ZAP70_HUMAN
ID ZAP70_HUMAN Reviewed; 619 AA.
AC P43403; A6NFP4; Q6PIA4; Q8IXD6; Q9UBS6;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 238.
DE RecName: Full=Tyrosine-protein kinase ZAP-70;
DE EC=2.7.10.2;
DE AltName: Full=70 kDa zeta-chain associated protein;
DE AltName: Full=Syk-related tyrosine kinase;
GN Name=ZAP70; Synonyms=SRK;
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, INTERACTION WITH CD247,
RP TISSUE SPECIFICITY, AND PHOSPHORYLATION.
RX PubMed=1423621; DOI=10.1016/0092-8674(92)90598-7;
RA Chan A.C., Iwashima M., Turck C.W., Weiss A.;
RT "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta
RT chain.";
RL Cell 71:649-662(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Leukocyte;
RX PubMed=14985102; DOI=10.1016/j.bbrc.2004.01.127;
RA Kuroyama H., Ikeda T., Kasai M., Yamasaki S., Tatsumi M., Utsuyama M.,
RA Saito T., Hirokawa K.;
RT "Identification of a novel isoform of ZAP-70, truncated ZAP kinase.";
RL Biochem. Biophys. Res. Commun. 315:935-941(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Blood, and Brain;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 521-547, VARIANT IMD48 LEU-GLU-GLN-541 INS,
RP FUNCTION, AND INVOLVEMENT IN IMD48.
RC TISSUE=Lymphoid tissue;
RX PubMed=8124727; DOI=10.1016/0092-8674(94)90368-9;
RA Arpaia E., Shahar M., Dadi H., Cohen A., Roifman C.M.;
RT "Defective T cell receptor signaling and CD8+ thymic selection in humans
RT lacking zap-70 kinase.";
RL Cell 76:947-958(1994).
RN [6]
RP CHARACTERIZATION OF TAM-BINDING.
RX PubMed=7528772; DOI=10.1084/jem.181.1.375;
RA Isakov N., Wange R.L., Burgess W.H., Watts J.D., Aebersold R.,
RA Samelson L.E.;
RT "ZAP-70 binding specificity to T cell receptor tyrosine-based activation
RT motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based
RT activation motifs with varying affinity.";
RL J. Exp. Med. 181:375-380(1995).
RN [7]
RP PHOSPHORYLATION AT TYR-492 AND TYR-493, AND MUTAGENESIS OF TYR-492 AND
RP TYR-493.
RX PubMed=7781602; DOI=10.1002/j.1460-2075.1995.tb07247.x;
RA Chan A.C., Dalton M., Johnson R., Kong G.H., Wang T., Thoma R.,
RA Kurosaki T.;
RT "Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is
RT required for lymphocyte antigen receptor function.";
RL EMBO J. 14:2499-2508(1995).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF LCP2.
RX PubMed=8702662; DOI=10.1074/jbc.271.33.19641;
RA Bubeck Wardenburg J., Fu C., Jackman J.K., Flotow H., Wilkinson S.E.,
RA Williams D.H., Johnson R., Kong G., Chan A.C., Findell P.R.;
RT "Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is
RT required for T-cell receptor function.";
RL J. Biol. Chem. 271:19641-19644(1996).
RN [9]
RP PHOSPHORYLATION AT TYR-292, AND MUTAGENESIS OF TYR-292.
RX PubMed=8943331; DOI=10.1128/mcb.16.12.6765;
RA Zhao Q., Weiss A.;
RT "Enhancement of lymphocyte responsiveness by a gain-of-function mutation of
RT ZAP-70.";
RL Mol. Cell. Biol. 16:6765-6774(1996).
RN [10]
RP INTERACTION WITH VAV1, AND MUTAGENESIS OF TYR-315.
RX PubMed=9151714; DOI=10.1084/jem.185.10.1877;
RA Wu J., Zhao Q., Kurosaki T., Weiss A.;
RT "The Vav binding site (Y315) in ZAP-70 is critical for antigen receptor-
RT mediated signal transduction.";
RL J. Exp. Med. 185:1877-1882(1997).
RN [11]
RP TISSUE SPECIFICITY.
RX PubMed=9378960;
RA Gary-Gouy H., Lang V., Sarun S., Boumsell L., Bismuth G.;
RT "In vivo association of CD5 with tyrosine-phosphorylated ZAP-70 and p21
RT phospho-zeta molecules in human CD3+ thymocytes.";
RL J. Immunol. 159:3739-3747(1997).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF LAT.
RX PubMed=9489702; DOI=10.1016/s0092-8674(00)80901-0;
RA Zhang W., Sloan-Lancaster J., Kitchen J., Trible R.P., Samelson L.E.;
RT "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to
RT cellular activation.";
RL Cell 92:83-92(1998).
RN [13]
RP SUBCELLULAR LOCATION.
RX PubMed=9813084; DOI=10.1083/jcb.143.3.613;
RA Sloan-Lancaster J., Presley J., Ellenberg J., Yamazaki T.,
RA Lippincott-Schwartz J., Samelson L.E.;
RT "ZAP-70 association with T cell receptor zeta (TCRzeta): fluorescence
RT imaging of dynamic changes upon cellular stimulation.";
RL J. Cell Biol. 143:613-624(1998).
RN [14]
RP PHOSPHORYLATION AT TYR-315 AND TYR-319, AND MUTAGENESIS OF TYR-315 AND
RP TYR-319.
RX PubMed=10037717; DOI=10.1074/jbc.274.10.6285;
RA Di Bartolo V., Mege D., Germain V., Pelosi M., Dufour E., Michel F.,
RA Magistrelli G., Isacchi A., Acuto O.;
RT "Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a
RT critical role in T cell antigen receptor signaling.";
RL J. Biol. Chem. 274:6285-6294(1999).
RN [15]
RP INTERACTION WITH CBL AND SLA.
RX PubMed=10449770; DOI=10.1073/pnas.96.17.9775;
RA Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J.;
RT "SLAP, a dimeric adapter protein, plays a functional role in T cell
RT receptor signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999).
RN [16]
RP FUNCTION IN CD3Z UBIQUITINATION.
RX PubMed=11353765; DOI=10.1074/jbc.m010738200;
RA Wang H.Y., Altman Y., Fang D., Elly C., Dai Y., Shao Y., Liu Y.C.;
RT "Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor
RT function of Zap-70.";
RL J. Biol. Chem. 276:26004-26011(2001).
RN [17]
RP INTERACTION WITH FCRL3.
RX PubMed=12051764; DOI=10.1016/s0006-291x(02)00332-7;
RA Xu M.-J., Zhao R., Cao H., Zhao Z.J.;
RT "SPAP2, an Ig family receptor containing both ITIMs and ITAMs.";
RL Biochem. Biophys. Res. Commun. 293:1037-1046(2002).
RN [18]
RP MUTAGENESIS OF TYR-315.
RX PubMed=11828374;
RX DOI=10.1002/1521-4141(200202)32:2<568::aid-immu568>3.0.co;2-q;
RA Di Bartolo V., Malissen M., Dufour E., Sechet E., Malissen B., Acuto O.;
RT "Tyrosine 315 determines optimal recruitment of ZAP-70 to the T cell
RT antigen receptor.";
RL Eur. J. Immunol. 32:568-575(2002).
RN [19]
RP INTERACTION WITH SHB.
RX PubMed=12084069; DOI=10.1046/j.1432-1033.2002.03008.x;
RA Lindholm C.K., Henriksson M.L., Hallberg B., Welsh M.;
RT "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells.";
RL Eur. J. Biochem. 269:3279-3288(2002).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=12522270; DOI=10.1073/pnas.2436191100;
RA Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T., Ericson C.,
RA Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C.;
RT "Profiling of tyrosine phosphorylation pathways in human cells using mass
RT spectrometry.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=15144186; DOI=10.1021/ac035352d;
RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
RA Peters E.C.;
RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from
RT human T cells using immobilized metal affinity chromatography and tandem
RT mass spectrometry.";
RL Anal. Chem. 76:2763-2772(2004).
RN [22]
RP INTERACTION WITH NFAM1.
RX PubMed=15143214; DOI=10.1073/pnas.0401119101;
RA Ohtsuka M., Arase H., Takeuchi A., Yamasaki S., Shiina R., Suenaga T.,
RA Sakurai D., Yokosuka T., Arase N., Iwashima M., Kitamura T., Moriya H.,
RA Saito T.;
RT "NFAM1, an immunoreceptor tyrosine-based activation motif-bearing molecule
RT that regulates B cell development and signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:8126-8131(2004).
RN [23]
RP PHOSPHORYLATION BY LCK.
RX PubMed=16339550; DOI=10.4049/jimmunol.175.12.8123;
RA Gelkop S., Gish G.D., Babichev Y., Pawson T., Isakov N.;
RT "T cell activation-induced CrkII binding to the Zap70 protein tyrosine
RT kinase is mediated by Lck-dependent phosphorylation of Zap70 tyrosine
RT 315.";
RL J. Immunol. 175:8123-8132(2005).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-248, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [25]
RP TISSUE SPECIFICITY.
RX PubMed=16467082; DOI=10.1158/1078-0432.ccr-05-1531;
RA Crespo M., Villamor N., Gine E., Muntanola A., Colomer D., Marafioti T.,
RA Jones M., Camos M., Campo E., Montserrat E., Bosch F.;
RT "ZAP-70 expression in normal pro/pre B cells, mature B cells, and in B-cell
RT acute lymphoblastic leukemia.";
RL Clin. Cancer Res. 12:726-734(2006).
RN [26]
RP DEPHOSPHORYLATION BY PTN22.
RX PubMed=16461343; DOI=10.1074/jbc.m600498200;
RA Wu J., Katrekar A., Honigberg L.A., Smith A.M., Conn M.T., Tang J.,
RA Jeffery D., Mortara K., Sampang J., Williams S.R., Buggy J., Clark J.M.;
RT "Identification of substrates of human protein-tyrosine phosphatase
RT PTPN22.";
RL J. Biol. Chem. 281:11002-11010(2006).
RN [27]
RP REVIEW ON FUNCTION.
RX PubMed=19290920; DOI=10.1111/j.1600-065x.2008.00753.x;
RA Au-Yeung B.B., Deindl S., Hsu L.Y., Palacios E.H., Levin S.E., Kuriyan J.,
RA Weiss A.;
RT "The structure, regulation, and function of ZAP-70.";
RL Immunol. Rev. 228:41-57(2009).
RN [28]
RP INTERACTION WITH FCRL3.
RX PubMed=19843936; DOI=10.4049/jimmunol.0901982;
RA Kochi Y., Myouzen K., Yamada R., Suzuki A., Kurosaki T., Nakamura Y.,
RA Yamamoto K.;
RT "FCRL3, an autoimmune susceptibility gene, has inhibitory potential on B-
RT cell receptor-mediated signaling.";
RL J. Immunol. 183:5502-5510(2009).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-292, 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 [30]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-603, 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 [31]
RP FUNCTION, AND DOMAIN.
RX PubMed=20135127; DOI=10.1007/s00281-010-0196-x;
RA Fischer A., Picard C., Chemin K., Dogniaux S., le Deist F., Hivroz C.;
RT "ZAP70: a master regulator of adaptive immunity.";
RL Semin. Immunopathol. 32:107-116(2010).
RN [32]
RP FUNCTION, INTERACTION WITH OTUD7B AND UBASH3B, UBIQUITINATION AT LYS-544,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF LYS-304; LYS-538
RP AND LYS-544.
RX PubMed=26903241; DOI=10.1084/jem.20151426;
RA Hu H., Wang H., Xiao Y., Jin J., Chang J.H., Zou Q., Xie X., Cheng X.,
RA Sun S.C.;
RT "Otud7b facilitates T cell activation and inflammatory responses by
RT regulating Zap70 ubiquitination.";
RL J. Exp. Med. 213:399-414(2016).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 3-256 IN COMPLEX WITH CD247, AND
RP INTERACTION WITH CD247.
RX PubMed=7659156; DOI=10.1038/377032a0;
RA Hatada M.H., Lu X., Laird E.R., Green J., Morgenstern J.P., Lou M.,
RA Marr C.S., Phillips T.B., Ram M.K., Theriault K., Zoller M.J., Karas L.K.;
RT "Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with
RT the T-cell receptor.";
RL Nature 377:32-38(1995).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 286-297 IN COMPLEX WITH CBL, AND
RP INTERACTION WITH CBL.
RX PubMed=10078535; DOI=10.1038/18050;
RA Meng W., Sawasdikosol S., Burakoff S.J., Eck M.J.;
RT "Structure of the amino-terminal domain of Cbl complexed to its binding
RT site on ZAP-70 kinase.";
RL Nature 398:84-90(1999).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 289-297 IN COMPLEX WITH CBL AND
RP UBE2L3.
RX PubMed=10966114; DOI=10.1016/s0092-8674(00)00057-x;
RA Zheng N., Wang P., Jeffrey P.D., Pavletich N.P.;
RT "Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-
RT protein ligases.";
RL Cell 102:533-539(2000).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-256.
RX PubMed=12450381; DOI=10.1021/bi026465e;
RA Folmer R.H., Geschwindner S., Xue Y.;
RT "Crystal structure and NMR studies of the apo SH2 domains of ZAP-70: two
RT bikes rather than a tandem.";
RL Biochemistry 41:14176-14184(2002).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 327-606 IN COMPLEX WITH
RP STAUROSPORINE, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF ASP-479, AND
RP ACTIVITY REGULATION.
RX PubMed=15292186; DOI=10.1074/jbc.m407096200;
RA Jin L., Pluskey S., Petrella E.C., Cantin S.M., Gorga J.C.,
RA Rynkiewicz M.J., Pandey P., Strickler J.E., Babine R.E., Weaver D.T.,
RA Seidl K.J.;
RT "The three-dimensional structure of the ZAP-70 kinase domain in complex
RT with staurosporine: implications for the design of selective inhibitors.";
RL J. Biol. Chem. 279:42818-42825(2004).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 1-606 OF MUTANT ASN-461 IN COMPLEX
RP WITH MAGNESIUM AND ATP ANALOG, ACTIVE SITE, AND MUTAGENESIS OF TRP-131;
RP LEU-133; ALA-141; SER-144; GLN-145; PRO-147; TYR-315; TYR-319; ASP-461;
RP TYR-597 AND TYR-598.
RX PubMed=17512407; DOI=10.1016/j.cell.2007.03.039;
RA Deindl S., Kadlecek T.A., Brdicka T., Cao X., Weiss A., Kuriyan J.;
RT "Structural basis for the inhibition of tyrosine kinase activity of ZAP-
RT 70.";
RL Cell 129:735-746(2007).
RN [39]
RP VARIANT IMD48 ARG-518.
RX PubMed=8202713; DOI=10.1126/science.8202713;
RA Chan A.C., Kadlecek T.A., Elder M.E., Filipovich A.H., Kuo W.-L.,
RA Iwashima M., Parslow T.G., Weiss A.;
RT "ZAP-70 deficiency in an autosomal recessive form of severe combined
RT immunodeficiency.";
RL Science 264:1599-1601(1994).
RN [40]
RP VARIANT IMD48 HIS-465.
RX PubMed=11412303; DOI=10.1046/j.1365-2567.2001.01246.x;
RA Toyabe S., Watanabe A., Harada W., Karasawa T., Uchiyama M.;
RT "Specific immunoglobulin E responses in ZAP-70-deficient patients are
RT mediated by Syk-dependent T-cell receptor signalling.";
RL Immunology 103:164-171(2001).
RN [41]
RP VARIANT IMD48 CYS-465.
RX PubMed=11123350; DOI=10.4049/jimmunol.166.1.656;
RA Elder M.E., Skoda-Smith S., Kadlecek T.A., Wang F., Wu J., Weiss A.;
RT "Distinct T cell developmental consequences in humans and mice expressing
RT identical mutations in the DLAARN motif of ZAP-70.";
RL J. Immunol. 166:656-661(2001).
RN [42]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-175; LEU-191; GLU-448 AND LEU-523.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [43]
RP VARIANTS IMD48 ARG-337; VAL-507 AND ARG-564.
RX PubMed=18509675; DOI=10.1007/s00431-008-0718-x;
RA Turul T., Tezcan I., Artac H., de Bruin-Versteeg S., Barendregt B.H.,
RA Reisli I., Sanal O., van Dongen J.J., van der Burg M.;
RT "Clinical heterogeneity can hamper the diagnosis of patients with ZAP70
RT deficiency.";
RL Eur. J. Pediatr. 168:87-93(2009).
RN [44]
RP VARIANTS ADMIO2 TRP-192 AND PRO-360, CHARACTERIZATION OF VARIANTS ADMIO2
RP TRP-192 AND PRO-360, INVOLVEMENT IN ADMIO2, INTERACTION WITH CD247, AND
RP MUTAGENESIS OF ARG-37; ARG-190; 315-TYR--TYR-319; ASP-327 AND LYS-362.
RX PubMed=26783323; DOI=10.1084/jem.20150888;
RA Chan A.Y., Punwani D., Kadlecek T.A., Cowan M.J., Olson J.L., Mathes E.F.,
RA Sunderam U., Fu S.M., Srinivasan R., Kuriyan J., Brenner S.E., Weiss A.,
RA Puck J.M.;
RT "A novel human autoimmune syndrome caused by combined hypomorphic and
RT activating mutations in ZAP-70.";
RL J. Exp. Med. 213:155-165(2016).
CC -!- FUNCTION: Tyrosine kinase that plays an essential role in regulation of
CC the adaptive immune response. Regulates motility, adhesion and cytokine
CC expression of mature T-cells, as well as thymocyte development.
CC Contributes also to the development and activation of primary B-
CC lymphocytes. When antigen presenting cells (APC) activate T-cell
CC receptor (TCR), a serie of phosphorylations lead to the recruitment of
CC ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through
CC ITAM motif at the plasma membrane. This recruitment serves to
CC localization to the stimulated TCR and to relieve its autoinhibited
CC conformation. Release of ZAP70 active conformation is further
CC stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70
CC phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In
CC turn, a large number of signaling molecules are recruited and
CC ultimately lead to lymphokine production, T-cell proliferation and
CC differentiation. Furthermore, ZAP70 controls cytoskeleton
CC modifications, adhesion and mobility of T-lymphocytes, thus ensuring
CC correct delivery of effectors to the APC. ZAP70 is also required for
CC TCR-CD247/CD3Z internalization and degradation through interaction with
CC the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2.
CC Thus, ZAP70 regulates both T-cell activation switch on and switch off
CC by modulating TCR expression at the T-cell surface. During thymocyte
CC development, ZAP70 promotes survival and cell-cycle progression of
CC developing thymocytes before positive selection (when cells are still
CC CD4/CD8 double negative). Additionally, ZAP70-dependent signaling
CC pathway may also contribute to primary B-cells formation and activation
CC through B-cell receptor (BCR). {ECO:0000269|PubMed:11353765,
CC ECO:0000269|PubMed:12051764, ECO:0000269|PubMed:1423621,
CC ECO:0000269|PubMed:20135127, ECO:0000269|PubMed:26903241,
CC ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8702662,
CC ECO:0000269|PubMed:9489702}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028,
CC ECO:0000269|PubMed:15292186};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-493 in the
CC activation loop. Inhibited by staurosporine.
CC {ECO:0000269|PubMed:15292186}.
CC -!- SUBUNIT: Interacts with CD247/CD3Z; this interaction docks ZAP70 at the
CC stimulated TCR (PubMed:1423621, PubMed:7659156, PubMed:26783323).
CC Interacts with NFAM1 (PubMed:15143214). Interacts with adapter protein
CC SLA; this interaction negatively regulates T-cell receptor signaling
CC (PubMed:10449770). Interacts with FCRL3 (PubMed:12051764,
CC PubMed:19843936). Interacts with VAV1 (PubMed:9151714). Interacts with
CC CBL; this interaction promotes ubiquitination, internalization and
CC subsequent degradation of CD247/CD3Z (PubMed:10449770,
CC PubMed:10078535). Identified in a complex with CBL and UBE2L3
CC (PubMed:10966114). Interacts with SHB (PubMed:12084069). Interacts with
CC adapter protein SLA2; this interaction negatively regulates T-cell
CC receptor signaling. Interacts with CBLB. Interacts (via SH2 domains)
CC with RHOH; this interaction regulates ZAP70 subcellular localization.
CC Interacts with DEF6 (By similarity). Interacts (ubiquitinated form)
CC with OTUD7B and UBASH3B (PubMed:26903241).
CC {ECO:0000250|UniProtKB:P43404, ECO:0000269|PubMed:10078535,
CC ECO:0000269|PubMed:10449770, ECO:0000269|PubMed:10966114,
CC ECO:0000269|PubMed:12051764, ECO:0000269|PubMed:12084069,
CC ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:15143214,
CC ECO:0000269|PubMed:19843936, ECO:0000269|PubMed:26783323,
CC ECO:0000269|PubMed:26903241, ECO:0000269|PubMed:7659156,
CC ECO:0000269|PubMed:9151714}.
CC -!- INTERACTION:
CC P43403; P22681: CBL; NbExp=3; IntAct=EBI-1211276, EBI-518228;
CC P43403; P20963: CD247; NbExp=23; IntAct=EBI-1211276, EBI-1165705;
CC P43403; P07766: CD3E; NbExp=3; IntAct=EBI-1211276, EBI-1211297;
CC P43403; P00533: EGFR; NbExp=3; IntAct=EBI-1211276, EBI-297353;
CC P43403; P10721: KIT; NbExp=2; IntAct=EBI-1211276, EBI-1379503;
CC P43403; P06239: LCK; NbExp=2; IntAct=EBI-1211276, EBI-1348;
CC P43403; P08581: MET; NbExp=2; IntAct=EBI-1211276, EBI-1039152;
CC P43403; Q9Y2R2: PTPN22; NbExp=4; IntAct=EBI-1211276, EBI-1211241;
CC P43403; Q8N1K5-1: THEMIS; NbExp=3; IntAct=EBI-1211276, EBI-15102259;
CC P43403; Q8BGG7: Ubash3b; Xeno; NbExp=10; IntAct=EBI-1211276, EBI-8846415;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9813084}. Cell
CC membrane {ECO:0000269|PubMed:9813084}; Peripheral membrane protein
CC {ECO:0000269|PubMed:9813084}. Note=In quiescent T-lymphocytes, it is
CC cytoplasmic. Upon TCR activation, it is recruited at the plasma
CC membrane by interacting with CD247/CD3Z. Colocalizes together with RHOH
CC in the immunological synapse. RHOH is required for its proper
CC localization to the cell membrane and cytoskeleton fractions in the
CC thymocytes (By similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P43403-1; Sequence=Displayed;
CC Name=2; Synonyms=TZK;
CC IsoId=P43403-2; Sequence=VSP_031156;
CC Name=3;
CC IsoId=P43403-3; Sequence=VSP_031157, VSP_031158;
CC -!- TISSUE SPECIFICITY: Expressed in T- and natural killer cells. Also
CC present in early thymocytes and pro/pre B-cells.
CC {ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:16467082,
CC ECO:0000269|PubMed:9378960}.
CC -!- DOMAIN: Composed of 2 N-terminal SH2 domains and a C-terminal kinase
CC domain. The tandem SH2 domains bind to the doubly phosphorylated
CC tyrosine-based activation motif (ITAM) of CD247/CD3Z and the non-
CC canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH
CC (By similarity). The interdomain B located between the second SH2 and
CC the kinase domain contains 3 tyrosines (Tyr-292, Tyr-315, Tyr-319) that
CC are phosphorylated following TCR activation. These sites have been
CC implicated in binding to other signaling molecules including CBL or
CC VAV1. Thus, ZAP70 can also function as a scaffold by recruiting
CC additional factors to the stimulated TCR complex. {ECO:0000250,
CC ECO:0000269|PubMed:20135127}.
CC -!- PTM: Phosphorylated on tyrosine residues upon T-cell antigen receptor
CC (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319 are essential
CC for ZAP70 positive function on T-lymphocyte activation whereas Tyr-292
CC has a negative regulatory role. Within the C-terminal kinase domain,
CC Tyr-492 and Tyr-493 are phosphorylated after TCR induction, Tyr-492
CC playing a negative regulatory role and Tyr-493 a positive. Tyr-493 is
CC dephosphorylated by PTN22. {ECO:0000269|PubMed:10037717,
CC ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:16339550,
CC ECO:0000269|PubMed:8943331}.
CC -!- PTM: Ubiquitinated in response to T cell activation. Deubiquitinated by
CC OTUD7B. {ECO:0000269|PubMed:26903241}.
CC -!- DISEASE: Immunodeficiency 48 (IMD48) [MIM:269840]: A form of severe
CC immunodeficiency characterized by a selective absence of CD8+ T-cells.
CC {ECO:0000269|PubMed:11123350, ECO:0000269|PubMed:11412303,
CC ECO:0000269|PubMed:18509675, ECO:0000269|PubMed:8124727,
CC ECO:0000269|PubMed:8202713}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Autoimmune disease, multisystem, infantile-onset, 2 (ADMIO2)
CC [MIM:617006]: An autosomal recessive, autoimmune disorder characterized
CC by systemic manifestations including blistering skin disease,
CC uncontrollable bullous pemphigoid, inflammatory colitis, autoimmune
CC hypothyroidism, proteinuria and nephrotic syndrome.
CC {ECO:0000269|PubMed:26783323}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. SYK/ZAP-70 subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
CC -!- WEB RESOURCE: Name=ZAP70base; Note=ZAP70 mutation db;
CC URL="http://structure.bmc.lu.se/idbase/ZAP70base/";
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DR EMBL; L05148; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AB083211; BAC43747.1; -; mRNA.
DR EMBL; AC016699; AAX93187.1; -; Genomic_DNA.
DR EMBL; BC039039; AAH39039.1; -; mRNA.
DR EMBL; BC053878; AAH53878.1; -; mRNA.
DR CCDS; CCDS33254.1; -. [P43403-1]
DR CCDS; CCDS33255.1; -. [P43403-2]
DR PIR; A44266; A44266.
DR PIR; A49955; A49955.
DR RefSeq; NP_001070.2; NM_001079.3. [P43403-1]
DR RefSeq; NP_997402.1; NM_207519.1. [P43403-2]
DR PDB; 1FBV; X-ray; 2.90 A; B=289-297.
DR PDB; 1M61; X-ray; 2.50 A; A=1-256.
DR PDB; 1U59; X-ray; 2.30 A; A=327-606.
DR PDB; 2CBL; X-ray; 2.10 A; B=286-297.
DR PDB; 2OQ1; X-ray; 1.90 A; A=3-256.
DR PDB; 2OZO; X-ray; 2.60 A; A=1-606.
DR PDB; 2Y1N; X-ray; 2.00 A; B/D=286-297.
DR PDB; 3ZNI; X-ray; 2.21 A; B/F/J/N=286-297.
DR PDB; 4A4B; X-ray; 2.79 A; B=286-297.
DR PDB; 4A4C; X-ray; 2.70 A; B=286-297.
DR PDB; 4K2R; X-ray; 3.00 A; A=1-606.
DR PDB; 4XZ0; X-ray; 2.00 A; A=1-259.
DR PDB; 4XZ1; X-ray; 2.80 A; A=1-259.
DR PDB; 5O76; X-ray; 2.47 A; B/D=286-297.
DR PDBsum; 1FBV; -.
DR PDBsum; 1M61; -.
DR PDBsum; 1U59; -.
DR PDBsum; 2CBL; -.
DR PDBsum; 2OQ1; -.
DR PDBsum; 2OZO; -.
DR PDBsum; 2Y1N; -.
DR PDBsum; 3ZNI; -.
DR PDBsum; 4A4B; -.
DR PDBsum; 4A4C; -.
DR PDBsum; 4K2R; -.
DR PDBsum; 4XZ0; -.
DR PDBsum; 4XZ1; -.
DR PDBsum; 5O76; -.
DR AlphaFoldDB; P43403; -.
DR SMR; P43403; -.
DR BioGRID; 113367; 68.
DR CORUM; P43403; -.
DR DIP; DIP-38781N; -.
DR ELM; P43403; -.
DR IntAct; P43403; 76.
DR MINT; P43403; -.
DR STRING; 9606.ENSP00000264972; -.
DR BindingDB; P43403; -.
DR ChEMBL; CHEMBL2803; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB02010; Staurosporine.
DR DrugCentral; P43403; -.
DR GuidetoPHARMACOLOGY; 2285; -.
DR GlyGen; P43403; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P43403; -.
DR MetOSite; P43403; -.
DR PhosphoSitePlus; P43403; -.
DR BioMuta; ZAP70; -.
DR DMDM; 1177044; -.
DR jPOST; P43403; -.
DR MassIVE; P43403; -.
DR MaxQB; P43403; -.
DR PaxDb; P43403; -.
DR PeptideAtlas; P43403; -.
DR PRIDE; P43403; -.
DR ProteomicsDB; 55631; -. [P43403-1]
DR ProteomicsDB; 55632; -. [P43403-2]
DR ProteomicsDB; 55633; -. [P43403-3]
DR Antibodypedia; 685; 2256 antibodies from 50 providers.
DR CPTC; P43403; 1 antibody.
DR DNASU; 7535; -.
DR Ensembl; ENST00000264972.10; ENSP00000264972.5; ENSG00000115085.14. [P43403-1]
DR Ensembl; ENST00000451498.2; ENSP00000400475.2; ENSG00000115085.14. [P43403-2]
DR GeneID; 7535; -.
DR KEGG; hsa:7535; -.
DR MANE-Select; ENST00000264972.10; ENSP00000264972.5; NM_001079.4; NP_001070.2.
DR UCSC; uc002syd.2; human. [P43403-1]
DR CTD; 7535; -.
DR DisGeNET; 7535; -.
DR GeneCards; ZAP70; -.
DR GeneReviews; ZAP70; -.
DR HGNC; HGNC:12858; ZAP70.
DR HPA; ENSG00000115085; Tissue enhanced (bone marrow, lymphoid tissue).
DR MalaCards; ZAP70; -.
DR MIM; 176947; gene.
DR MIM; 269840; phenotype.
DR MIM; 617006; phenotype.
DR neXtProt; NX_P43403; -.
DR OpenTargets; ENSG00000115085; -.
DR Orphanet; 911; Combined immunodeficiency due to ZAP70 deficiency.
DR PharmGKB; PA37447; -.
DR VEuPathDB; HostDB:ENSG00000115085; -.
DR eggNOG; ENOG502QT06; Eukaryota.
DR GeneTree; ENSGT00940000159185; -.
DR HOGENOM; CLU_000288_7_2_1; -.
DR InParanoid; P43403; -.
DR OMA; ACPNTSA; -.
DR OrthoDB; 827472at2759; -.
DR PhylomeDB; P43403; -.
DR TreeFam; TF351629; -.
DR BRENDA; 2.7.10.2; 2681.
DR PathwayCommons; P43403; -.
DR Reactome; R-HSA-202430; Translocation of ZAP-70 to Immunological synapse.
DR Reactome; R-HSA-202433; Generation of second messenger molecules.
DR Reactome; R-HSA-9013407; RHOH GTPase cycle.
DR SignaLink; P43403; -.
DR SIGNOR; P43403; -.
DR BioGRID-ORCS; 7535; 10 hits in 1101 CRISPR screens.
DR ChiTaRS; ZAP70; human.
DR EvolutionaryTrace; P43403; -.
DR GeneWiki; ZAP70; -.
DR GenomeRNAi; 7535; -.
DR Pharos; P43403; Tchem.
DR PRO; PR:P43403; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P43403; protein.
DR Bgee; ENSG00000115085; Expressed in granulocyte and 109 other tissues.
DR Genevisible; P43403; HS.
DR GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; TAS:HGNC-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
DR GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
DR GO; GO:0042101; C:T cell receptor complex; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0001784; F:phosphotyrosine residue binding; IMP:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0002250; P:adaptive immune response; TAS:UniProtKB.
DR GO; GO:0042113; P:B cell activation; TAS:UniProtKB.
DR GO; GO:0043366; P:beta selection; IEA:Ensembl.
DR GO; GO:0019722; P:calcium-mediated signaling; IEA:Ensembl.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0006955; P:immune response; IDA:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0035556; P:intracellular signal transduction; NAS:UniProtKB.
DR GO; GO:0045060; P:negative thymic T cell selection; IEA:Ensembl.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:MGI.
DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IEA:Ensembl.
DR GO; GO:0046641; P:positive regulation of alpha-beta T cell proliferation; IEA:Ensembl.
DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IEA:Ensembl.
DR GO; GO:0045582; P:positive regulation of T cell differentiation; IDA:MGI.
DR GO; GO:0045059; P:positive thymic T cell selection; IDA:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0042110; P:T cell activation; TAS:UniProtKB.
DR GO; GO:0070489; P:T cell aggregation; TAS:UniProtKB.
DR GO; GO:0030217; P:T cell differentiation; NAS:UniProtKB.
DR GO; GO:0072678; P:T cell migration; TAS:UniProtKB.
DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR CDD; cd09938; SH2_N-SH2_Zap70_Syk_like; 1.
DR DisProt; DP01123; -.
DR Gene3D; 1.10.930.10; -; 1.
DR Gene3D; 3.30.505.10; -; 2.
DR IDEAL; IID00553; -.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR023420; Kinase_SYK/ZAP-70_inter-SH2_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR035838; SYK/ZAP-70_N_SH2.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR012234; Tyr_kinase_non-rcpt_SYK/ZAP70.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF00017; SH2; 2.
DR PIRSF; PIRSF000604; TyrPK_SYK; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00252; SH2; 2.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF55550; SSF55550; 2.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50001; SH2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Adaptive immunity; Alternative splicing;
KW ATP-binding; Cell membrane; Cytoplasm; Disease variant; Immunity;
KW Isopeptide bond; Kinase; Membrane; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat; SCID; SH2 domain; Transferase;
KW Tyrosine-protein kinase; Ubl conjugation.
FT CHAIN 1..619
FT /note="Tyrosine-protein kinase ZAP-70"
FT /id="PRO_0000088168"
FT DOMAIN 10..102
FT /note="SH2 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 163..254
FT /note="SH2 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 338..600
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 103..162
FT /note="Interdomain A"
FT REGION 255..337
FT /note="Interdomain B"
FT REGION 260..309
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 274..288
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 461
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028,
FT ECO:0000269|PubMed:15292186, ECO:0000269|PubMed:17512407"
FT BINDING 345..352
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 369
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 248
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:15592455"
FT MOD_RES 289
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:15144186"
FT MOD_RES 292
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:8943331,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 315
FT /note="Phosphotyrosine; by LCK"
FT /evidence="ECO:0000269|PubMed:10037717"
FT MOD_RES 319
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:10037717"
FT MOD_RES 492
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:7781602"
FT MOD_RES 493
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:7781602"
FT MOD_RES 603
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT CROSSLNK 544
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:26903241"
FT VAR_SEQ 1..307
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14985102"
FT /id="VSP_031156"
FT VAR_SEQ 1..126
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_031157"
FT VAR_SEQ 127..134
FT /note="VRQTWKLE -> MRLGPRWK (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_031158"
FT VARIANT 175
FT /note="R -> L (in dbSNP:rs55964305)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041846"
FT VARIANT 191
FT /note="P -> L (in dbSNP:rs56403250)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041847"
FT VARIANT 192
FT /note="R -> W (in ADMIO2; decreases interaction with
FT phosphorylated CD247; decreases ZAP70 phosphorylation; no
FT effect on subcellular localization of CD69 at the cell
FT surface; dbSNP:rs199840952)"
FT /evidence="ECO:0000269|PubMed:26783323"
FT /id="VAR_077137"
FT VARIANT 337
FT /note="L -> R (in IMD48; dbSNP:rs1254428002)"
FT /evidence="ECO:0000269|PubMed:18509675"
FT /id="VAR_065623"
FT VARIANT 360
FT /note="R -> P (in ADMIO2; no effect on interaction with
FT phosphorylated CD247; increases TCR-induced Y-319 and Y-493
FT phosphorylation of ZAP70 and phosphorylation of LAT and
FT LCP2; increases subcellular localization of CD69 at the
FT cell surface; weakly decreases autoinhibition conformation;
FT dbSNP:rs869025224)"
FT /evidence="ECO:0000269|PubMed:26783323"
FT /id="VAR_077138"
FT VARIANT 448
FT /note="G -> E (in a head and neck squamous cell carcinoma
FT sample; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041848"
FT VARIANT 465
FT /note="R -> C (in IMD48; dbSNP:rs113994174)"
FT /evidence="ECO:0000269|PubMed:11123350"
FT /id="VAR_065624"
FT VARIANT 465
FT /note="R -> H (in IMD48; dbSNP:rs137853201)"
FT /evidence="ECO:0000269|PubMed:11412303"
FT /id="VAR_015538"
FT VARIANT 507
FT /note="A -> V (in IMD48)"
FT /evidence="ECO:0000269|PubMed:18509675"
FT /id="VAR_065625"
FT VARIANT 518
FT /note="S -> R (in IMD48; dbSNP:rs104893674)"
FT /evidence="ECO:0000269|PubMed:8202713"
FT /id="VAR_006351"
FT VARIANT 523
FT /note="W -> L (in dbSNP:rs56189815)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041849"
FT VARIANT 541
FT /note="K -> KLEQ (in IMD48)"
FT /evidence="ECO:0000269|PubMed:8124727"
FT /id="VAR_038688"
FT VARIANT 564
FT /note="C -> R (in IMD48)"
FT /evidence="ECO:0000269|PubMed:18509675"
FT /id="VAR_065626"
FT MUTAGEN 37
FT /note="R->K: Decreases interaction with phosphorylated
FT CD247; when associated with K-190."
FT /evidence="ECO:0000269|PubMed:26783323"
FT MUTAGEN 131
FT /note="W->A: Increased constitutive kinase activity."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 133
FT /note="L->A: Increased constitutive kinase activity."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 141
FT /note="A->E: Increased constitutive kinase activity."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 144
FT /note="S->A: Increased kinase activity after activation by
FT LCK."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 145
FT /note="Q->A: Increased kinase activity after activation by
FT LCK."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 147
FT /note="P->A: Increased kinase activity after activation by
FT LCK."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 190
FT /note="R->K: Decreases interaction with phosphorylated
FT CD247; when associated with K-37."
FT /evidence="ECO:0000269|PubMed:26783323"
FT MUTAGEN 292
FT /note="Y->F: Induces constitutive TCR stimulation-
FT independent NFAT induction."
FT /evidence="ECO:0000269|PubMed:8943331"
FT MUTAGEN 304
FT /note="K->R: No effect on ubiquitination."
FT /evidence="ECO:0000269|PubMed:26903241"
FT MUTAGEN 314
FT /note="V->A: Increased constitutive kinase activity."
FT MUTAGEN 315..319
FT /note="YESPY->AESPA: Increases strongly constitutive kinase
FT activity on LAT phosphorylation."
FT /evidence="ECO:0000269|PubMed:26783323"
FT MUTAGEN 315
FT /note="Y->A: Increased constitutive kinase activity; when
FT associated with F-319."
FT /evidence="ECO:0000269|PubMed:10037717,
FT ECO:0000269|PubMed:11828374, ECO:0000269|PubMed:17512407,
FT ECO:0000269|PubMed:9151714"
FT MUTAGEN 315
FT /note="Y->F: Increased constitutive kinase activity; when
FT associated with F-319. About 75% loss of CD247/CD3Z-binding
FT in stimulated TCR and complete loss of VAV1 interaction."
FT /evidence="ECO:0000269|PubMed:10037717,
FT ECO:0000269|PubMed:11828374, ECO:0000269|PubMed:17512407,
FT ECO:0000269|PubMed:9151714"
FT MUTAGEN 319
FT /note="Y->A: Increased constitutive kinase activity; when
FT associated with F-315."
FT /evidence="ECO:0000269|PubMed:10037717,
FT ECO:0000269|PubMed:17512407"
FT MUTAGEN 319
FT /note="Y->F: Increased constitutive kinase activity; when
FT associated with F-315. About 80% loss of TCR-induced NFAT
FT activation."
FT /evidence="ECO:0000269|PubMed:10037717,
FT ECO:0000269|PubMed:17512407"
FT MUTAGEN 327
FT /note="D->P: Increases constitutive kinase activity on LAT
FT phosphorylation, strongly increases subcellular
FT localization of CD69 at the cell surface and decreases
FT autoinhibition conformation."
FT /evidence="ECO:0000269|PubMed:26783323"
FT MUTAGEN 362
FT /note="K->E: Increases constitutive kinase activity on LAT
FT phosphorylation, strongly increases subcellular
FT localization of CD69 at the cell surface and decreases
FT autoinhibition conformation."
FT /evidence="ECO:0000269|PubMed:26783323"
FT MUTAGEN 461
FT /note="D->N: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 479
FT /note="D->N: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:15292186"
FT MUTAGEN 492
FT /note="Y->F: Increases kinase activity."
FT /evidence="ECO:0000269|PubMed:7781602"
FT MUTAGEN 493
FT /note="Y->F: Impairs kinase activity."
FT /evidence="ECO:0000269|PubMed:7781602"
FT MUTAGEN 538
FT /note="K->R: No effect on ubiquitination."
FT /evidence="ECO:0000269|PubMed:26903241"
FT MUTAGEN 544
FT /note="K->R: Strongly decreased ubiquitination."
FT /evidence="ECO:0000269|PubMed:26903241"
FT MUTAGEN 597
FT /note="Y->A: Increased kinase activity after activation by
FT LCK."
FT /evidence="ECO:0000269|PubMed:17512407"
FT MUTAGEN 598
FT /note="Y->A: Increased kinase activity after activation by
FT LCK."
FT /evidence="ECO:0000269|PubMed:17512407"
FT TURN 4..7
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 11..14
FT /evidence="ECO:0007829|PDB:1M61"
FT HELIX 17..26
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 34..38
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 40..42
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 46..52
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 55..63
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:2OQ1"
FT HELIX 80..89
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 94..96
FT /evidence="ECO:0007829|PDB:2OQ1"
FT HELIX 114..131
FT /evidence="ECO:0007829|PDB:2OQ1"
FT HELIX 135..156
FT /evidence="ECO:0007829|PDB:2OQ1"
FT HELIX 157..160
FT /evidence="ECO:0007829|PDB:2OQ1"
FT HELIX 170..178
FT /evidence="ECO:0007829|PDB:2OQ1"
FT TURN 179..181
FT /evidence="ECO:0007829|PDB:1M61"
FT STRAND 186..191
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 197..204
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 207..215
FT /evidence="ECO:0007829|PDB:2OQ1"
FT TURN 217..219
FT /evidence="ECO:0007829|PDB:4XZ1"
FT STRAND 221..223
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 229..231
FT /evidence="ECO:0007829|PDB:2OQ1"
FT HELIX 232..241
FT /evidence="ECO:0007829|PDB:2OQ1"
FT STRAND 246..248
FT /evidence="ECO:0007829|PDB:2OQ1"
FT HELIX 309..311
FT /evidence="ECO:0007829|PDB:4K2R"
FT STRAND 316..320
FT /evidence="ECO:0007829|PDB:2OZO"
FT HELIX 322..326
FT /evidence="ECO:0007829|PDB:4K2R"
FT HELIX 334..336
FT /evidence="ECO:0007829|PDB:1U59"
FT STRAND 337..345
FT /evidence="ECO:0007829|PDB:1U59"
FT STRAND 350..357
FT /evidence="ECO:0007829|PDB:1U59"
FT STRAND 364..371
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 377..392
FT /evidence="ECO:0007829|PDB:1U59"
FT STRAND 401..415
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 422..426
FT /evidence="ECO:0007829|PDB:1U59"
FT TURN 430..432
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 435..454
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 464..466
FT /evidence="ECO:0007829|PDB:1U59"
FT STRAND 467..471
FT /evidence="ECO:0007829|PDB:1U59"
FT STRAND 474..477
FT /evidence="ECO:0007829|PDB:1U59"
FT TURN 482..485
FT /evidence="ECO:0007829|PDB:2OZO"
FT HELIX 503..505
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 508..513
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 518..533
FT /evidence="ECO:0007829|PDB:1U59"
FT TURN 534..536
FT /evidence="ECO:0007829|PDB:4K2R"
FT TURN 539..542
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 546..553
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 566..574
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 580..582
FT /evidence="ECO:0007829|PDB:1U59"
FT HELIX 586..601
FT /evidence="ECO:0007829|PDB:1U59"
SQ SEQUENCE 619 AA; 69872 MW; D1E1A8EC66FA116F CRC64;
MPDPAAHLPF FYGSISRAEA EEHLKLAGMA DGLFLLRQCL RSLGGYVLSL VHDVRFHHFP
IERQLNGTYA IAGGKAHCGP AELCEFYSRD PDGLPCNLRK PCNRPSGLEP QPGVFDCLRD
AMVRDYVRQT WKLEGEALEQ AIISQAPQVE KLIATTAHER MPWYHSSLTR EEAERKLYSG
AQTDGKFLLR PRKEQGTYAL SLIYGKTVYH YLISQDKAGK YCIPEGTKFD TLWQLVEYLK
LKADGLIYCL KEACPNSSAS NASGAAAPTL PAHPSTLTHP QRRIDTLNSD GYTPEPARIT
SPDKPRPMPM DTSVYESPYS DPEELKDKKL FLKRDNLLIA DIELGCGNFG SVRQGVYRMR
KKQIDVAIKV LKQGTEKADT EEMMREAQIM HQLDNPYIVR LIGVCQAEAL MLVMEMAGGG
PLHKFLVGKR EEIPVSNVAE LLHQVSMGMK YLEEKNFVHR DLAARNVLLV NRHYAKISDF
GLSKALGADD SYYTARSAGK WPLKWYAPEC INFRKFSSRS DVWSYGVTMW EALSYGQKPY
KKMKGPEVMA FIEQGKRMEC PPECPPELYA LMSDCWIYKW EDRPDFLTVE QRMRACYYSL
ASKVEGPPGS TQKAEAACA
