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 02-SEP-2026, entry version 257. DE RecName: Full=Tyrosine-protein kinase ZAP-70; DE EC=2.7.10.2 {ECO:0000269|PubMed:15292186}; 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 FUNCTION. RX PubMed=7509083; DOI=10.1126/science.7509083; RA Iwashima M., Irving B.A., van Oers N.S., Chan A.C., Weiss A.; RT "Sequential interactions of the TCR with two distinct cytoplasmic tyrosine RT kinases."; RL Science 263:1136-1139(1994). RN [7] 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 [8] 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 [9] 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 [10] 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 [11] 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 [12] RP TISSUE SPECIFICITY. RX PubMed=9378960; DOI=10.4049/jimmunol.159.8.3739; 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 [13] 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 [14] 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 [15] 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 [16] 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 [17] 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 [18] 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 [19] 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 [20] 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 [21] 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 [22] 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 [23] 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 [24] 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 [25] 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 [26] 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 [27] 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 [28] 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 [29] 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 [30] 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 [31] 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 [32] 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 [33] 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 [34] RP FUNCTION. RX PubMed=38614099; DOI=10.1016/j.cell.2024.03.019; RA Deng S., Zhang Y., Wang H., Liang W., Xie L., Li N., Fang Y., Wang Y., RA Liu J., Chi H., Sun Y., Ye R., Shan L., Shi J., Shen Z., Wang Y., Wang S., RA Brosseau J.P., Wang F., Liu G., Quan Y., Xu J.; RT "ITPRIPL1 binds CD3epsilon to impede T cell activation and enable tumor RT immune evasion."; RL Cell 187:2305-2323.e33(2024). RN [35] 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 [36] 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 [37] 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 [38] 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 [39] 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 [40] 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 RT ZAP-70."; RL Cell 129:735-746(2007). RN [41] 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 [42] 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 [43] 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 [44] 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 [45] 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 [46] 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. Also CC contributes to the development and activation of primary B-lymphocytes. CC When antigen presenting cells (APC) activate T-cell receptor (TCR), a CC serie of phosphorylations lead to the recruitment of ZAP70 to the CC phosphorylated TCR components CD3E and CD247/CD3Z through ITAM motif at CC the plasma membrane (PubMed:7509083). 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:38614099, ECO:0000269|PubMed:7509083, CC ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8702662, CC ECO:0000269|PubMed:9489702}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:20101, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:61978, 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:26783323, PubMed:7659156). 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:10078535, CC PubMed:10449770). 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="https://databases.lovd.nl/shared/genes/ZAP70"; 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; 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_001079.4. [P43403-1] DR RefSeq; NP_001365523.1; NM_001378594.1. [P43403-1] DR RefSeq; NP_001432938.1; NM_001446009.1. [P43403-1] DR RefSeq; NP_001432940.1; NM_001446011.1. [P43403-1] DR RefSeq; NP_001432941.1; NM_001446012.1. [P43403-1] DR RefSeq; NP_997402.1; NM_207519.2. [P43403-2] DR RefSeq; XP_054188975.1; XM_054333000.1. [P43403-2] DR RefSeq; XP_054199775.1; XM_054343800.1. [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 PDB; 7SIY; X-ray; 1.48 A; Z=292-296. DR AlphaFoldDB; P43403; -. DR MDRepo; P43403; -. DR SMR; P43403; -. DR BioGRID; 113367; 73. DR CORUM; P43403; -. DR DIP; DIP-38781N; -. DR ELM; P43403; -. DR FunCoup; P43403; 588. DR IntAct; P43403; 77. DR MINT; P43403; -. DR NDEx; IQUERY-CP-ZAP70; 22 NDEx IQuery Curated Pathways. 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 GlyCosmos; P43403; 1 site, 1 glycan. 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 PaxDb; 9606-ENSP00000264972; -. DR PeptideAtlas; P43403; -. DR ProteomicsDB; 55631; -. [P43403-1] DR ProteomicsDB; 55632; -. [P43403-2] DR ProteomicsDB; 55633; -. [P43403-3] DR Antibodypedia; 685; 2329 antibodies from 53 providers. DR CPTC; P43403; 1 antibody. DR DNASU; 7535; -. DR Ensembl; ENST00000264972.10; ENSP00000264972.5; ENSG00000115085.17. [P43403-1] DR Ensembl; ENST00000451498.2; ENSP00000400475.2; ENSG00000115085.17. [P43403-2] DR Ensembl; ENST00000698508.2; ENSP00000513759.1; ENSG00000115085.17. [P43403-1] DR Ensembl; ENST00000708152.1; ENSP00000517108.1; ENSG00000291603.1. [P43403-1] DR Ensembl; ENST00000708154.1; ENSP00000517109.1; ENSG00000291603.1. [P43403-1] DR Ensembl; ENST00000708159.1; ENSP00000517110.1; ENSG00000291603.1. [P43403-2] DR Ensembl; ENST00000885386.1; ENSP00000555445.1; ENSG00000115085.17. [P43403-1] DR Ensembl; ENST00000885387.1; ENSP00000555446.1; ENSG00000115085.17. [P43403-1] 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 AGR; HGNC:12858; -. DR ClinPGx; PA37447; -. 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 OpenTargets; ENSG00000115085; -. DR Orphanet; 911; Combined immunodeficiency due to ZAP70 deficiency. 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; 535945at2759; -. DR PAN-GO; P43403; 2 GO annotations based on evolutionary models. DR PhylomeDB; P43403; -. 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 Reactome; R-HSA-9725371; Nuclear events stimulated by ALK signaling in cancer. DR SignaLink; P43403; -. DR SIGNOR; P43403; -. DR Agora; ENSG00000115085; -. DR BioGRID-ORCS; 7535; 20 hits in 1186 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 111 other cell types or tissues. DR GO; GO:0005911; C:cell-cell junction; IEA:Ensembl. DR GO; GO:0005737; C:cytoplasm; IDA:UniProt. DR GO; GO:0005829; C:cytosol; TAS:Reactome. 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; IEA:Ensembl. DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProt. DR GO; GO:0002250; P:adaptive immune response; TAS:UniProtKB. DR GO; GO:0042113; P:B cell activation; TAS:UniProtKB. DR GO; GO:0006955; P:immune response; IDA:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; NAS:UniProtKB. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:MGI. 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:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0042110; P:T cell activation; IDA:UniProt. 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; IDA:UniProt. DR CDD; cd05115; PTKc_Zap-70; 1. DR CDD; cd10402; SH2_C-SH2_Zap70; 1. DR CDD; cd09938; SH2_N-SH2_Zap70_Syk_like; 1. DR DisProt; DP01123; -. DR FunFam; 1.10.930.10:FF:000001; Tyrosine-protein kinase; 1. DR FunFam; 3.30.200.20:FF:000185; Tyrosine-protein kinase; 1. DR FunFam; 3.30.505.10:FF:000031; Tyrosine-protein kinase; 1. DR FunFam; 3.30.505.10:FF:000063; Tyrosine-protein kinase; 1. DR FunFam; 1.10.510.10:FF:000216; Tyrosine-protein kinase SYK; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 3.30.505.10; SH2 domain; 2. DR Gene3D; 1.10.930.10; Syk Kinase, Chain A, domain 2; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID00553; -. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR023420; Kinase_SYK/ZAP-70_inter-SH2_sf. DR InterPro; IPR050198; Non-receptor_tyrosine_kinases. 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 PANTHER; PTHR24418; TYROSINE-PROTEIN KINASE; 1. 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; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF55550; SH2 domain; 2. 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. 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 PDBsum; 7SIY; -. 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 Proteomics identification; Reference proteome; Repeat; SCID; SH2 domain; KW Transferase; 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 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 FT stimulation-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 103..105 FT /evidence="ECO:0007829|PDB:2OQ1" FT HELIX 108..110 FT /evidence="ECO:0007829|PDB:4XZ0" 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 294..296 FT /evidence="ECO:0007829|PDB:2Y1N" 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 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:2OZO" FT HELIX 546..553 FT /evidence="ECO:0007829|PDB:1U59" FT HELIX 558..561 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 //