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 27-MAR-2024, entry version 203. 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; P13569: CFTR; NbExp=9; IntAct=EBI-1171942, EBI-349854; 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 89. 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 SwissPalm; Q9UN37; -. DR BioMuta; VPS4A; -. DR DMDM; 62511240; -. DR EPD; Q9UN37; -. DR jPOST; Q9UN37; -. DR MassIVE; Q9UN37; -. DR MaxQB; Q9UN37; -. DR PaxDb; 9606-ENSP00000254950; -. DR PeptideAtlas; Q9UN37; -. DR ProteomicsDB; 85248; -. DR Pumba; Q9UN37; -. DR Antibodypedia; 8035; 183 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 AGR; HGNC:13488; -. DR CTD; 27183; -. DR DisGeNET; 27183; -. DR GeneCards; VPS4A; -. DR HGNC; HGNC:13488; VPS4A. DR HPA; ENSG00000132612; Low tissue specificity. DR MalaCards; VPS4A; -. 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; IEWTNEF; -. DR OrthoDB; 276256at2759; -. 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; 159 hits in 1155 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 204 other cell types or tissues. DR ExpressionAtlas; Q9UN37; baseline and differential. DR GO; GO:1904949; C:ATPase complex; NAS: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; NAS: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: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; NAS:ComplexPortal. DR GO; GO:0006914; P:autophagy; NAS: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; NAS:ComplexPortal. DR GO; GO:0016236; P:macroautophagy; NAS:ParkinsonsUK-UCL. DR GO; GO:0090148; P:membrane fission; NAS: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 chromosome alignment; 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; NAS: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; NAS: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:0015031; P:protein transport; IEA:UniProtKB-KW. 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 CDD; cd19521; RecA-like_VPS4; 1. DR Gene3D; 1.10.8.60; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR Gene3D; 1.20.58.80; Phosphotransferase system, lactose/cellobiose-type IIA subunit; 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; IPR015415; Spast_Vps4_C. DR InterPro; IPR045253; VPS4_MIT. DR PANTHER; PTHR23074; AAA DOMAIN-CONTAINING; 1. DR PANTHER; PTHR23074:SF177; VACUOLAR PROTEIN SORTING-ASSOCIATED PROTEIN 4A; 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; MIT domain; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS00674; AAA; 1. DR Genevisible; Q9UN37; HS. 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; uncertain significance; FT dbSNP:rs1965431981)" 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; uncertain 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; uncertain 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; dbSNP:rs1965484288)" 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; FT patient-derived induced erythroblasts show defective FT cytokinesis; dbSNP:rs1965499910)" 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; uncertain 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 //