Vacuolar protein sorting-associated protein 4A (VPS4A)
The protein contains 437 amino acids for an estimated molecular weight of 48898 Da.
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. 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).', '(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). (updated: April 7, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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Biological Process
Abscission
Actomyosin contractile ring contraction
Cell division
Cytoskeleton-dependent cytokinesis
Endosomal transport
Endosomal vesicle fusion
ESCRT complex disassembly
ESCRT III complex disassembly
Intracellular cholesterol transport
Late endosomal microautophagy
Macroautophagy
Membrane organization
Midbody abscission
Mitotic cytokinesis checkpoint signaling
Mitotic metaphase plate congression
Mitotic nuclear membrane reassembly
Multivesicular body assembly
Negative regulation of cytokinesis
Nuclear envelope organization
Nuclear membrane reassembly
Nucleus organization
Positive regulation of exosomal secretion
Positive regulation of viral budding via host ESCRT complex
Positive regulation of viral life cycle
Positive regulation of viral release from host cell
Protein targeting to lysosome
Protein transport
Regulation of protein localization
Regulation of protein localization to plasma membrane
Septum digestion after cytokinesis
Ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
Ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway
Vacuole organization
Vesicle budding from membrane
Vesicle uncoating
Vesicle-mediated transport
Viral budding via host ESCRT complex
Viral life cycle
Viral process
Viral release from host cell
The reference OMIM entry for this protein is 609982
Vacuolar protein sorting 4, yeast, homolog of, a; vps4a
Vps4
DESCRIPTION
VPS4A belongs to the AAA (ATPases associated with diverse cellular activities) protein family and is involved in lysosomal/endosomal membrane trafficking (Beyer et al., 2003).CLONING
By searching databases for proteins similar to yeast Vps4, Bishop and Woodman (2000) identified an EST for VPS4A, which they called VPS4, that had been isolated from a human brain cDNA library. The deduced 432-amino acid protein contains an N-terminal coiled-coil domain and a central AAA domain. Fluorescence-tagged VPS4 was expressed in the cytosol of transfected rat kidney cells. By searching for ESTs similar to yeast Vps4, followed by screening a human keratinocyte cell line cDNA library, Scheuring et al. (2001) cloned VPS4A. The deduced 437-amino acid protein has 5 additional N-terminal amino acids compared with the VPS4A protein reported by Bishop and Woodman (2000). VPS4A shares 80% amino acid identity with VPS4B (609983) and 59% identity with yeast Vps4. Northern blot analysis detected a ubiquitously expressed 2.3-kb transcript. Using Northern blot analysis, Beyer et al. (2003) found that mouse Vps4a and Vps4b were variably expressed in all tissues examined. Most tissues showed a strong bias for one or the other Vps4, but some expressed both equally.GENE FUNCTION
By transient expression in rodent kidney cells, Bishop and Woodman (2000) found that ATPase-defective mutants of human VPS4 localized to membranes, including those of endocytic vacuoles, and induced endosomal vacuolation. Many endosomal vacuoles induced by VPS4 mutants were substantially enriched in cholesterol relative to the endosomal compartments of untransfected cells. Mutant VPS4 did not associate with Golgi or endoplasmic reticulum membranes or with cell surface membranes recycling to the trans-Golgi, nor did it alter their function. Bishop and Woodman (2000) concluded that VPS4 is involved in postendosomal cholesterol sorting. Scheuring et al. (2001) found that heterologous expression of human VPS4A in Vps4-null yeast partially suppressed the temperature-sensitive growth defect and partly complemented the vacuolar protein sorting defect. VPS4A distributed throughout the cytosol of transfected wildtype yeast and occasionally concentrated in small dots close to vacuoles. VPS4A with a glu228-to-gln (E228Q) mutation within the AAA domain induced dominant-negative vacuolar protein sorting defects in wildtype yeast cells. Two-hybrid experiments suggested that VPS4A and VPS4B could form heteromeric complexes, and the interaction was stronger if dominant-negative mutants were involved. Neither protein formed homomeric complexes. Lata et al. (2008) found that the endosomal sorting complex required for transport (ESCRT)-III proteins CHMP2A (610893) and CHMP3 (610052) (charged multivesicular body proteins 2A and 3) could assemble in vitro into helical tubular structures that expose their membrane-interaction sites on the outside of the tubule, whereas the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. CHMP2A and CHMP3 copolymerized in solution, and their membrane targeting was cooperatively enhanced on planar lipid bilayers. Lata et al. (2008) concluded that such helical CHMP structures could thus assemble within the neck of an inwardly budding vesicle, catalyzing late steps in budding under the control of VPS4. Using yeast 2-hybrid screens, followed by c ... More on the omim web site
April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 609982 was added.
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed