Q9UN37 · VPS4A_HUMAN
- ProteinVacuolar protein sorting-associated protein 4A
- GeneVPS4A
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids437 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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. It is required for proper accomplishment of various processes including the regulation of endosome size, primary cilium organization, mitotic spindle organization, chromosome segregation, and nuclear envelope sealing and spindle disassembly during anaphase (PubMed:33186545).
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).
Critical for normal erythroblast cytokinesis and correct erythropoiesis (PubMed:33186543).
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).
Critical for normal erythroblast cytokinesis and correct erythropoiesis (PubMed:33186543).
(Microbial infection) 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).
Catalytic activity
- ATP + H2O = ADP + H+ + phosphate
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameVacuolar protein sorting-associated protein 4A
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9UN37
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Late endosome membrane ; Peripheral membrane protein
Note: Membrane-associated in the prevacuolar endosomal compartment. Localizes to the midbody of dividing cells, interaction with ZFYVE19/ANCHR mediates retention at midbody (PubMed:24814515).
Localized in two distinct rings on either side of the Flemming body
Localized in two distinct rings on either side of the Flemming body
Keywords
- Cellular component
Disease & Variants
Involvement in disease
CIMDAG syndrome (CIMDAG)
- Note
- DescriptionAn autosomal dominant syndrome characterized by global developmental delay, severely impaired intellectual development, poor or absent speech, microcephaly, growth retardation, poor motor skills with inability to walk, hypotonia and spasticity, and cataracts. Cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination are apparent on brain imaging. Affected individuals show hematologic abnormalities mostly consistent with congenital dyserythropoietic anemia.
- See alsoMIM:619273
Natural variants in CIMDAG
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_085594 | 28 | A>V | in CIMDAG; uncertain significance; dbSNP:rs1965431981 | |
VAR_085596 | 203 | G>E | in CIMDAG; patient peripheral red blood cells show abnormal CD71 expression indicating defective endosomal trafficking; dbSNP:rs1965484288 | |
VAR_085597 | 206 | E>K | in CIMDAG | |
VAR_085598 | 284 | R>G | in CIMDAG; has a dominant negative effect on the regulation of endosomal size resulting in enlarged endosomal vacuoles; patient cells also have abnormal nuclear envelope morphology and primary cilium defects; no effect on protein abundance in patient cells; dbSNP:rs1965499910 | |
VAR_085599 | 284 | R>W | in CIMDAG; has a dominant negative effect on the regulation of endosomal size resulting in enlarged endosomal vacuoles; patient cells also have abnormal nuclear envelope morphology and primary cilium defects; no effect on protein abundance in patient cells; patient-derived induced erythroblasts show defective cytokinesis; dbSNP:rs1965499910 |
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 13 | Diminishes interaction with IST1. | ||||
Sequence: V → A or D | ||||||
Mutagenesis | 13 | Abolishes interaction with CHMP6, no effect on interaction with CHMP1A. | ||||
Sequence: V → D | ||||||
Mutagenesis | 13 | Greatly diminishes localization to punctate class E compartments; when associated with Q-173. | ||||
Sequence: V → D | ||||||
Natural variant | VAR_085594 | 28 | in CIMDAG; uncertain significance; dbSNP:rs1965431981 | |||
Sequence: A → V | ||||||
Mutagenesis | 64 | Abolishes interaction with CHMP1B; diminishes interaction with IST1. | ||||
Sequence: L → A or D | ||||||
Mutagenesis | 64 | Greatly diminishes localization to punctate class E compartments and partially restores HIV-1 release; when associated with Q-173. | ||||
Sequence: L → D | ||||||
Mutagenesis | 64 | Modestly reduces interaction with CHMP6. | ||||
Sequence: L → D | ||||||
Mutagenesis | 68 | Diminishes interaction with CHMP1B. | ||||
Sequence: E → D | ||||||
Natural variant | VAR_085595 | 168 | found in a patient with non-specific intellectual disability; uncertain significance | |||
Sequence: Missing | ||||||
Mutagenesis | 173 | 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. | ||||
Sequence: K → Q | ||||||
Natural variant | VAR_078655 | 193 | found in a patient with a CIMDAG-like intellectual disability syndrome; uncertain significance | |||
Sequence: Missing | ||||||
Mutagenesis | 201-202 | Strongly impairs HIV-1 release. | ||||
Sequence: WL → AA | ||||||
Natural variant | VAR_085596 | 203 | in CIMDAG; patient peripheral red blood cells show abnormal CD71 expression indicating defective endosomal trafficking; dbSNP:rs1965484288 | |||
Sequence: G → E | ||||||
Mutagenesis | 203 | Impairs HIV-1 release. | ||||
Sequence: G → A | ||||||
Natural variant | VAR_085597 | 206 | in CIMDAG | |||
Sequence: E → K | ||||||
Mutagenesis | 228 | 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. | ||||
Sequence: E → Q | ||||||
Natural variant | VAR_085598 | 284 | in CIMDAG; has a dominant negative effect on the regulation of endosomal size resulting in enlarged endosomal vacuoles; patient cells also have abnormal nuclear envelope morphology and primary cilium defects; no effect on protein abundance in patient cells; dbSNP:rs1965499910 | |||
Sequence: R → G | ||||||
Natural variant | VAR_085599 | 284 | in CIMDAG; has a dominant negative effect on the regulation of endosomal size resulting in enlarged endosomal vacuoles; patient cells also have abnormal nuclear envelope morphology and primary cilium defects; no effect on protein abundance in patient cells; patient-derived induced erythroblasts show defective cytokinesis; dbSNP:rs1965499910 | |||
Sequence: R → W | ||||||
Natural variant | VAR_085600 | 337 | found in a patient with non-specific intellectual disability; uncertain significance | |||
Sequence: I → V |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 391 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000084765 | 1-437 | UniProt | Vacuolar protein sorting-associated protein 4A | |||
Sequence: MTTSTLQKAIDLVTKATEEDKAKNYEEALRLYQHAVEYFLHAIKYEAHSDKAKESIRAKCVQYLDRAEKLKDYLRSKEKHGKKPVKENQSEGKGSDSDSEGDNPEKKKLQEQLMGAVVMEKPNIRWNDVAGLEGAKEALKEAVILPIKFPHLFTGKRTPWRGILLFGPPGTGKSYLAKAVATEANNSTFFSVSSSDLMSKWLGESEKLVKNLFELARQHKPSIIFIDEVDSLCGSRNENESEAARRIKTEFLVQMQGVGNNNDGTLVLGATNIPWVLDSAIRRRFEKRIYIPLPEEAARAQMFRLHLGSTPHNLTDANIHELARKTEGYSGADISIIVRDSLMQPVRKVQSATHFKKVCGPSRTNPSMMIDDLLTPCSPGDPGAMEMTWMDVPGDKLLEPVVCMSDMLRSLATTRPTVNADDLLKVKKFSEDFGQES | |||||||
Modified residue | 8 | UniProt | N6-acetyllysine | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 90 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 95 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 95 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 97 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 97 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 99 | PRIDE | Phosphoserine | ||||
Sequence: S |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Ubiquitously expressed.
Gene expression databases
Organism-specific databases
Interaction
Subunit
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
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
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9UN37 | CFTR P13569 | 9 | EBI-1171942, EBI-349854 | |
BINARY | Q9UN37 | CHMP1A Q9HD42 | 8 | EBI-1171942, EBI-1057156 | |
BINARY | Q9UN37 | CHMP1A Q9HD42-1 | 2 | EBI-1171942, EBI-15663713 | |
BINARY | Q9UN37 | CHMP1B Q7LBR1 | 4 | EBI-1171942, EBI-2118090 | |
BINARY | Q9UN37 | CHMP2A O43633 | 4 | EBI-1171942, EBI-2692789 | |
BINARY | Q9UN37 | CLIC3 O95833 | 3 | EBI-1171942, EBI-10192241 | |
BINARY | Q9UN37 | ZFYVE19 Q96K21-1 | 3 | EBI-1171942, EBI-16106990 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-84 | Interaction with CHMP1B | ||||
Sequence: MTTSTLQKAIDLVTKATEEDKAKNYEEALRLYQHAVEYFLHAIKYEAHSDKAKESIRAKCVQYLDRAEKLKDYLRSKEKHGKKP | ||||||
Domain | 2-80 | MIT | ||||
Sequence: TTSTLQKAIDLVTKATEEDKAKNYEEALRLYQHAVEYFLHAIKYEAHSDKAKESIRAKCVQYLDRAEKLKDYLRSKEKH | ||||||
Region | 75-106 | Disordered | ||||
Sequence: RSKEKHGKKPVKENQSEGKGSDSDSEGDNPEK |
Domain
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).
Sequence similarities
Belongs to the AAA ATPase family.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length437
- Mass (Da)48,898
- Last updated2000-05-01 v1
- ChecksumC3CC556FB84F105C
Computationally mapped potential isoform sequences
There are 12 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0AAQ5BI38 | A0AAQ5BI38_HUMAN | VPS4A | 185 | ||
A0AAQ5BI50 | A0AAQ5BI50_HUMAN | VPS4A | 324 | ||
A0AAQ5BI51 | A0AAQ5BI51_HUMAN | VPS4A | 222 | ||
A0AAQ5BI54 | A0AAQ5BI54_HUMAN | VPS4A | 375 | ||
A0AAQ5BI57 | A0AAQ5BI57_HUMAN | VPS4A | 41 | ||
A0AAQ5BI29 | A0AAQ5BI29_HUMAN | VPS4A | 436 | ||
A0AAQ5BI15 | A0AAQ5BI15_HUMAN | VPS4A | 360 | ||
A0AAQ5BI89 | A0AAQ5BI89_HUMAN | VPS4A | 396 | ||
A0AAQ5BI04 | A0AAQ5BI04_HUMAN | VPS4A | 357 | ||
A0AAQ5BI05 | A0AAQ5BI05_HUMAN | VPS4A | 364 | ||
A0AAQ5BI14 | A0AAQ5BI14_HUMAN | VPS4A | 56 | ||
A0AAQ5BI17 | A0AAQ5BI17_HUMAN | VPS4A | 94 |
Sequence caution
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 79 | in Ref. 3; AAL75948 and 5; AAF17203 | ||||
Sequence: K → E | ||||||
Sequence conflict | 185 | in Ref. 3; AAL75948 | ||||
Sequence: N → T | ||||||
Sequence conflict | 284 | in Ref. 8; AAD42971 | ||||
Sequence: R → K |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF255952 EMBL· GenBank· DDBJ | AAK52408.1 EMBL· GenBank· DDBJ | mRNA | ||
AF282903 EMBL· GenBank· DDBJ | AAG01470.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF132747 EMBL· GenBank· DDBJ | AAL75948.1 EMBL· GenBank· DDBJ | mRNA | Frameshift | |
AF159063 EMBL· GenBank· DDBJ | AAD49227.1 EMBL· GenBank· DDBJ | mRNA | ||
AF112215 EMBL· GenBank· DDBJ | AAF17203.1 EMBL· GenBank· DDBJ | mRNA | ||
AK315026 EMBL· GenBank· DDBJ | BAG37514.1 EMBL· GenBank· DDBJ | mRNA | ||
CH471092 EMBL· GenBank· DDBJ | EAW83263.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC047932 EMBL· GenBank· DDBJ | AAH47932.1 EMBL· GenBank· DDBJ | mRNA | ||
AF155740 EMBL· GenBank· DDBJ | AAD42971.1 EMBL· GenBank· DDBJ | mRNA |