P3C2A_HUMAN
ID P3C2A_HUMAN Reviewed; 1686 AA.
AC O00443; B0LPH2; B4E2G4; Q14CQ9;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 10-JUL-2007, sequence version 2.
DT 03-AUG-2022, entry version 197.
DE RecName: Full=Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha;
DE Short=PI3K-C2-alpha;
DE Short=PtdIns-3-kinase C2 subunit alpha;
DE EC=2.7.1.137 {ECO:0000269|PubMed:10766823, ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:9337861};
DE EC=2.7.1.153 {ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:9337861};
DE EC=2.7.1.154 {ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:9337861};
DE AltName: Full=Phosphoinositide 3-kinase-C2-alpha;
GN Name=PIK3C2A;
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]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP COFACTOR, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE
RP SPECIFICITY.
RX PubMed=9337861; DOI=10.1042/bj3260139;
RA Domin J., Pages F., Volinia S., Rittenhouse S.E., Zvelebil M.J.,
RA Stein R.C., Waterfield M.D.;
RT "Cloning of a human phosphoinositide 3-kinase with a C2 domain which
RT displays reduced sensitivity to the inhibitor wortmannin.";
RL Biochem. J. 326:139-147(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Trachea;
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 [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [5]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 [7]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=10766823; DOI=10.1074/jbc.275.16.11943;
RA Domin J., Gaidarov I., Smith M.E.K., Keen J.H., Waterfield M.D.;
RT "The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the
RT trans-Golgi network and present in clathrin-coated vesicles.";
RL J. Biol. Chem. 275:11943-11950(2000).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND IDENTIFICATION IN A COMPLEX
RP WITH ERBB2 AND EGFR.
RX PubMed=10805725; DOI=10.1128/mcb.20.11.3817-3830.2000;
RA Arcaro A., Zvelebil M.J., Wallasch C., Ullrich A., Waterfield M.D.,
RA Domin J.;
RT "Class II phosphoinositide 3-kinases are downstream targets of activated
RT polypeptide growth factor receptors.";
RL Mol. Cell. Biol. 20:3817-3830(2000).
RN [9]
RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, PHOSPHORYLATION, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=11606566; DOI=10.1074/jbc.m104610200;
RA Didichenko S.A., Thelen M.;
RT "Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization
RT sequence and associates with nuclear speckles.";
RL J. Biol. Chem. 276:48135-48142(2001).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP INTERACTION WITH CLATHRIN, AND MUTAGENESIS OF 103-LEU--ASP-107.
RX PubMed=11239472; DOI=10.1016/s1097-2765(01)00191-5;
RA Gaidarov I., Smith M.E.K., Domin J., Keen J.H.;
RT "The class II phosphoinositide 3-kinase C2alpha is activated by clathrin
RT and regulates clathrin-mediated membrane trafficking.";
RL Mol. Cell 7:443-449(2001).
RN [11]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=14563213; DOI=10.1186/1472-6890-3-4;
RA El Sheikh S.S., Domin J., Tomtitchong P., Abel P., Stamp G., Lalani E.-N.;
RT "Topographical expression of class IA and class II phosphoinositide 3-
RT kinase enzymes in normal human tissues is consistent with a role in
RT differentiation.";
RL BMC Clin. Pathol. 3:4-4(2003).
RN [12]
RP FUNCTION, PHOSPHORYLATION AT SER-259, MUTAGENESIS OF SER-254; SER-259;
RP SER-262 AND SER-266, LACK OF PHOSPHORYLATION AT SER-244; SER-249; SER-251;
RP SER-254; SER-262 AND SER-266, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=12719431; DOI=10.1074/jbc.m301657200;
RA Didichenko S.A., Fragoso C.M., Thelen M.;
RT "Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the
RT protein for degradation.";
RL J. Biol. Chem. 278:26055-26064(2003).
RN [13]
RP FUNCTION IN ASSEMBLY AND CELLULAR DISTRIBUTION OF CLATHRIN, INTERACTION
RP WITH CLATHRIN, MUTAGENESIS OF ASP-1250, AND REGION.
RX PubMed=16215232; DOI=10.1074/jbc.m507731200;
RA Gaidarov I., Zhao Y., Keen J.H.;
RT "Individual phosphoinositide 3-kinase C2alpha domain activities
RT independently regulate clathrin function.";
RL J. Biol. Chem. 280:40766-40772(2005).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108 AND SER-259, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-60; SER-108; SER-259 AND
RP SER-338, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [19]
RP FUNCTION IN DYNAMIN-INDEPENDENT ENDOCYTOSIS.
RX PubMed=21081650; DOI=10.1242/jcs.071712;
RA Krag C., Malmberg E.K., Salcini A.E.;
RT "PI3KC2alpha, a class II PI3K, is required for dynamin-independent
RT internalization pathways.";
RL J. Cell Sci. 123:4240-4250(2010).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108 AND SER-259, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [21]
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 [22]
RP TISSUE SPECIFICITY.
RX PubMed=21127054; DOI=10.1074/jbc.m110.200295;
RA Dominguez V., Raimondi C., Somanath S., Bugliani M., Loder M.K.,
RA Edling C.E., Divecha N., da Silva-Xavier G., Marselli L., Persaud S.J.,
RA Turner M.D., Rutter G.A., Marchetti P., Falasca M., Maffucci T.;
RT "Class II phosphoinositide 3-kinase regulates exocytosis of insulin
RT granules in pancreatic beta cells.";
RL J. Biol. Chem. 286:4216-4225(2011).
RN [23]
RP REVIEW ON FUNCTION.
RX PubMed=17371240; DOI=10.1042/bst0350211;
RA Falasca M., Maffucci T.;
RT "Role of class II phosphoinositide 3-kinase in cell signalling.";
RL Biochem. Soc. Trans. 35:211-214(2007).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259 AND SER-327, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108; SER-259; SER-327;
RP SER-630; SER-1281 AND SER-1553, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-259, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [27]
RP FUNCTION, INVOLVEMENT IN OCSKD, VARIANT OCSKD 195-TYR--LEU-1686 DEL, AND
RP CHARACTERIZATION OF VARIANT OCSKD 195-TYR--LEU-1686 DEL.
RX PubMed=31034465; DOI=10.1371/journal.pgen.1008088;
RA Tiosano D., Baris H.N., Chen A., Hitzert M.M., Schueler M., Gulluni F.,
RA Wiesener A., Bergua A., Mory A., Copeland B., Gleeson J.G., Rump P.,
RA van Meer H., Sival D.A., Haucke V., Kriwinsky J., Knaup K.X., Reis A.,
RA Hauer N.N., Hirsch E., Roepman R., Pfundt R., Thiel C.T., Wiesener M.S.,
RA Aslanyan M.G., Buchner D.A.;
RT "Mutations in PIK3C2A cause syndromic short stature, skeletal
RT abnormalities, and cataracts associated with ciliary dysfunction.";
RL PLoS Genet. 15:E1008088-E1008088(2019).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 1405-1544, PHOSPHOINOSITIDE
RP BINDING, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ARG-1488; VAL-1490;
RP LEU-1491; ARG-1493 AND ARG-1503.
RX PubMed=17038310; DOI=10.1074/jbc.m607079200;
RA Stahelin R.V., Karathanassis D., Bruzik K.S., Waterfield M.D., Bravo J.,
RA Williams R.L., Cho W.;
RT "Structural and membrane binding analysis of the Phox homology domain of
RT phosphoinositide 3-kinase-C2alpha.";
RL J. Biol. Chem. 281:39396-39406(2006).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1421-1532.
RA Parkinson G.N., Vines D., Driscoll P.C., Djordjevic S.;
RT "Ligand-binding specificity of PI3kinase C2alpha PX domain.";
RL Submitted (OCT-2006) to the PDB data bank.
CC -!- FUNCTION: Generates phosphatidylinositol 3-phosphate (PtdIns3P) and
CC phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as
CC second messengers. Has a role in several intracellular trafficking
CC events. Functions in insulin signaling and secretion. Required for
CC translocation of the glucose transporter SLC2A4/GLUT4 to the plasma
CC membrane and glucose uptake in response to insulin-mediated RHOQ
CC activation. Regulates insulin secretion through two different
CC mechanisms: involved in glucose-induced insulin secretion downstream of
CC insulin receptor in a pathway that involves AKT1 activation and
CC TBC1D4/AS160 phosphorylation, and participates in the late step of
CC insulin granule exocytosis probably in insulin granule fusion.
CC Synthesizes PtdIns3P in response to insulin signaling. Functions in
CC clathrin-coated endocytic vesicle formation and distribution. Regulates
CC dynamin-independent endocytosis, probably by recruiting EEA1 to
CC internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on
CC large dense core vesicles. Participates in calcium induced contraction
CC of vascular smooth muscle by regulating myosin light chain (MLC)
CC phosphorylation through a mechanism involving Rho kinase-dependent
CC phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role
CC in the EGF signaling cascade. May be involved in mitosis and UV-induced
CC damage response. Required for maintenance of normal renal structure and
CC function by supporting normal podocyte function. Involved in the
CC regulation of ciliogenesis and trafficking of ciliary components
CC (PubMed:31034465). {ECO:0000269|PubMed:10766823,
CC ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:11239472,
CC ECO:0000269|PubMed:12719431, ECO:0000269|PubMed:16215232,
CC ECO:0000269|PubMed:21081650, ECO:0000269|PubMed:31034465,
CC ECO:0000269|PubMed:9337861}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-
CC phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4-bisphosphate) + ADP + H(+); Xref=Rhea:RHEA:18373,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57658,
CC ChEBI:CHEBI:58178, ChEBI:CHEBI:456216; EC=2.7.1.154;
CC Evidence={ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:11239472,
CC ECO:0000269|PubMed:9337861};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:18374;
CC Evidence={ECO:0000305|PubMed:9337861};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a
CC 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP +
CC H(+); Xref=Rhea:RHEA:12709, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:57880, ChEBI:CHEBI:58088, ChEBI:CHEBI:456216;
CC EC=2.7.1.137; Evidence={ECO:0000269|PubMed:10766823,
CC ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:11239472,
CC ECO:0000269|PubMed:9337861};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12710;
CC Evidence={ECO:0000305|PubMed:9337861};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-
CC bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4,5-trisphosphate) + ADP + H(+); Xref=Rhea:RHEA:21292,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57836,
CC ChEBI:CHEBI:58456, ChEBI:CHEBI:456216; EC=2.7.1.153;
CC Evidence={ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:9337861};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21293;
CC Evidence={ECO:0000305|PubMed:9337861};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:9337861};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:9337861};
CC Note=Ca(2+) or Mg(2+). Mn(2+) cannot be used.
CC {ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:9337861};
CC -!- ACTIVITY REGULATION: Activated by insulin (By similarity). Only
CC slightly inhibited by wortmannin and LY294002. Activated by clathrin.
CC {ECO:0000250|UniProtKB:Q61194, ECO:0000269|PubMed:10766823,
CC ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:9337861}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=122 uM for PtdIns (in the absence of phosphatidylserine)
CC {ECO:0000269|PubMed:9337861};
CC KM=64 uM for PtdIns (in the presence of phosphatidylserine)
CC {ECO:0000269|PubMed:9337861};
CC KM=25 uM for PtdIns4P (in the presence of phosphatidylserine)
CC {ECO:0000269|PubMed:9337861};
CC KM=15 uM for ATP (with PtdIns as substrate) (in the absence of
CC phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC KM=32 uM for ATP (with PtdIns as substrate) (in the presence of
CC phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC KM=54 uM for ATP (with PtdIns4P as substrate) (in the presence of
CC phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC Vmax=990 pmol/min/mg enzyme with PtdIns as substrate (in the absence
CC of phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC Vmax=200 pmol/min/mg enzyme with PtdIns as substrate (in the presence
CC of phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC Vmax=240 pmol/min/mg enzyme with PtdIns4P as substrate (in the
CC presence of phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC Vmax=6800 pmol/min/mg enzyme toward ATP with PtdIns as substrate (in
CC the absence of phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC Vmax=805 pmol/min/mg enzyme toward ATP with PtdIns as substrate (in
CC the presence of phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC Vmax=880 pmol/min/mg enzyme toward ATP with PtdIns4P as substrate (in
CC the presence of phosphatidylserine) {ECO:0000269|PubMed:9337861};
CC Note=In the absence of the carrier phosphatidylserine, enzymatic
CC kinetics toward PtdIns4P are non-linear.;
CC -!- SUBUNIT: Part of a complex with ERBB2 and EGFR (PubMed:10805725).
CC Interacts with clathrin trimers (PubMed:11239472, PubMed:16215232).
CC Interacts with SBF2/MTMR13 (By similarity).
CC {ECO:0000250|UniProtKB:Q61194, ECO:0000269|PubMed:10805725,
CC ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:16215232}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10766823,
CC ECO:0000269|PubMed:11239472, ECO:0000269|PubMed:17038310}. Cytoplasmic
CC vesicle, clathrin-coated vesicle {ECO:0000269|PubMed:10766823,
CC ECO:0000269|PubMed:11239472}. Nucleus {ECO:0000269|PubMed:11606566}.
CC Cytoplasm {ECO:0000269|PubMed:11606566, ECO:0000269|PubMed:14563213}.
CC Golgi apparatus, trans-Golgi network {ECO:0000269|PubMed:10766823,
CC ECO:0000269|PubMed:11239472}. Note=Inserts preferentially into
CC membranes containing PtdIns(4,5)P2 (PubMed:17038310). Associated with
CC RNA-containing structures (PubMed:11606566).
CC {ECO:0000269|PubMed:11606566, ECO:0000269|PubMed:17038310}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O00443-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O00443-2; Sequence=VSP_056158;
CC -!- TISSUE SPECIFICITY: Expressed in columnar and transitional epithelia,
CC mononuclear cells, smooth muscle cells, and endothelial cells lining
CC capillaries and small venules (at protein level). Ubiquitously
CC expressed, with highest levels in heart, placenta and ovary, and lowest
CC levels in the kidney. Detected at low levels in islets of Langerhans
CC from type 2 diabetes mellitus individuals.
CC {ECO:0000269|PubMed:14563213, ECO:0000269|PubMed:21127054,
CC ECO:0000269|PubMed:9337861}.
CC -!- PTM: Phosphorylated upon insulin stimulation; which may lead to enzyme
CC activation (By similarity). Phosphorylated on Ser-259 during mitosis
CC and upon UV irradiation; which does not change enzymatic activity but
CC leads to proteasomal degradation. Ser-259 phosphorylation may be
CC mediated by CDK1 or JNK, depending on the physiological state of the
CC cell. {ECO:0000250|UniProtKB:Q61194, ECO:0000269|PubMed:11606566,
CC ECO:0000269|PubMed:12719431}.
CC -!- DISEASE: Oculoskeletodental syndrome (OCSKD) [MIM:618440]: An autosomal
CC recessive syndrome characterized by congenital cataracts, short
CC stature, dysmorphic features with coarse facies, dental anomalies,
CC multiple skeletal abnormalities, and neurological manifestations. Other
CC recurrent features include hearing loss, secondary glaucoma, and
CC nephrocalcinosis. {ECO:0000269|PubMed:31034465}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. {ECO:0000255|PROSITE-
CC ProRule:PRU00879, ECO:0000255|PROSITE-ProRule:PRU00880}.
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DR EMBL; Y13367; CAA73797.1; -; mRNA.
DR EMBL; AK304262; BAG65126.1; -; mRNA.
DR EMBL; EU332862; ABY87551.1; -; Genomic_DNA.
DR EMBL; AC107956; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC116533; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC126389; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW68447.1; -; Genomic_DNA.
DR EMBL; BC113658; AAI13659.1; -; mRNA.
DR CCDS; CCDS7824.1; -. [O00443-1]
DR PIR; PC4345; PC4345.
DR RefSeq; NP_001308307.1; NM_001321378.1. [O00443-1]
DR RefSeq; NP_002636.2; NM_002645.3. [O00443-1]
DR RefSeq; XP_016873413.1; XM_017017924.1. [O00443-1]
DR PDB; 2AR5; X-ray; 1.80 A; A=1421-1532.
DR PDB; 2IWL; X-ray; 2.60 A; X=1405-1544.
DR PDB; 2REA; X-ray; 2.50 A; A=1421-1532.
DR PDB; 2RED; X-ray; 2.10 A; A=1421-1532.
DR PDB; 6BTY; X-ray; 1.68 A; A/B=1559-1686.
DR PDB; 6BTZ; X-ray; 1.85 A; A/B/C/D=1559-1686.
DR PDB; 6BU0; X-ray; 2.43 A; A/B/C=1559-1686.
DR PDB; 6BUB; X-ray; 2.60 A; A=1405-1544.
DR PDBsum; 2AR5; -.
DR PDBsum; 2IWL; -.
DR PDBsum; 2REA; -.
DR PDBsum; 2RED; -.
DR PDBsum; 6BTY; -.
DR PDBsum; 6BTZ; -.
DR PDBsum; 6BU0; -.
DR PDBsum; 6BUB; -.
DR AlphaFoldDB; O00443; -.
DR SASBDB; O00443; -.
DR SMR; O00443; -.
DR BioGRID; 111304; 157.
DR CORUM; O00443; -.
DR DIP; DIP-33727N; -.
DR ELM; O00443; -.
DR IntAct; O00443; 64.
DR MINT; O00443; -.
DR STRING; 9606.ENSP00000265970; -.
DR BindingDB; O00443; -.
DR ChEMBL; CHEMBL1075102; -.
DR GuidetoPHARMACOLOGY; 2150; -.
DR SwissLipids; SLP:000000892; -.
DR GlyGen; O00443; 3 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; O00443; -.
DR PhosphoSitePlus; O00443; -.
DR BioMuta; PIK3C2A; -.
DR EPD; O00443; -.
DR jPOST; O00443; -.
DR MassIVE; O00443; -.
DR MaxQB; O00443; -.
DR PaxDb; O00443; -.
DR PeptideAtlas; O00443; -.
DR PRIDE; O00443; -.
DR ProteomicsDB; 47892; -. [O00443-1]
DR ProteomicsDB; 5816; -.
DR Antibodypedia; 24799; 702 antibodies from 34 providers.
DR DNASU; 5286; -.
DR Ensembl; ENST00000265970.11; ENSP00000265970.6; ENSG00000011405.14. [O00443-1]
DR Ensembl; ENST00000691414.1; ENSP00000509400.1; ENSG00000011405.14. [O00443-1]
DR GeneID; 5286; -.
DR KEGG; hsa:5286; -.
DR MANE-Select; ENST00000691414.1; ENSP00000509400.1; NM_002645.4; NP_002636.2.
DR UCSC; uc001mmq.6; human. [O00443-1]
DR CTD; 5286; -.
DR DisGeNET; 5286; -.
DR GeneCards; PIK3C2A; -.
DR HGNC; HGNC:8971; PIK3C2A.
DR HPA; ENSG00000011405; Low tissue specificity.
DR MalaCards; PIK3C2A; -.
DR MIM; 603601; gene.
DR MIM; 618440; phenotype.
DR neXtProt; NX_O00443; -.
DR OpenTargets; ENSG00000011405; -.
DR Orphanet; 557003; Oculocerebrodental syndrome.
DR PharmGKB; PA33304; -.
DR VEuPathDB; HostDB:ENSG00000011405; -.
DR eggNOG; KOG0905; Eukaryota.
DR GeneTree; ENSGT00940000157813; -.
DR HOGENOM; CLU_002191_0_2_1; -.
DR InParanoid; O00443; -.
DR OMA; EKPTCLP; -.
DR PhylomeDB; O00443; -.
DR TreeFam; TF102031; -.
DR BioCyc; MetaCyc:HS00315-MON; -.
DR BRENDA; 2.7.1.154; 2681.
DR PathwayCommons; O00443; -.
DR Reactome; R-HSA-1660499; Synthesis of PIPs at the plasma membrane.
DR Reactome; R-HSA-1660514; Synthesis of PIPs at the Golgi membrane.
DR Reactome; R-HSA-1660516; Synthesis of PIPs at the early endosome membrane.
DR Reactome; R-HSA-1660517; Synthesis of PIPs at the late endosome membrane.
DR Reactome; R-HSA-432722; Golgi Associated Vesicle Biogenesis.
DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
DR SABIO-RK; O00443; -.
DR SignaLink; O00443; -.
DR SIGNOR; O00443; -.
DR BioGRID-ORCS; 5286; 19 hits in 1092 CRISPR screens.
DR ChiTaRS; PIK3C2A; human.
DR EvolutionaryTrace; O00443; -.
DR GeneWiki; PIK3C2A; -.
DR GenomeRNAi; 5286; -.
DR Pharos; O00443; Tchem.
DR PRO; PR:O00443; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; O00443; protein.
DR Bgee; ENSG00000011405; Expressed in secondary oocyte and 214 other tissues.
DR ExpressionAtlas; O00443; baseline and differential.
DR Genevisible; O00443; HS.
DR GO; GO:0030136; C:clathrin-coated vesicle; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0031982; C:vesicle; IDA:UniProtKB.
DR GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; IDA:UniProtKB.
DR GO; GO:0035005; F:1-phosphatidylinositol-4-phosphate 3-kinase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0030276; F:clathrin binding; IDA:UniProtKB.
DR GO; GO:0035004; F:phosphatidylinositol 3-kinase activity; TAS:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; IEA:InterPro.
DR GO; GO:0052742; F:phosphatidylinositol kinase activity; IBA:GO_Central.
DR GO; GO:0052812; F:phosphatidylinositol-3,4-bisphosphate 5-kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; IDA:UniProtKB.
DR GO; GO:0016477; P:cell migration; IBA:GO_Central.
DR GO; GO:0048268; P:clathrin coat assembly; TAS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IMP:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0006887; P:exocytosis; TAS:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0061024; P:membrane organization; TAS:Reactome.
DR GO; GO:0014065; P:phosphatidylinositol 3-kinase signaling; IBA:GO_Central.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:ProtInc.
DR GO; GO:0046854; P:phosphatidylinositol phosphate biosynthetic process; IBA:GO_Central.
DR GO; GO:0036092; P:phosphatidylinositol-3-phosphate biosynthetic process; IBA:GO_Central.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IBA:GO_Central.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:CACAO.
DR GO; GO:0090050; P:positive regulation of cell migration involved in sprouting angiogenesis; IMP:BHF-UCL.
DR GO; GO:0014829; P:vascular associated smooth muscle contraction; TAS:UniProtKB.
DR CDD; cd05176; PI3Kc_C2_alpha; 1.
DR CDD; cd07289; PX_PI3K_C2_alpha; 1.
DR Gene3D; 1.10.1070.11; -; 1.
DR Gene3D; 1.25.40.70; -; 1.
DR Gene3D; 2.60.40.150; -; 2.
DR Gene3D; 3.30.1520.10; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR036940; PI3/4_kinase_cat_sf.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR037705; PI3K-C2-alpha_dom.
DR InterPro; IPR002420; PI3K-type_C2_dom.
DR InterPro; IPR001263; PI3K_accessory_dom.
DR InterPro; IPR042236; PI3K_accessory_sf.
DR InterPro; IPR000341; PI3K_Ras-bd_dom.
DR InterPro; IPR015433; PI_Kinase.
DR InterPro; IPR001683; PX_dom.
DR InterPro; IPR036871; PX_dom_sf.
DR InterPro; IPR042133; PX_PI3K_C2_alpha.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR PANTHER; PTHR10048; PTHR10048; 1.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF00454; PI3_PI4_kinase; 1.
DR Pfam; PF00792; PI3K_C2; 1.
DR Pfam; PF00794; PI3K_rbd; 1.
DR Pfam; PF00613; PI3Ka; 1.
DR Pfam; PF00787; PX; 1.
DR SMART; SM00239; C2; 2.
DR SMART; SM00142; PI3K_C2; 1.
DR SMART; SM00144; PI3K_rbd; 1.
DR SMART; SM00145; PI3Ka; 1.
DR SMART; SM00146; PI3Kc; 1.
DR SMART; SM00312; PX; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR SUPFAM; SSF49562; SSF49562; 2.
DR SUPFAM; SSF54236; SSF54236; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF64268; SSF64268; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS51547; C2_PI3K; 1.
DR PROSITE; PS00915; PI3_4_KINASE_1; 1.
DR PROSITE; PS00916; PI3_4_KINASE_2; 1.
DR PROSITE; PS50290; PI3_4_KINASE_3; 1.
DR PROSITE; PS51546; PI3K_RBD; 1.
DR PROSITE; PS51545; PIK_HELICAL; 1.
DR PROSITE; PS50195; PX; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Cataract;
KW Cell membrane; Cytoplasm; Cytoplasmic vesicle; Disease variant; Dwarfism;
KW Endocytosis; Exocytosis; Golgi apparatus; Kinase; Lipid metabolism;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330"
FT CHAIN 2..1686
FT /note="Phosphatidylinositol 4-phosphate 3-kinase C2 domain-
FT containing subunit alpha"
FT /id="PRO_0000088795"
FT DOMAIN 421..509
FT /note="PI3K-RBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00879"
FT DOMAIN 682..841
FT /note="C2 PI3K-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041,
FT ECO:0000255|PROSITE-ProRule:PRU00880"
FT DOMAIN 861..1037
FT /note="PIK helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00878"
FT DOMAIN 1105..1383
FT /note="PI3K/PI4K catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT DOMAIN 1422..1538
FT /note="PX"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00147"
FT DOMAIN 1555..1678
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT REGION 1..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..142
FT /note="Interaction with clathrin; sufficient to induce
FT clathrin assembly"
FT /evidence="ECO:0000269|PubMed:16215232"
FT REGION 348..367
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 618..639
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1111..1117
FT /note="G-loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1247..1255
FT /note="Catalytic loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1266..1292
FT /note="Activation loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1488..1493
FT /note="Interaction with PtdIns(4,5)P2-containing membranes"
FT /evidence="ECO:0000250|UniProtKB:Q61194"
FT MOTIF 1608..1619
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:11606566"
FT COMPBIAS 17..51
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 244
FT /note="Not phosphorylated"
FT /evidence="ECO:0000269|PubMed:12719431"
FT SITE 249
FT /note="Not phosphorylated"
FT /evidence="ECO:0000269|PubMed:12719431"
FT SITE 251
FT /note="Not phosphorylated"
FT /evidence="ECO:0000269|PubMed:12719431"
FT SITE 254
FT /note="Not phosphorylated"
FT /evidence="ECO:0000269|PubMed:12719431"
FT SITE 262
FT /note="Not phosphorylated"
FT /evidence="ECO:0000269|PubMed:12719431"
FT SITE 266
FT /note="Not phosphorylated"
FT /evidence="ECO:0000269|PubMed:12719431"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 60
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 108
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 259
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:12719431,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 327
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 338
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 630
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1281
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1553
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 484..1686
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056158"
FT VARIANT 195..1686
FT /note="Missing (in OCSKD; no protein detected by Wester
FT blot in patient cells)"
FT /evidence="ECO:0000269|PubMed:31034465"
FT /id="VAR_082616"
FT VARIANT 1415
FT /note="T -> A (in dbSNP:rs11604561)"
FT /id="VAR_023333"
FT MUTAGEN 103..107
FT /note="LLLDD->AAAAA: Reduces clathrin binding."
FT /evidence="ECO:0000269|PubMed:11239472"
FT MUTAGEN 254
FT /note="S->A: No effect on phosphorylation in vitro."
FT /evidence="ECO:0000269|PubMed:12719431"
FT MUTAGEN 259
FT /note="S->A,D,E: Abolishes phosphorylation, no change in
FT activity."
FT /evidence="ECO:0000269|PubMed:12719431"
FT MUTAGEN 259
FT /note="S->A: Protects from proteolysis."
FT /evidence="ECO:0000269|PubMed:12719431"
FT MUTAGEN 262
FT /note="S->A: No effect on phosphorylation in vitro."
FT /evidence="ECO:0000269|PubMed:12719431"
FT MUTAGEN 266
FT /note="S->A: No effect on phosphorylation in vitro."
FT /evidence="ECO:0000269|PubMed:12719431"
FT MUTAGEN 1250
FT /note="D->A: Abolishes lipid kinase activity. Affects
FT clathrin distribution when combined with a truncation
FT encompassing the region of clathrin interaction."
FT /evidence="ECO:0000269|PubMed:16215232"
FT MUTAGEN 1488
FT /note="R->A: Reduces affinity for PtdIns(4,5)P2-containing
FT membranes 7-fold."
FT /evidence="ECO:0000269|PubMed:17038310"
FT MUTAGEN 1490
FT /note="V->A: Reduces affinity for PtdIns(4,5)P2-containing
FT membranes 7-fold."
FT /evidence="ECO:0000269|PubMed:17038310"
FT MUTAGEN 1491
FT /note="L->A: Reduces affinity for PtdIns(4,5)P2-containing
FT membranes 5-fold."
FT /evidence="ECO:0000269|PubMed:17038310"
FT MUTAGEN 1493
FT /note="R->A: Reduces affinity for PtdIns(4,5)P2-containing
FT membranes 23-fold."
FT /evidence="ECO:0000269|PubMed:17038310"
FT MUTAGEN 1503
FT /note="R->A: Abolishes interaction with PtdIns(4,5)P2-
FT containing membranes."
FT /evidence="ECO:0000269|PubMed:17038310"
FT CONFLICT 5
FT /note="S -> F (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT CONFLICT 15
FT /note="S -> F (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT CONFLICT 483
FT /note="N -> K (in Ref. 2; BAG65126)"
FT /evidence="ECO:0000305"
FT CONFLICT 796
FT /note="F -> C (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT CONFLICT 799
FT /note="K -> R (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT CONFLICT 922
FT /note="V -> G (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT CONFLICT 1129
FT /note="M -> L (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT CONFLICT 1450
FT /note="R -> W (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT CONFLICT 1464
FT /note="D -> V (in Ref. 1; CAA73797)"
FT /evidence="ECO:0000305"
FT HELIX 1418..1421
FT /evidence="ECO:0007829|PDB:2IWL"
FT STRAND 1422..1433
FT /evidence="ECO:0007829|PDB:2AR5"
FT STRAND 1437..1440
FT /evidence="ECO:0007829|PDB:2AR5"
FT STRAND 1443..1450
FT /evidence="ECO:0007829|PDB:2AR5"
FT STRAND 1457..1462
FT /evidence="ECO:0007829|PDB:2AR5"
FT HELIX 1463..1476
FT /evidence="ECO:0007829|PDB:2AR5"
FT HELIX 1479..1481
FT /evidence="ECO:0007829|PDB:2AR5"
FT STRAND 1491..1495
FT /evidence="ECO:0007829|PDB:2AR5"
FT HELIX 1498..1515
FT /evidence="ECO:0007829|PDB:2AR5"
FT HELIX 1519..1522
FT /evidence="ECO:0007829|PDB:2AR5"
FT HELIX 1525..1530
FT /evidence="ECO:0007829|PDB:2AR5"
FT STRAND 1532..1534
FT /evidence="ECO:0007829|PDB:2AR5"
FT TURN 1535..1537
FT /evidence="ECO:0007829|PDB:2IWL"
FT STRAND 1562..1570
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1573..1582
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1587..1590
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1594..1602
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1622..1631
FT /evidence="ECO:0007829|PDB:6BTY"
FT HELIX 1634..1637
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1641..1648
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1651..1653
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1656..1664
FT /evidence="ECO:0007829|PDB:6BTY"
FT HELIX 1665..1667
FT /evidence="ECO:0007829|PDB:6BTY"
FT STRAND 1674..1679
FT /evidence="ECO:0007829|PDB:6BTY"
SQ SEQUENCE 1686 AA; 190680 MW; 904AA5470F80DAC6 CRC64;
MAQISSNSGF KECPSSHPEP TRAKDVDKEE ALQMEAEALA KLQKDRQVTD NQRGFELSSS
TRKKAQVYNK QDYDLMVFPE SDSQKRALDI DVEKLTQAEL EKLLLDDSFE TKKTPVLPVT
PILSPSFSAQ LYFRPTIQRG QWPPGLPGPS TYALPSIYPS TYSKQAAFQN GFNPRMPTFP
STEPIYLSLP GQSPYFSYPL TPATPFHPQG SLPIYRPVVS TDMAKLFDKI ASTSEFLKNG
KARTDLEITD SKVSNLQVSP KSEDISKFDW LDLDPLSKPK VDNVEVLDHE EEKNVSSLLA
KDPWDAVLLE ERSTANCHLE RKVNGKSLSV ATVTRSQSLN IRTTQLAKAQ GHISQKDPNG
TSSLPTGSSL LQEVEVQNEE MAAFCRSITK LKTKFPYTNH RTNPGYLLSP VTAQRNICGE
NASVKVSIDI EGFQLPVTFT CDVSSTVEII IMQALCWVHD DLNQVDVGSY VLKVCGQEEV
LQNNHCLGSH EHIQNCRKWD TEIRLQLLTF SAMCQNLART AEDDETPVDL NKHLYQIEKP
CKEAMTRHPV EELLDSYHNQ VELALQIENQ HRAVDQVIKA VRKICSALDG VETLAITESV
KKLKRAVNLP RSKTADVTSL FGGEDTSRSS TRGSLNPENP VQVSINQLTA AIYDLLRLHA
NSGRSPTDCA QSSKSVKEAW TTTEQLQFTI FAAHGISSNW VSNYEKYYLI CSLSHNGKDL
FKPIQSKKVG TYKNFFYLIK WDELIIFPIQ ISQLPLESVL HLTLFGILNQ SSGSSPDSNK
QRKGPEALGK VSLPLFDFKR FLTCGTKLLY LWTSSHTNSV PGTVTKKGYV MERIVLQVDF
PSPAFDIIYT TPQVDRSIIQ QHNLETLEND IKGKLLDILH KDSSLGLSKE DKAFLWEKRY
YCFKHPNCLP KILASAPNWK WVNLAKTYSL LHQWPALYPL IALELLDSKF ADQEVRSLAV
TWIEAISDDE LTDLLPQFVQ ALKYEIYLNS SLVQFLLSRA LGNIQIAHNL YWLLKDALHD
VQFSTRYEHV LGALLSVGGK RLREELLKQT KLVQLLGGVA EKVRQASGSA RQVVLQRSME
RVQSFFQKNK CRLPLKPSLV AKELNIKSCS FFSSNAVPLK VTMVNADPMG EEINVMFKVG
EDLRQDMLAL QMIKIMDKIW LKEGLDLRMV IFKCLSTGRD RGMVELVPAS DTLRKIQVEY
GVTGSFKDKP LAEWLRKYNP SEEEYEKASE NFIYSCAGCC VATYVLGICD RHNDNIMLRS
TGHMFHIDFG KFLGHAQMFG SFKRDRAPFV LTSDMAYVIN GGEKPTIRFQ LFVDLCCQAY
NLIRKQTNLF LNLLSLMIPS GLPELTSIQD LKYVRDALQP QTTDAEATIF FTRLIESSLG
SIATKFNFFI HNLAQLRFSG LPSNDEPILS FSPKTYSFRQ DGRIKEVSVF TYHKKYNPDK
HYIYVVRILR EGQIEPSFVF RTFDEFQELH NKLSIIFPLW KLPGFPNRMV LGRTHIKDVA
AKRKIELNSY LQSLMNASTD VAECDLVCTF FHPLLRDEKA EGIARSADAG SFSPTPGQIG
GAVKLSISYR NGTLFIMVMH IKDLVTEDGA DPNPYVKTYL LPDNHKTSKR KTKISRKTRN
PTFNEMLVYS GYSKETLRQR ELQLSVLSAE SLRENFFLGG VTLPLKDFNL SKETVKWYQL
TAATYL
