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Protein

Vacuolar protein sorting-associated protein 4A

Gene

VPS4A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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)DescriptionActionsGraphical viewLength
Nucleotide bindingi167 – 174ATPCurated8

GO - Molecular functioni

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

GO - Biological processi

Keywordsi

Molecular functionHydrolase
Biological processCell cycle, Cell division, Protein transport, Transport
LigandATP-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

EuPathDBiHostDB:ENSG00000132612.15
HGNCiHGNC:13488 VPS4A
MIMi609982 gene
neXtProtiNX_Q9UN37

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

Endosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi13V → A or D: Diminishes interaction with IST1. 2 Publications1
Mutagenesisi13V → D: Abolishes interaction with CHMP6, no effect on interaction with CHMP1A. 2 Publications1
Mutagenesisi13V → D: Greatly diminishes localization to punctate class E compartments; when associated with Q-173. 2 Publications1
Mutagenesisi64L → A or D: Abolishes interaction with CHMP1B; diminishes interaction with IST1. 5 Publications1
Mutagenesisi64L → D: Greatly diminishes localization to punctate class E compartments and partially restores HIV-1 release; when associated with Q-173. 5 Publications1
Mutagenesisi64L → D: Modestly reduces interaction with CHMP6. 5 Publications1
Mutagenesisi68E → D: Diminishes interaction with CHMP1B. 1 Publication1
Mutagenesisi173K → 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 Publications1
Mutagenesisi201 – 202WL → AA: Strongly impairs HIV-1 release. 1 Publication2
Mutagenesisi203G → A: Impairs HIV-1 release. 1 Publication1
Mutagenesisi228E → 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 Publications1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi27183
OpenTargetsiENSG00000132612
PharmGKBiPA38362

Polymorphism and mutation databases

BioMutaiVPS4A
DMDMi62511240

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000847651 – 437Vacuolar protein sorting-associated protein 4AAdd BLAST437

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei8N6-acetyllysineCombined sources1
Modified residuei95PhosphoserineBy similarity1
Modified residuei97PhosphoserineBy similarity1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ9UN37
MaxQBiQ9UN37
PaxDbiQ9UN37
PeptideAtlasiQ9UN37
PRIDEiQ9UN37
ProteomicsDBi85248

PTM databases

iPTMnetiQ9UN37
PhosphoSitePlusiQ9UN37

Expressioni

Tissue specificityi

Ubiquitously expressed.2 Publications

Gene expression databases

BgeeiENSG00000132612 Expressed in 228 organ(s), highest expression level in vagina
CleanExiHS_VPS4A
ExpressionAtlasiQ9UN37 baseline and differential
GenevisibleiQ9UN37 HS

Organism-specific databases

HPAiCAB018751
CAB034411
HPA060092

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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi118059, 45 interactors
ComplexPortaliCPX-338 VPS4A/B complex
DIPiDIP-44585N
IntActiQ9UN37, 22 interactors
MINTiQ9UN37
STRINGi9606.ENSP00000254950

Structurei

Secondary structure

1437
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9UN37
SMRiQ9UN37
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9UN37

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini2 – 80MITAdd BLAST79

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 84Interaction with CHMP1BAdd BLAST84

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

Phylogenomic databases

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

Family and domain databases

InterProiView protein in InterPro
IPR003593 AAA+_ATPase
IPR003959 ATPase_AAA_core
IPR003960 ATPase_AAA_CS
IPR007330 MIT
IPR036181 MIT_dom_sf
IPR027417 P-loop_NTPase
IPR015415 Vps4_C
PfamiView protein in Pfam
PF00004 AAA, 1 hit
PF04212 MIT, 1 hit
PF09336 Vps4_C, 1 hit
SMARTiView protein in SMART
SM00382 AAA, 1 hit
SM00745 MIT, 1 hit
SUPFAMiSSF116846 SSF116846, 1 hit
SSF52540 SSF52540, 1 hit
PROSITEiView protein in PROSITE
PS00674 AAA, 1 hit

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)DescriptionActionsGraphical viewLength
Sequence conflicti79K → E in AAL75948 (Ref. 3) Curated1
Sequence conflicti79K → E in AAF17203 (PubMed:10931946).Curated1
Sequence conflicti185N → T in AAL75948 (Ref. 3) Curated1
Sequence conflicti284R → K in AAD42971 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_078655193Missing Probable disease-associated mutation found in a patient with severe intellecutal disabillity and microcephaly. 1 Publication1

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

Similar proteinsi

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
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1YXRNMR-A1-77[»]
2JQ9NMR-A1-84[»]
2K3WNMR-A1-84[»]
ProteinModelPortaliQ9UN37
SMRiQ9UN37
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118059, 45 interactors
ComplexPortaliCPX-338 VPS4A/B complex
DIPiDIP-44585N
IntActiQ9UN37, 22 interactors
MINTiQ9UN37
STRINGi9606.ENSP00000254950

PTM databases

iPTMnetiQ9UN37
PhosphoSitePlusiQ9UN37

Polymorphism and mutation databases

BioMutaiVPS4A
DMDMi62511240

Proteomic databases

EPDiQ9UN37
MaxQBiQ9UN37
PaxDbiQ9UN37
PeptideAtlasiQ9UN37
PRIDEiQ9UN37
ProteomicsDBi85248

Protocols and materials databases

DNASUi27183
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi27183
DisGeNETi27183
EuPathDBiHostDB:ENSG00000132612.15
GeneCardsiVPS4A
HGNCiHGNC:13488 VPS4A
HPAiCAB018751
CAB034411
HPA060092
MIMi609982 gene
neXtProtiNX_Q9UN37
OpenTargetsiENSG00000132612
PharmGKBiPA38362
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0739 Eukaryota
ENOG410XRHN LUCA
GeneTreeiENSGT00550000074466
HOGENOMiHOG000225146
HOVERGENiHBG057074
InParanoidiQ9UN37
KOiK12196
OMAiVKQLFTM
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
PROiPR:Q9UN37
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000132612 Expressed in 228 organ(s), highest expression level in vagina
CleanExiHS_VPS4A
ExpressionAtlasiQ9UN37 baseline and differential
GenevisibleiQ9UN37 HS

Family and domain databases

InterProiView protein in InterPro
IPR003593 AAA+_ATPase
IPR003959 ATPase_AAA_core
IPR003960 ATPase_AAA_CS
IPR007330 MIT
IPR036181 MIT_dom_sf
IPR027417 P-loop_NTPase
IPR015415 Vps4_C
PfamiView protein in Pfam
PF00004 AAA, 1 hit
PF04212 MIT, 1 hit
PF09336 Vps4_C, 1 hit
SMARTiView protein in SMART
SM00382 AAA, 1 hit
SM00745 MIT, 1 hit
SUPFAMiSSF116846 SSF116846, 1 hit
SSF52540 SSF52540, 1 hit
PROSITEiView protein in PROSITE
PS00674 AAA, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiVPS4A_HUMAN
AccessioniPrimary (citable) accession number: Q9UN37
Secondary accession number(s): B2RCB7
, Q8TF07, Q9UI03, Q9Y582
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: May 1, 2000
Last modified: November 7, 2018
This is version 171 of the entry and version 1 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. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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