UniProt Accession

 ZAP70_HUMAN; P43403; A6NFP4; Q6PIA4; Q8IXD6; Q9UBS6 

Genbank Protein ID

 L05148; AB083211; AC016699; BC039039; BC053878 

Genbank Nucleotide ID

 BAC43747.1; AAX93187.1; AAH39039.1; AAH53878.1 

Protein Name

 Tyrosine-protein kinase ZAP-70 

Protein Synonyms/Alias

 70 kDa zeta-chain associated protein; Syk-related tyrosine kinase 

Gene Name

 ZAP70 

Gene Synonyms/Alias

 SRK 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
25	AEAEEHLKLAGMADG	ubiquitination	[1, 2, 3]
75	TYAIAGGKAHCGPAE	ubiquitination	[2, 3]
100	GLPCNLRKPCNRPSG	ubiquitination	[1, 2, 3]
132	DYVRQTWKLEGEALE	ubiquitination	[1, 2]
151	SQAPQVEKLIATTAH	ubiquitination	[2]
176	TREEAERKLYSGAQT	ubiquitination	[1, 2]
186	SGAQTDGKFLLRPRK	ubiquitination	[2, 3]
193	KFLLRPRKEQGTYAL	ubiquitination	[2, 3]
217	HYLISQDKAGKYCIP	ubiquitination	[2, 3]
251	DGLIYCLKEACPNSS	ubiquitination	[2]
326	YSDPEELKDKKLFLK	ubiquitination	[1, 2]
329	PEELKDKKLFLKRDN	ubiquitination	[2]
361	QGVYRMRKKQIDVAI	ubiquitination	[1, 2, 3]
362	GVYRMRKKQIDVAIK	ubiquitination	[1, 2, 3]
369	KQIDVAIKVLKQGTE	ubiquitination	[2]
372	DVAIKVLKQGTEKAD	ubiquitination	[2]
377	VLKQGTEKADTEEMM	ubiquitination	[1, 2, 3]
429	LHKFLVGKREEIPVS	ubiquitination	[2]
455	GMKYLEEKNFVHRDL	ubiquitination	[2, 3]
476	LVNRHYAKISDFGLS	ubiquitination	[1, 2]
484	ISDFGLSKALGADDS	ubiquitination	[1, 2, 3]
500	YTARSAGKWPLKWYA	ubiquitination	[1, 2, 3]
504	SAGKWPLKWYAPECI	ubiquitination	[2]
556	MAFIEQGKRMECPPE	ubiquitination	[1, 2]
603	CYYSLASKVEGPPGS	acetylation	[3, 4]
603	CYYSLASKVEGPPGS	ubiquitination	[1, 2, 3]
613	GPPGSTQKAEAACA*	ubiquitination	[1, 2, 3]

Reference

 [1] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [4] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861] 

Functional Description

 Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). 

Sequence Annotation

 DOMAIN 10 102 SH2 1.
 DOMAIN 163 254 SH2 2.
 DOMAIN 338 600 Protein kinase.
 NP_BIND 345 352 ATP.
 REGION 103 162 Interdomain A.
 REGION 255 337 Interdomain B.
 ACT_SITE 461 461 Proton acceptor.
 BINDING 369 369 ATP.
 MOD_RES 248 248 Phosphotyrosine.
 MOD_RES 289 289 Phosphoserine.
 MOD_RES 292 292 Phosphotyrosine.
 MOD_RES 315 315 Phosphotyrosine; by LCK.
 MOD_RES 319 319 Phosphotyrosine.
 MOD_RES 492 492 Phosphotyrosine; by autocatalysis.
 MOD_RES 603 603 N6-acetyllysine.  

Keyword

 3D-structure; Acetylation; Adaptive immunity; Alternative splicing; ATP-binding; Cell membrane; Complete proteome; Cytoplasm; Disease mutation; Immunity; Kinase; Membrane; Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome; Repeat; SCID; SH2 domain; Transferase; Tyrosine-protein kinase. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 619 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0001772; C:immunological synapse; IEA:Compara.
 GO:0042101; C:T cell receptor complex; IDA:MGI.
 GO:0005524; F:ATP binding; NAS:UniProtKB.
 GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; TAS:UniProtKB.
 GO:0002250; P:adaptive immune response; TAS:UniProtKB.
 GO:0042113; P:B cell activation; TAS:UniProtKB.
 GO:0043366; P:beta selection; IEA:Compara.
 GO:0007243; P:intracellular protein kinase cascade; NAS:UniProtKB.
 GO:0045060; P:negative thymic T cell selection; IEA:Compara.
 GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:MGI.
 GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IEA:Compara.
 GO:0046641; P:positive regulation of alpha-beta T cell proliferation; IEA:Compara.
 GO:0050850; P:positive regulation of calcium-mediated signaling; IEA:Compara.
 GO:0045582; P:positive regulation of T cell differentiation; IDA:MGI.
 GO:0045059; P:positive thymic T cell selection; IDA:MGI.
 GO:0046777; P:protein autophosphorylation; IEA:Compara.
 GO:0070489; P:T cell aggregation; TAS:UniProtKB.
 GO:0072678; P:T cell migration; TAS:UniProtKB.
 GO:0050852; P:T cell receptor signaling pathway; TAS:UniProtKB. 

Interpro

 IPR011009; Kinase-like_dom.
 IPR023420; Kinase_SYK/ZAP-70_inter-SH2.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
 IPR000980; SH2.
 IPR008266; Tyr_kinase_AS.
 IPR020635; Tyr_kinase_cat_dom.
 IPR012234; Tyr_kinase_non-rcpt_SYK/ZAP70. 

Pfam

 PF07714; Pkinase_Tyr
 PF00017; SH2 

SMART

 SM00252; SH2
 SM00219; TyrKc 

PROSITE

 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00109; PROTEIN_KINASE_TYR
 PS50001; SH2 

PRINTS

 PR00401; SH2DOMAIN.
 PR00109; TYRKINASE.