-436.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9UN37.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini2 – 8079MITAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 8484Interaction with CHMP1BAdd
BLAST

Domaini

The MIT domain serves as an adapter for ESCRT-III proteins. It forms an asymmetric three-helix bundle that binds amphipathic MIM (MIT interacting motif) helices along the groove between MIT helices 2 and 3 present in a subset of ESCRT-III proteins thus establishing the canonical MIM-MIT interaction. In an extended conformation along the groove between helices 1 and 3, also binds to a type-2 MIT interacting motif (MIM2).By similarity

Sequence similaritiesi

Belongs to the AAA ATPase family.Sequence analysis
Contains 1 MIT domain.Sequence analysis

Phylogenomic databases

eggNOGiKOG0739. Eukaryota.
ENOG410XRHN. LUCA.
GeneTreeiENSGT00550000074466.
HOGENOMiHOG000225146.
HOVERGENiHBG057074.
InParanoidiQ9UN37.
KOiK12196.
OMAiNPSMMID.
OrthoDBiEOG091G0Q8J.
PhylomeDBiQ9UN37.
TreeFamiTF105012.

Family and domain databases

Gene3Di1.20.58.280. 1 hit.
3.40.50.300. 1 hit.
InterProiIPR003593. AAA+_ATPase.
IPR003959. ATPase_AAA_core.
IPR003960. ATPase_AAA_CS.
IPR007330. MIT.
IPR027417. P-loop_NTPase.
IPR015415. Vps4_C.
IPR031255. VPS4A.
[Graphical view]
PANTHERiPTHR23074:SF82. PTHR23074:SF82. 2 hits.
PfamiPF00004. AAA. 1 hit.
PF04212. MIT. 1 hit.
PF09336. Vps4_C. 1 hit.
[Graphical view]
SMARTiSM00382. AAA. 1 hit.
SM00745. MIT. 1 hit.
[Graphical view]
SUPFAMiSSF116846. SSF116846. 1 hit.
SSF52540. SSF52540. 1 hit.
PROSITEiPS00674. AAA. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9UN37-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MTTSTLQKAI DLVTKATEED KAKNYEEALR LYQHAVEYFL HAIKYEAHSD
60 70 80 90 100
KAKESIRAKC VQYLDRAEKL KDYLRSKEKH GKKPVKENQS EGKGSDSDSE
110 120 130 140 150
GDNPEKKKLQ EQLMGAVVME KPNIRWNDVA GLEGAKEALK EAVILPIKFP
160 170 180 190 200
HLFTGKRTPW RGILLFGPPG TGKSYLAKAV ATEANNSTFF SVSSSDLMSK
210 220 230 240 250
WLGESEKLVK NLFELARQHK PSIIFIDEVD SLCGSRNENE SEAARRIKTE
260 270 280 290 300
FLVQMQGVGN NNDGTLVLGA TNIPWVLDSA IRRRFEKRIY IPLPEEAARA
310 320 330 340 350
QMFRLHLGST PHNLTDANIH ELARKTEGYS GADISIIVRD SLMQPVRKVQ
360 370 380 390 400
SATHFKKVCG PSRTNPSMMI DDLLTPCSPG DPGAMEMTWM DVPGDKLLEP
410 420 430
VVCMSDMLRS LATTRPTVNA DDLLKVKKFS EDFGQES
Length:437
Mass (Da):48,898
Last modified:May 1, 2000 - v1
Checksum:iC3CC556FB84F105C
GO

Sequence cautioni

The sequence AAL75948 differs from that shown. Reason: Frameshift at positions 123, 133, 157 and 163. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti79 – 791K → E in AAL75948 (Ref. 3) Curated
Sequence conflicti79 – 791K → E in AAF17203 (PubMed:10931946).Curated
Sequence conflicti185 – 1851N → T in AAL75948 (Ref. 3) Curated
Sequence conflicti284 – 2841R → K in AAD42971 (PubMed:15489334).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF255952 mRNA. Translation: AAK52408.1.
AF282903 Genomic DNA. Translation: AAG01470.1.
AF132747 mRNA. Translation: AAL75948.1. Frameshift.
AF159063 mRNA. Translation: AAD49227.1.
AF112215 mRNA. Translation: AAF17203.1.
AK315026 mRNA. Translation: BAG37514.1.
CH471092 Genomic DNA. Translation: EAW83263.1.
BC047932 mRNA. Translation: AAH47932.1.
AF155740 mRNA. Translation: AAD42971.1.
CCDSiCCDS45517.1.
RefSeqiNP_037377.1. NM_013245.2.
UniGeneiHs.128420.

Genome annotation databases

EnsembliENST00000254950; ENSP00000254950; ENSG00000132612.
GeneIDi27183.
KEGGihsa:27183.
UCSCiuc002eww.4. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF255952 mRNA. Translation: AAK52408.1.
AF282903 Genomic DNA. Translation: AAG01470.1.
AF132747 mRNA. Translation: AAL75948.1. Frameshift.
AF159063 mRNA. Translation: AAD49227.1.
AF112215 mRNA. Translation: AAF17203.1.
AK315026 mRNA. Translation: BAG37514.1.
CH471092 Genomic DNA. Translation: EAW83263.1.
BC047932 mRNA. Translation: AAH47932.1.
AF155740 mRNA. Translation: AAD42971.1.
CCDSiCCDS45517.1.
RefSeqiNP_037377.1. NM_013245.2.
UniGeneiHs.128420.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1YXRNMR-A1-77[»]
2JQ9NMR-A1-84[»]
2K3WNMR-A1-84[»]
ProteinModelPortaliQ9UN37.
SMRiQ9UN37. Positions 1-77, 116-436.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118059. 28 interactions.
DIPiDIP-44585N.
IntActiQ9UN37. 15 interactions.
STRINGi9606.ENSP00000254950.

PTM databases

iPTMnetiQ9UN37.
PhosphoSiteiQ9UN37.

Polymorphism and mutation databases

BioMutaiVPS4A.
DMDMi62511240.

Proteomic databases

EPDiQ9UN37.
MaxQBiQ9UN37.
PaxDbiQ9UN37.
PeptideAtlasiQ9UN37.
PRIDEiQ9UN37.

Protocols and materials databases

DNASUi27183.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000254950; ENSP00000254950; ENSG00000132612.
GeneIDi27183.
KEGGihsa:27183.
UCSCiuc002eww.4. human.

Organism-specific databases

CTDi27183.
GeneCardsiVPS4A.
HGNCiHGNC:13488. VPS4A.
HPAiCAB018751.
CAB034411.
MIMi609982. gene.
neXtProtiNX_Q9UN37.
PharmGKBiPA38362.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0739. Eukaryota.
ENOG410XRHN. LUCA.
GeneTreeiENSGT00550000074466.
HOGENOMiHOG000225146.
HOVERGENiHBG057074.
InParanoidiQ9UN37.
KOiK12196.
OMAiNPSMMID.
OrthoDBiEOG091G0Q8J.
PhylomeDBiQ9UN37.
TreeFamiTF105012.

Enzyme and pathway databases

ReactomeiR-HSA-162588. Budding and maturation of HIV virion.
R-HSA-917729. Endosomal Sorting Complex Required For Transport (ESCRT).

Miscellaneous databases

ChiTaRSiVPS4A. human.
EvolutionaryTraceiQ9UN37.
GeneWikiiVPS4A.
GenomeRNAii27183.
PROiQ9UN37.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000132612.
CleanExiHS_VPS4A.
ExpressionAtlasiQ9UN37. baseline and differential.
GenevisibleiQ9UN37. HS.

Family and domain databases

Gene3Di1.20.58.280. 1 hit.
3.40.50.300. 1 hit.
InterProiIPR003593. AAA+_ATPase.
IPR003959. ATPase_AAA_core.
IPR003960. ATPase_AAA_CS.
IPR007330. MIT.
IPR027417. P-loop_NTPase.
IPR015415. Vps4_C.
IPR031255. VPS4A.
[Graphical view]
PANTHERiPTHR23074:SF82. PTHR23074:SF82. 2 hits.
PfamiPF00004. AAA. 1 hit.
PF04212. MIT. 1 hit.
PF09336. Vps4_C. 1 hit.
[Graphical view]
SMARTiSM00382. AAA. 1 hit.
SM00745. MIT. 1 hit.
[Graphical view]
SUPFAMiSSF116846. SSF116846. 1 hit.
SSF52540. SSF52540. 1 hit.
PROSITEiPS00674. AAA. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiVPS4A_HUMAN
AccessioniPrimary (citable) accession number: Q9UN37
Secondary accession number(s): B2RCB7
, Q8TF07, Q9UI03, Q9Y582
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: May 1, 2000
Last modified: September 7, 2016
This is version 150 of the entry and version 1 of the sequence. [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. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.