VPS4A_HUMAN
ID VPS4A_HUMAN Reviewed; 437 AA.
AC Q9UN37; B2RCB7; Q8TF07; Q9UI03; Q9Y582;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 194.
DE RecName: Full=Vacuolar protein sorting-associated protein 4A {ECO:0000305};
DE EC=3.6.4.6 {ECO:0000250|UniProtKB:O75351};
DE AltName: Full=Protein SKD2;
DE AltName: Full=VPS4-1;
DE Short=hVPS4;
GN Name=VPS4A {ECO:0000312|EMBL:AAG01470.1};
GN Synonyms=VPS4 {ECO:0000312|EMBL:AAD42971.1};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000305, ECO:0000312|EMBL:AAK52408.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, INTERACTION WITH VPS4B, AND MUTAGENESIS OF GLU-228.
RC TISSUE=Keratinocyte;
RX PubMed=11563910; DOI=10.1006/jmbi.2001.4917;
RA Scheuring S., Roehricht R.A., Schoening-Burkhardt B., Beyer A., Mueller S.,
RA Abts H.F., Koehrer K.;
RT "Mammalian cells express two VPS4 proteins both of which are involved in
RT intracellular protein trafficking.";
RL J. Mol. Biol. 312:469-480(2001).
RN [2] {ECO:0000312|EMBL:AAG01470.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=12594041; DOI=10.1016/s0378-1119(02)01205-2;
RA Beyer A., Scheuring S., Mueller S., Mincheva A., Lichter P., Koehrer K.;
RT "Comparative sequence and expression analyses of four mammalian VPS4
RT genes.";
RL Gene 305:47-59(2003).
RN [3] {ECO:0000312|EMBL:AAL75948.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Ding J.B., Yu L., Zhao S.Y.;
RT "Cloning of a new human cDNA homologous to Homo sapiens SKD1 protein.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0000312|EMBL:AAL75948.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Heart;
RA Patejunas G.;
RT "Isolation of a homolog of SKD1.";
RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases.
RN [5] {ECO:0000312|EMBL:AAF17203.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Hypothalamus {ECO:0000312|EMBL:AAF17203.1};
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W.,
RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J.,
RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z.,
RA Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis
RT and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7] {ECO:0000312|EMBL:AAL75948.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8] {ECO:0000312|EMBL:AAH47932.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9] {ECO:0000305, ECO:0000312|EMBL:AAD42971.1}
RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-437, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF LYS-173 AND GLU-228.
RC TISSUE=Brain {ECO:0000312|EMBL:AAD42971.1};
RX PubMed=10637304; DOI=10.1091/mbc.11.1.227;
RA Bishop N., Woodman P.;
RT "ATPase-defective mammalian VPS4 localizes to aberrant endosomes and
RT impairs cholesterol trafficking.";
RL Mol. Biol. Cell 11:227-239(2000).
RN [10]
RP FUNCTION IN VIRUS RELEASE, AND MUTAGENESIS OF LYS-173 AND GLU-228.
RX PubMed=11595185; DOI=10.1016/s0092-8674(01)00506-2;
RA Garrus J.E., von Schwedler U.K., Pornillos O.W., Morham S.G., Zavitz K.H.,
RA Wang H.E., Wettstein D.A., Stray K.M., Cote M., Rich R.L., Myszka D.G.,
RA Sundquist W.I.;
RT "Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1
RT budding.";
RL Cell 107:55-65(2001).
RN [11] {ECO:0000305}
RP INTERACTION WITH CHMP1A, AND MUTAGENESIS OF GLU-228.
RX PubMed=11559748; DOI=10.1242/jcs.114.13.2395;
RA Howard T.L., Stauffer D.R., Degnin C.R., Hollenberg S.M.;
RT "CHMP1 functions as a member of a newly defined family of vesicle
RT trafficking proteins.";
RL J. Cell Sci. 114:2395-2404(2001).
RN [12] {ECO:0000305}
RP INTERACTION WITH CHMP1A; CHMP1B; CHMP2A; CHMP4A; CHMP4B; CHMP4C AND CHMP6.
RX PubMed=14505570; DOI=10.1016/s0092-8674(03)00714-1;
RA von Schwedler U.K., Stuchell M., Mueller B., Ward D.M., Chung H.-Y.,
RA Morita E., Wang H.E., Davis T., He G.P., Cimbora D.M., Scott A.,
RA Kraeusslich H.-G., Kaplan J., Morham S.G., Sundquist W.I.;
RT "The protein network of HIV budding.";
RL Cell 114:701-713(2003).
RN [13]
RP INTERACTION WITH CHMP1A; CHMP1B; CHMP2A; CHMP2B AND CHMP3.
RX PubMed=14519844; DOI=10.1073/pnas.2133846100;
RA Martin-Serrano J., Yarovoy A., Perez-Caballero D., Bieniasz P.D.;
RT "Divergent retroviral late-budding domains recruit vacuolar protein sorting
RT factors by using alternative adaptor proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:12414-12419(2003).
RN [14]
RP ERRATUM OF PUBMED:14519844.
RA Martin-Serrano J., Yarovoy A., Perez-Caballero D., Bieniasz P.D.;
RL Proc. Natl. Acad. Sci. U.S.A. 100:152845-152845(2003).
RN [15] {ECO:0000305}
RP FUNCTION, AND MUTAGENESIS OF GLU-228.
RX PubMed=15075231; DOI=10.1242/jcs.00998;
RA Sachse M., Strous G.J., Klumperman J.;
RT "ATPase-deficient hVPS4 impairs formation of internal endosomal vesicles
RT and stabilizes bilayered clathrin coats on endosomal vacuoles.";
RL J. Cell Sci. 117:1699-1708(2004).
RN [16]
RP MUTAGENESIS OF 201-TRP-LEU-202 AND GLY-203.
RX PubMed=16193069; DOI=10.1038/sj.emboj.7600818;
RA Scott A., Chung H.Y., Gonciarz-Swiatek M., Hill G.C., Whitby F.G.,
RA Gaspar J., Holton J.M., Viswanathan R., Ghaffarian S., Hill C.P.,
RA Sundquist W.I.;
RT "Structural and mechanistic studies of VPS4 proteins.";
RL EMBO J. 24:3658-3669(2005).
RN [17]
RP SUBCELLULAR LOCATION.
RX PubMed=17853893; DOI=10.1038/sj.emboj.7601850;
RA Morita E., Sandrin V., Chung H.Y., Morham S.G., Gygi S.P., Rodesch C.K.,
RA Sundquist W.I.;
RT "Human ESCRT and ALIX proteins interact with proteins of the midbody and
RT function in cytokinesis.";
RL EMBO J. 26:4215-4227(2007).
RN [18]
RP INTERACTION WITH SPAST.
RX PubMed=18997780; DOI=10.1038/nsmb.1512;
RA Yang D., Rismanchi N., Renvoise B., Lippincott-Schwartz J., Blackstone C.,
RA Hurley J.H.;
RT "Structural basis for midbody targeting of spastin by the ESCRT-III protein
RT CHMP1B.";
RL Nat. Struct. Mol. Biol. 15:1278-1286(2008).
RN [19]
RP INTERACTION WITH IST1, AND MUTAGENESIS OF LEU-64.
RX PubMed=19129480; DOI=10.1091/mbc.e08-05-0474;
RA Agromayor M., Carlton J.G., Phelan J.P., Matthews D.R., Carlin L.M.,
RA Ameer-Beg S., Bowers K., Martin-Serrano J.;
RT "Essential role of hIST1 in cytokinesis.";
RL Mol. Biol. Cell 20:1374-1387(2009).
RN [20]
RP INTERACTION WITH IST1, AND MUTAGENESIS OF VAL-13 AND LEU-64.
RX PubMed=19129479; DOI=10.1091/mbc.e08-05-0475;
RA Bajorek M., Morita E., Skalicky J.J., Morham S.G., Babst M.,
RA Sundquist W.I.;
RT "Biochemical analyses of human IST1 and its function in cytokinesis.";
RL Mol. Biol. Cell 20:1360-1373(2009).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-8, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [23]
RP INTERACTION WITH CHMP1B; CHMP2A; CHMP3; CHMP4B AND CHMP6.
RX PubMed=21543490; DOI=10.1128/jvi.02610-10;
RA Kuang Z., Seo E.J., Leis J.;
RT "Mechanism of inhibition of retrovirus release from cells by interferon-
RT induced gene ISG15.";
RL J. Virol. 85:7153-7161(2011).
RN [24]
RP FUNCTION.
RX PubMed=22660413; DOI=10.1038/ncb2502;
RA Baietti M.F., Zhang Z., Mortier E., Melchior A., Degeest G., Geeraerts A.,
RA Ivarsson Y., Depoortere F., Coomans C., Vermeiren E., Zimmermann P.,
RA David G.;
RT "Syndecan-syntenin-ALIX regulates the biogenesis of exosomes.";
RL Nat. Cell Biol. 14:677-685(2012).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH ZFYVE19.
RX PubMed=24814515; DOI=10.1038/ncb2959;
RA Thoresen S.B., Campsteijn C., Vietri M., Schink K.O., Liestoel K.,
RA Andersen J.S., Raiborg C., Stenmark H.;
RT "ANCHR mediates Aurora-B-dependent abscission checkpoint control through
RT retention of VPS4.";
RL Nat. Cell Biol. 16:550-560(2014).
RN [26]
RP STRUCTURE BY NMR OF 1-77, INTERACTION WITH CHMP1B, AND MUTAGENESIS OF
RP LEU-64 AND GLU-68.
RX PubMed=16174732; DOI=10.1073/pnas.0502165102;
RA Scott A., Gaspar J., Stuchell-Brereton M.D., Alam S.L., Skalicky J.J.,
RA Sundquist W.I.;
RT "Structure and ESCRT-III protein interactions of the MIT domain of human
RT VPS4A.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:13813-13818(2005).
RN [27]
RP STRUCTURE BY NMR OF 1-84 IN COMPLEX WITH CHMP1A, INTERACTION WITH CHMP2B,
RP AND MUTAGENESIS OF LEU-64 AND LYS-173.
RX PubMed=17928862; DOI=10.1038/nature06172;
RA Stuchell-Brereton M.D., Skalicky J.J., Kieffer C., Karren M.A.,
RA Ghaffarian S., Sundquist W.I.;
RT "ESCRT-III recognition by VPS4 ATPases.";
RL Nature 449:740-744(2007).
RN [28]
RP STRUCTURE BY NMR OF 1-84 IN COMPLEX WITH CHMP6, INTERACTION WITH CHMP1A,
RP AND MUTAGENESIS OF VAL-13; LEU-64 AND LYS-173.
RX PubMed=18606141; DOI=10.1016/j.devcel.2008.05.014;
RA Kieffer C., Skalicky J.J., Morita E., De Domenico I., Ward D.M., Kaplan J.,
RA Sundquist W.I.;
RT "Two distinct modes of ESCRT-III recognition are required for VPS4
RT functions in lysosomal protein targeting and HIV-1 budding.";
RL Dev. Cell 15:62-73(2008).
RN [29]
RP VARIANT SER-193 DEL.
RX PubMed=25356899; DOI=10.1371/journal.pgen.1004772;
RA Hamdan F.F., Srour M., Capo-Chichi J.M., Daoud H., Nassif C., Patry L.,
RA Massicotte C., Ambalavanan A., Spiegelman D., Diallo O., Henrion E.,
RA Dionne-Laporte A., Fougerat A., Pshezhetsky A.V., Venkateswaran S.,
RA Rouleau G.A., Michaud J.L.;
RT "De novo mutations in moderate or severe intellectual disability.";
RL PLoS Genet. 10:E1004772-E1004772(2014).
RN [30]
RP VARIANTS CIMDAG LYS-206; GLY-284 AND TRP-284, CHARACTERIZATION OF VARIANTS
RP CIMDAG GLY-284 AND TRP-284, INVOLVEMENT IN CIMDAG, VARIANTS PRO-168 DEL AND
RP VAL-337, AND FUNCTION.
RX PubMed=33186545; DOI=10.1016/j.ajhg.2020.10.012;
RG Genomics England Research Consortium;
RA Rodger C., Flex E., Allison R.J., Sanchis-Juan A., Hasenahuer M.A.,
RA Cecchetti S., French C.E., Edgar J.R., Carpentieri G., Ciolfi A.,
RA Pantaleoni F., Bruselles A., Onesimo R., Zampino G., Marcon F.,
RA Siniscalchi E., Lees M., Krishnakumar D., McCann E., Yosifova D.,
RA Jarvis J., Kruer M.C., Marks W., Campbell J., Allen L.E., Gustincich S.,
RA Raymond F.L., Tartaglia M., Reid E.;
RT "De Novo VPS4A mutations cause multisystem disease with abnormal
RT neurodevelopment.";
RL Am. J. Hum. Genet. 107:1129-1148(2020).
RN [31]
RP VARIANTS CIMDAG VAL-28; GLU-203 AND TRP-284, INVOLVEMENT IN CIMDAG,
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=33186543; DOI=10.1016/j.ajhg.2020.10.013;
RA Seu K.G., Trump L.R., Emberesh S., Lorsbach R.B., Johnson C., Meznarich J.,
RA Underhill H.R., Chou S.T., Sakthivel H., Nassar N.N., Seu K.J., Blanc L.,
RA Zhang W., Lutzko C.M., Kalfa T.A.;
RT "VPS4A mutations in humans cause syndromic congenital dyserythropoietic
RT anemia due to cytokinesis and trafficking defects.";
RL Am. J. Hum. Genet. 107:1149-1156(2020).
RN [32]
RP VARIANT CIMDAG TRP-284.
RX PubMed=33460484; DOI=10.1002/ajh.26099;
RA Lunati A., Petit A., Lapillonne H., Gameiro C., Saillour V., Garel C.,
RA Doummar D., Qebibo L., Aissat A., Fanen P., Bartolucci P., Galacteros F.,
RA Funalot B., Burglen L., Mansour-Hendili L.;
RT "VPS4A mutation in syndromic congenital hemolytic anemia without obvious
RT signs of dyserythropoiesis.";
RL Am. J. Hematol. 96:E121-E123(2021).
CC -!- FUNCTION: Involved in late steps of the endosomal multivesicular bodies
CC (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and
CC catalyzes their disassembly, possibly in combination with membrane
CC fission. Redistributes the ESCRT-III components to the cytoplasm for
CC further rounds of MVB sorting. MVBs contain intraluminal vesicles
CC (ILVs) that are generated by invagination and scission from the
CC limiting membrane of the endosome and mostly are delivered to lysosomes
CC enabling degradation of membrane proteins, such as stimulated growth
CC factor receptors, lysosomal enzymes and lipids. It is required for
CC proper accomplishment of various processes including the regulation of
CC endosome size, primary cilium organization, mitotic spindle
CC organization, chromosome segregation, and nuclear envelope sealing and
CC spindle disassembly during anaphase (PubMed:33186545). Involved in
CC cytokinesis: retained at the midbody by ZFYVE19/ANCHR and CHMP4C until
CC abscission checkpoint signaling is terminated at late cytokinesis. It
CC is then released following dephosphorylation of CHMP4C, leading to
CC abscission (PubMed:24814515). VPS4A/B are required for the exosomal
CC release of SDCBP, CD63 and syndecan (PubMed:22660413). Critical for
CC normal erythroblast cytokinesis and correct erythropoiesis
CC (PubMed:33186543). {ECO:0000269|PubMed:11563910,
CC ECO:0000269|PubMed:15075231, ECO:0000269|PubMed:22660413,
CC ECO:0000269|PubMed:24814515, ECO:0000269|PubMed:33186543,
CC ECO:0000269|PubMed:33186545}.
CC -!- FUNCTION: (Microbial infection) In conjunction with the ESCRT machinery
CC also appears to function in topologically equivalent membrane fission
CC events, such as the terminal stages of cytokinesis and enveloped virus
CC budding (HIV-1 and other lentiviruses). {ECO:0000269|PubMed:11595185}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.6;
CC Evidence={ECO:0000250|UniProtKB:O75351};
CC -!- SUBUNIT: Proposed to be monomeric or homodimeric in nucleotide-free
CC form and to oligomerize upon binding to ATP to form two stacked
CC hexameric or heptameric rings with a central pore through which ESCRT-
CC III substrates are translocated in an ATP-dependent manner (By
CC similarity). Interacts with CHMP1A, CHMP1B, CHMP2A, CHMP2B, CHMP3,
CC CHMP4A, CHMP4B, CHMP4C and CHMP6. Interacts with VPS4B; the interaction
CC suggests a heteromeric assembly with VPS4B. Interacts with SPAST.
CC Interacts with IST1. Interacts with ZFYVE19/ANCHR; leading to retain it
CC at midbody. {ECO:0000250, ECO:0000269|PubMed:11559748,
CC ECO:0000269|PubMed:11563910, ECO:0000269|PubMed:14505570,
CC ECO:0000269|PubMed:14519844, ECO:0000269|PubMed:16174732,
CC ECO:0000269|PubMed:17928862, ECO:0000269|PubMed:18606141,
CC ECO:0000269|PubMed:18997780, ECO:0000269|PubMed:19129479,
CC ECO:0000269|PubMed:19129480, ECO:0000269|PubMed:21543490,
CC ECO:0000269|PubMed:24814515}.
CC -!- INTERACTION:
CC Q9UN37; Q9HD42: CHMP1A; NbExp=6; IntAct=EBI-1171942, EBI-1057156;
CC Q9UN37; Q9HD42-1: CHMP1A; NbExp=2; IntAct=EBI-1171942, EBI-15663713;
CC Q9UN37; Q7LBR1: CHMP1B; NbExp=4; IntAct=EBI-1171942, EBI-2118090;
CC Q9UN37; O43633: CHMP2A; NbExp=3; IntAct=EBI-1171942, EBI-2692789;
CC Q9UN37; O95833: CLIC3; NbExp=3; IntAct=EBI-1171942, EBI-10192241;
CC Q9UN37; Q96K21-1: ZFYVE19; NbExp=3; IntAct=EBI-1171942, EBI-16106990;
CC -!- SUBCELLULAR LOCATION: Late endosome membrane
CC {ECO:0000250|UniProtKB:Q8VEJ9}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q8VEJ9}. Midbody {ECO:0000269|PubMed:24814515}.
CC Cytoplasm, cytoskeleton, spindle {ECO:0000269|PubMed:33186543}.
CC Note=Membrane-associated in the prevacuolar endosomal compartment.
CC Localizes to the midbody of dividing cells, interaction with
CC ZFYVE19/ANCHR mediates retention at midbody (PubMed:24814515).
CC Localized in two distinct rings on either side of the Flemming body.
CC {ECO:0000269|PubMed:24814515}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC {ECO:0000269|PubMed:10637304, ECO:0000269|PubMed:11563910}.
CC -!- DOMAIN: The MIT domain serves as an adapter for ESCRT-III proteins. It
CC forms an asymmetric three-helix bundle that binds amphipathic MIM (MIT
CC interacting motif) helices along the groove between MIT helices 2 and 3
CC present in a subset of ESCRT-III proteins thus establishing the
CC canonical MIM-MIT interaction. In an extended conformation along the
CC groove between helices 1 and 3, also binds to a type-2 MIT interacting
CC motif (MIM2). {ECO:0000250|UniProtKB:O75351}.
CC -!- DISEASE: CIMDAG syndrome (CIMDAG) [MIM:619273]: An autosomal dominant
CC syndrome characterized by global developmental delay, severely impaired
CC intellectual development, poor or absent speech, microcephaly, growth
CC retardation, poor motor skills with inability to walk, hypotonia and
CC spasticity, and cataracts. Cerebral and cerebellar atrophy, thin corpus
CC callosum, and delayed myelination are apparent on brain imaging.
CC Affected individuals show hematologic abnormalities mostly consistent
CC with congenital dyserythropoietic anemia. {ECO:0000269|PubMed:33186543,
CC ECO:0000269|PubMed:33186545, ECO:0000269|PubMed:33460484}. Note=The
CC disease may be caused by variants affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the AAA ATPase family. {ECO:0000255}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAL75948.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF255952; AAK52408.1; -; mRNA.
DR EMBL; AF282903; AAG01470.1; -; Genomic_DNA.
DR EMBL; AF132747; AAL75948.1; ALT_FRAME; mRNA.
DR EMBL; AF159063; AAD49227.1; -; mRNA.
DR EMBL; AF112215; AAF17203.1; -; mRNA.
DR EMBL; AK315026; BAG37514.1; -; mRNA.
DR EMBL; CH471092; EAW83263.1; -; Genomic_DNA.
DR EMBL; BC047932; AAH47932.1; -; mRNA.
DR EMBL; AF155740; AAD42971.1; -; mRNA.
DR CCDS; CCDS45517.1; -.
DR RefSeq; NP_037377.1; NM_013245.2.
DR PDB; 1YXR; NMR; -; A=1-77.
DR PDB; 2JQ9; NMR; -; A=1-84.
DR PDB; 2K3W; NMR; -; A=1-84.
DR PDBsum; 1YXR; -.
DR PDBsum; 2JQ9; -.
DR PDBsum; 2K3W; -.
DR AlphaFoldDB; Q9UN37; -.
DR BMRB; Q9UN37; -.
DR SMR; Q9UN37; -.
DR BioGRID; 118059; 81.
DR ComplexPortal; CPX-338; VPS4A/B complex.
DR DIP; DIP-44585N; -.
DR IntAct; Q9UN37; 34.
DR MINT; Q9UN37; -.
DR STRING; 9606.ENSP00000254950; -.
DR GlyGen; Q9UN37; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9UN37; -.
DR PhosphoSitePlus; Q9UN37; -.
DR BioMuta; VPS4A; -.
DR DMDM; 62511240; -.
DR EPD; Q9UN37; -.
DR jPOST; Q9UN37; -.
DR MassIVE; Q9UN37; -.
DR MaxQB; Q9UN37; -.
DR PaxDb; Q9UN37; -.
DR PeptideAtlas; Q9UN37; -.
DR PRIDE; Q9UN37; -.
DR ProteomicsDB; 85248; -.
DR Antibodypedia; 8035; 163 antibodies from 29 providers.
DR DNASU; 27183; -.
DR Ensembl; ENST00000254950.13; ENSP00000254950.11; ENSG00000132612.16.
DR GeneID; 27183; -.
DR KEGG; hsa:27183; -.
DR MANE-Select; ENST00000254950.13; ENSP00000254950.11; NM_013245.3; NP_037377.1.
DR UCSC; uc002eww.4; human.
DR CTD; 27183; -.
DR DisGeNET; 27183; -.
DR GeneCards; VPS4A; -.
DR HGNC; HGNC:13488; VPS4A.
DR HPA; ENSG00000132612; Low tissue specificity.
DR MIM; 609982; gene.
DR MIM; 619273; phenotype.
DR neXtProt; NX_Q9UN37; -.
DR OpenTargets; ENSG00000132612; -.
DR PharmGKB; PA38362; -.
DR VEuPathDB; HostDB:ENSG00000132612; -.
DR eggNOG; KOG0739; Eukaryota.
DR GeneTree; ENSGT00940000157319; -.
DR HOGENOM; CLU_000688_21_2_1; -.
DR InParanoid; Q9UN37; -.
DR OMA; MFELNVG; -.
DR OrthoDB; 787710at2759; -.
DR PhylomeDB; Q9UN37; -.
DR TreeFam; TF105012; -.
DR PathwayCommons; Q9UN37; -.
DR Reactome; R-HSA-162588; Budding and maturation of HIV virion.
DR Reactome; R-HSA-917729; Endosomal Sorting Complex Required For Transport (ESCRT).
DR Reactome; R-HSA-9610379; HCMV Late Events.
DR Reactome; R-HSA-9668328; Sealing of the nuclear envelope (NE) by ESCRT-III.
DR SignaLink; Q9UN37; -.
DR SIGNOR; Q9UN37; -.
DR BioGRID-ORCS; 27183; 156 hits in 1077 CRISPR screens.
DR ChiTaRS; VPS4A; human.
DR EvolutionaryTrace; Q9UN37; -.
DR GeneWiki; VPS4A; -.
DR GenomeRNAi; 27183; -.
DR Pharos; Q9UN37; Tbio.
DR PRO; PR:Q9UN37; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q9UN37; protein.
DR Bgee; ENSG00000132612; Expressed in gastrocnemius and 202 other tissues.
DR ExpressionAtlas; Q9UN37; baseline and differential.
DR Genevisible; Q9UN37; HS.
DR GO; GO:1904949; C:ATPase complex; IC:ComplexPortal.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IMP:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0090543; C:Flemming body; IDA:UniProtKB.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0030496; C:midbody; IDA:UniProtKB.
DR GO; GO:0005643; C:nuclear pore; IC:ComplexPortal.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0000922; C:spindle pole; IDA:UniProtKB.
DR GO; GO:0005774; C:vacuolar membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IMP:UniProtKB.
DR GO; GO:0016887; F:ATP hydrolysis activity; IMP:UniProtKB.
DR GO; GO:0140545; F:ATP-dependent protein disaggregase activity; NAS:ARUK-UCL.
DR GO; GO:0008022; F:protein C-terminus binding; IDA:UniProtKB.
DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:UniProtKB.
DR GO; GO:0009838; P:abscission; IMP:UniProtKB.
DR GO; GO:0000916; P:actomyosin contractile ring contraction; TAS:ARUK-UCL.
DR GO; GO:0097352; P:autophagosome maturation; IC:ComplexPortal.
DR GO; GO:0006914; P:autophagy; IC:ComplexPortal.
DR GO; GO:0051301; P:cell division; IDA:UniProtKB.
DR GO; GO:0061640; P:cytoskeleton-dependent cytokinesis; TAS:ARUK-UCL.
DR GO; GO:0016197; P:endosomal transport; IMP:UniProtKB.
DR GO; GO:0034058; P:endosomal vesicle fusion; IMP:UniProtKB.
DR GO; GO:1904896; P:ESCRT complex disassembly; NAS:ParkinsonsUK-UCL.
DR GO; GO:1904903; P:ESCRT III complex disassembly; NAS:ParkinsonsUK-UCL.
DR GO; GO:0032367; P:intracellular cholesterol transport; IMP:UniProtKB.
DR GO; GO:0061738; P:late endosomal microautophagy; ISS:ParkinsonsUK-UCL.
DR GO; GO:0061764; P:late endosome to lysosome transport via multivesicular body sorting pathway; IC:ComplexPortal.
DR GO; GO:0016236; P:macroautophagy; NAS:ParkinsonsUK-UCL.
DR GO; GO:0090148; P:membrane fission; IC:ComplexPortal.
DR GO; GO:0061952; P:midbody abscission; IMP:UniProtKB.
DR GO; GO:0044878; P:mitotic cytokinesis checkpoint signaling; IMP:UniProtKB.
DR GO; GO:0007080; P:mitotic metaphase plate congression; IMP:UniProtKB.
DR GO; GO:0007084; P:mitotic nuclear membrane reassembly; TAS:Reactome.
DR GO; GO:0036258; P:multivesicular body assembly; ISS:ParkinsonsUK-UCL.
DR GO; GO:0071985; P:multivesicular body sorting pathway; IC:ComplexPortal.
DR GO; GO:0060548; P:negative regulation of cell death; IC:ComplexPortal.
DR GO; GO:0032466; P:negative regulation of cytokinesis; IMP:UniProtKB.
DR GO; GO:0006998; P:nuclear envelope organization; TAS:ARUK-UCL.
DR GO; GO:0031468; P:nuclear membrane reassembly; TAS:ARUK-UCL.
DR GO; GO:0006997; P:nucleus organization; IMP:UniProtKB.
DR GO; GO:0001778; P:plasma membrane repair; IC:ComplexPortal.
DR GO; GO:1903543; P:positive regulation of exosomal secretion; IMP:UniProtKB.
DR GO; GO:1903774; P:positive regulation of viral budding via host ESCRT complex; IMP:UniProtKB.
DR GO; GO:0006622; P:protein targeting to lysosome; IMP:UniProtKB.
DR GO; GO:0032880; P:regulation of protein localization; IMP:UniProtKB.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; IMP:UniProtKB.
DR GO; GO:0043162; P:ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway; IMP:UniProtKB.
DR GO; GO:0090611; P:ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway; IMP:UniProtKB.
DR GO; GO:0007033; P:vacuole organization; IBA:GO_Central.
DR GO; GO:0006900; P:vesicle budding from membrane; IMP:UniProtKB.
DR GO; GO:0072319; P:vesicle uncoating; IMP:UniProtKB.
DR GO; GO:0016192; P:vesicle-mediated transport; IDA:UniProtKB.
DR GO; GO:0046761; P:viral budding from plasma membrane; IMP:UniProtKB.
DR GO; GO:0039702; P:viral budding via host ESCRT complex; IGI:UniProtKB.
DR GO; GO:0019076; P:viral release from host cell; IMP:UniProtKB.
DR CDD; cd02678; MIT_VPS4; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR IDEAL; IID00334; -.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR041569; AAA_lid_3.
DR InterPro; IPR003959; ATPase_AAA_core.
DR InterPro; IPR003960; ATPase_AAA_CS.
DR InterPro; IPR007330; MIT_dom.
DR InterPro; IPR036181; MIT_dom_sf.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR031255; VPS4.
DR InterPro; IPR015415; Vps4_C.
DR InterPro; IPR045253; VPS4_MIT.
DR PANTHER; PTHR23074:SF72; PTHR23074:SF72; 1.
DR Pfam; PF00004; AAA; 1.
DR Pfam; PF17862; AAA_lid_3; 1.
DR Pfam; PF04212; MIT; 1.
DR Pfam; PF09336; Vps4_C; 1.
DR SMART; SM00382; AAA; 1.
DR SMART; SM00745; MIT; 1.
DR SUPFAM; SSF116846; SSF116846; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS00674; AAA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Cataract; Cell cycle;
KW Cell division; Congenital dyserythropoietic anemia; Cytoplasm;
KW Cytoskeleton; Disease variant; Endosome; Hereditary hemolytic anemia;
KW Hydrolase; Intellectual disability; Membrane; Nucleotide-binding;
KW Phosphoprotein; Protein transport; Reference proteome; Transport.
FT CHAIN 1..437
FT /note="Vacuolar protein sorting-associated protein 4A"
FT /id="PRO_0000084765"
FT DOMAIN 2..80
FT /note="MIT"
FT REGION 1..84
FT /note="Interaction with CHMP1B"
FT REGION 75..106
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 167..174
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT MOD_RES 8
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 95
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q793F9"
FT MOD_RES 97
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q793F9"
FT VARIANT 28
FT /note="A -> V (in CIMDAG; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:33186543"
FT /id="VAR_085594"
FT VARIANT 168
FT /note="Missing (found in a patient with non-specific
FT intellectual disability; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:33186545"
FT /id="VAR_085595"
FT VARIANT 193
FT /note="Missing (found in a patient with a CIMDAG-like
FT intellectual disability syndrome; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25356899"
FT /id="VAR_078655"
FT VARIANT 203
FT /note="G -> E (in CIMDAG; patient peripheral red blood
FT cells show abnormal CD71 expression indicating defective
FT endosomal trafficking)"
FT /evidence="ECO:0000269|PubMed:33186543"
FT /id="VAR_085596"
FT VARIANT 206
FT /note="E -> K (in CIMDAG)"
FT /evidence="ECO:0000269|PubMed:33186545"
FT /id="VAR_085597"
FT VARIANT 284
FT /note="R -> G (in CIMDAG; has a dominant negative effect on
FT the regulation of endosomal size resulting in enlarged
FT endosomal vacuoles; patient cells also have abnormal
FT nuclear envelope morphology and primary cilium defects; no
FT effect on protein abundance in patient cells)"
FT /evidence="ECO:0000269|PubMed:33186545"
FT /id="VAR_085598"
FT VARIANT 284
FT /note="R -> W (in CIMDAG; has a dominant negative effect on
FT the regulation of endosomal size resulting in enlarged
FT endosomal vacuoles; patient cells also have abnormal
FT nuclear envelope morphology and primary cilium defects; no
FT effect on protein abundance in patient cells; patient-
FT derived induced erythroblasts show defective cytokinesis)"
FT /evidence="ECO:0000269|PubMed:33186543,
FT ECO:0000269|PubMed:33186545, ECO:0000269|PubMed:33460484"
FT /id="VAR_085599"
FT VARIANT 337
FT /note="I -> V (found in a patient with non-specific
FT intellectual disability; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:33186545"
FT /id="VAR_085600"
FT MUTAGEN 13
FT /note="V->A,D: Diminishes interaction with IST1."
FT /evidence="ECO:0000269|PubMed:18606141,
FT ECO:0000269|PubMed:19129479"
FT MUTAGEN 13
FT /note="V->D: Abolishes interaction with CHMP6, no effect on
FT interaction with CHMP1A."
FT /evidence="ECO:0000269|PubMed:18606141,
FT ECO:0000269|PubMed:19129479"
FT MUTAGEN 13
FT /note="V->D: Greatly diminishes localization to punctate
FT class E compartments; when associated with Q-173."
FT /evidence="ECO:0000269|PubMed:18606141,
FT ECO:0000269|PubMed:19129479"
FT MUTAGEN 64
FT /note="L->A,D: Abolishes interaction with CHMP1B;
FT diminishes interaction with IST1."
FT /evidence="ECO:0000269|PubMed:16174732,
FT ECO:0000269|PubMed:17928862, ECO:0000269|PubMed:18606141,
FT ECO:0000269|PubMed:19129479, ECO:0000269|PubMed:19129480"
FT MUTAGEN 64
FT /note="L->D: Greatly diminishes localization to punctate
FT class E compartments and partially restores HIV-1 release;
FT when associated with Q-173."
FT /evidence="ECO:0000269|PubMed:16174732,
FT ECO:0000269|PubMed:17928862, ECO:0000269|PubMed:18606141,
FT ECO:0000269|PubMed:19129479, ECO:0000269|PubMed:19129480"
FT MUTAGEN 64
FT /note="L->D: Modestly reduces interaction with CHMP6."
FT /evidence="ECO:0000269|PubMed:16174732,
FT ECO:0000269|PubMed:17928862, ECO:0000269|PubMed:18606141,
FT ECO:0000269|PubMed:19129479, ECO:0000269|PubMed:19129480"
FT MUTAGEN 68
FT /note="E->D: Diminishes interaction with CHMP1B."
FT /evidence="ECO:0000269|PubMed:16174732"
FT MUTAGEN 173
FT /note="K->Q: Defective in ATP-binding. Causes membrane
FT association. Induces vacuolation of endosomal compartments
FT and impairs cholesterol sorting. Inhibits HIV-1 release.
FT Greatly diminishes localization to punctate class E
FT compartments and partially restores HIV-1 release; when
FT associated with D-64. Greatly diminishes localization to
FT punctate class E compartments; when associated with D-173."
FT /evidence="ECO:0000269|PubMed:10637304,
FT ECO:0000269|PubMed:11595185, ECO:0000269|PubMed:17928862,
FT ECO:0000269|PubMed:18606141"
FT MUTAGEN 201..202
FT /note="WL->AA: Strongly impairs HIV-1 release."
FT /evidence="ECO:0000269|PubMed:16193069"
FT MUTAGEN 203
FT /note="G->A: Impairs HIV-1 release."
FT /evidence="ECO:0000269|PubMed:16193069"
FT MUTAGEN 228
FT /note="E->Q: Defective in ATP-hydrolysis. Causes membrane
FT association. Induces vacuolation of endosomal compartments
FT and impairs cholesterol and protein sorting. Inhibits HIV-1
FT release. Increases binding to CHMP1."
FT /evidence="ECO:0000269|PubMed:10637304,
FT ECO:0000269|PubMed:11559748, ECO:0000269|PubMed:11563910,
FT ECO:0000269|PubMed:11595185, ECO:0000269|PubMed:15075231"
FT CONFLICT 79
FT /note="K -> E (in Ref. 3; AAL75948 and 5; AAF17203)"
FT /evidence="ECO:0000305"
FT CONFLICT 185
FT /note="N -> T (in Ref. 3; AAL75948)"
FT /evidence="ECO:0000305"
FT CONFLICT 284
FT /note="R -> K (in Ref. 8; AAD42971)"
FT /evidence="ECO:0000305"
FT HELIX 5..21
FT /evidence="ECO:0007829|PDB:1YXR"
FT HELIX 25..45
FT /evidence="ECO:0007829|PDB:1YXR"
FT HELIX 50..76
FT /evidence="ECO:0007829|PDB:1YXR"
SQ SEQUENCE 437 AA; 48898 MW; C3CC556FB84F105C CRC64;
MTTSTLQKAI DLVTKATEED KAKNYEEALR LYQHAVEYFL HAIKYEAHSD KAKESIRAKC
VQYLDRAEKL KDYLRSKEKH GKKPVKENQS EGKGSDSDSE GDNPEKKKLQ EQLMGAVVME
KPNIRWNDVA GLEGAKEALK EAVILPIKFP HLFTGKRTPW RGILLFGPPG TGKSYLAKAV
ATEANNSTFF SVSSSDLMSK WLGESEKLVK NLFELARQHK PSIIFIDEVD SLCGSRNENE
SEAARRIKTE FLVQMQGVGN NNDGTLVLGA TNIPWVLDSA IRRRFEKRIY IPLPEEAARA
QMFRLHLGST PHNLTDANIH ELARKTEGYS GADISIIVRD SLMQPVRKVQ SATHFKKVCG
PSRTNPSMMI DDLLTPCSPG DPGAMEMTWM DVPGDKLLEP VVCMSDMLRS LATTRPTVNA
DDLLKVKKFS EDFGQES
