Tyrosine-protein kinase ZAP-70 - Homo sapiens (Human)

Preferred order of sections

Names and origin

Protein names

Recommended name:
Tyrosine-protein kinase ZAP-70
EC=2.7.10.2

Alternative name(s):
70 kDa zeta-chain associated protein
Syk-related tyrosine kinase

Gene names

Name:	ZAP70
Synonyms:	SRK

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	619 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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). Ref.1 Ref.5 Ref.8 Ref.12 Ref.17
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	Activated by phosphorylation at Tyr-493 in the activation loop. Inhibited by staurosporine.
Subunit structure	Interacts with NFAM1. Interacts with adapter proteins SLA and SLA2; these interactions negatively regulates T-cell receptor signaling. Interacts with CBLB By similarity. Interacts with DEF6. Interacts (via SH2 domains) with RHOH; this interaction regulates ZAP70 subcellular localization By similarity. Interacts with FCRL3. Interacts with VAV1. Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR. Interacts with CBL; this interaction promotes ubiquitination, internalization and subsequent degradation of CD247/CD3Z. Identified in a complex with CBL and UBE2L3.
Subcellular location	Cytoplasm. Cell membrane; Peripheral membrane protein. Note: In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. Co-localizes together with RHOH in the immunological synapse. RHOH is required for its proper localization to the cell membrane and cytoskeleton fractions in the thymocytes By similarity. Ref.13
Tissue specificity	Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells. Ref.1 Ref.11 Ref.26
Domain	Composed of 2 N-terminal SH2 domains and a C-terminal kinase domain. The tandem SH2 domains bind to the doubly phosphorylated tyrosine-based activation motif (ITAM) of CD247/CD3Z and the non-canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH By similarity. The interdomain B located between the second SH2 and the kinase domain contains 3 tyrosines (Tyr-292, Tyr-315, Tyr-319) that are phosphorylated following TCR activation. These sites have been implicated in binding to other signaling molecules including CBL or VAV1. Thus, ZAP70 can also function as a scaffold by recruiting additional factors to the stimulated TCR complex.
Post-translational modification	Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319 are essential for ZAP70 positive function on T-lymphocyte activation whereas Tyr-292 has a negative regulatory role. Within the C-terminal kinase domain, Tyr-492 and Tyr-493 are phosphorylated after TCR induction, Tyr-492 playing a negative regulatory role and Tyr-493 a positive. Ref.1 Ref.8 Ref.9 Ref.12 Ref.14 Ref.20 Ref.22 Ref.23 Ref.24 Ref.25 Ref.27 Ref.28
Involvement in disease	Defects in ZAP70 are the cause of selective T-cell defect (STD) [MIM:176947]. STD is an autosomal recessive form of severe combined immunodeficiency characterized by a selective absence of CD8-type T-cells. Ref.5 Ref.38 Ref.39 Ref.40 Ref.42
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily. Contains 1 protein kinase domain. Contains 2 SH2 domains.

Ontologies

Keywords
Biological process	Adaptive immunity Immunity
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation SCID
Domain	Repeat SH2 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	B cell activation Traceable author statement Ref.31. Source: UniProtKB T cell aggregation Traceable author statement Ref.31. Source: UniProtKB T cell migration Traceable author statement Ref.31. Source: UniProtKB T cell receptor signaling pathway Traceable author statement Ref.31. Source: UniProtKB adaptive immune response Traceable author statement Ref.31. Source: UniProtKB intracellular protein kinase cascade Non-traceable author statement Ref.1. Source: UniProtKB positive regulation of T cell differentiation Inferred from direct assay. Source: MGI positive thymic T cell selection Inferred from direct assay. Source: MGI
Cellular component	T cell receptor complex Inferred from direct assay. Source: MGI cytosol Traceable author statement. Source: Reactome
Molecular function	ATP binding Non-traceable author statement Ref.1. Source: UniProtKB non-membrane spanning protein tyrosine kinase activity Traceable author statement Ref.31. Source: UniProtKB protein binding Inferred from physical interaction Ref.6. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
PTPN22	Q9Y2R2	4	EBI-1211276,EBI-1211241

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P43403-1) This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P43403-2) Also known as: TZK; The sequence of this isoform differs from the canonical sequence as follows: 1-307: Missing.

Isoform 3 (identifier: P43403-3) The sequence of this isoform differs from the canonical sequence as follows: 1-126: Missing. 127-134: VRQTWKLE → MRLGPRWK
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 619

619

Tyrosine-protein kinase ZAP-70

PRO_0000088168

Regions

Domain

10 – 102

93

SH2 1

Domain

163 – 254

92

SH2 2

Domain

338 – 600

263

Protein kinase

Nucleotide binding

345 – 352

8

ATP

Region

103 – 162

60

Interdomain A

Region

255 – 337

83

Interdomain B

Sites

Active site

461

1

Proton acceptor

Binding site

369

1

ATP

Amino acid modifications

Modified residue

248

1

Phosphotyrosine Ref.24 Ref.27

Modified residue

289

1

Phosphoserine Ref.22

Modified residue

292

1

Phosphotyrosine Ref.9 Ref.20 Ref.24 Ref.25 Ref.27 Ref.28

Modified residue

315

1

Phosphotyrosine; by LCK Ref.14 Ref.20 Ref.24 Ref.25

Modified residue

319

1

Phosphotyrosine Ref.14 Ref.20 Ref.24 Ref.25

Modified residue

492

1

Phosphotyrosine; by autocatalysis Ref.20 Ref.24 Ref.25 Ref.27 Ref.28

Modified residue

493

1

Phosphotyrosine Ref.20 Ref.24 Ref.25

Modified residue

603

1

N6-acetyllysine Ref.29

Natural variations

Alternative sequence

1 – 307

307

Missing in isoform 2.

VSP_031156

Alternative sequence

1 – 126

126

Missing in isoform 3.

VSP_031157

Alternative sequence

127 – 134

8

VRQTWKLE → MRLGPRWK in isoform 3.

VSP_031158

Natural variant

175

1

R → L. Ref.41
Corresponds to variant rs55964305 [ dbSNP | Ensembl ].

VAR_041846

Natural variant

191

1

P → L. Ref.41
Corresponds to variant rs56403250 [ dbSNP | Ensembl ].

VAR_041847

Natural variant

337

1

L → R in STD. Ref.42

VAR_065623

Natural variant

448

1

G → E in a head and neck squamous cell carcinoma sample; somatic mutation. Ref.41

VAR_041848

Natural variant

465

1

R → C in STD. Ref.40

VAR_065624

Natural variant

465

1

R → H in STD. Ref.39

VAR_015538

Natural variant

507

1

A → V in STD. Ref.42

VAR_065625

Natural variant

518

1

S → R in STD. Ref.38

VAR_006351

Natural variant

523

1

W → L. Ref.41
Corresponds to variant rs56189815 [ dbSNP | Ensembl ].

VAR_041849

Natural variant

541

1

K → KLEQ in STD.

VAR_038688

Natural variant

564

1

C → R in STD. Ref.42

VAR_065626

Experimental info

Mutagenesis

131

1

W → A: Increased constitutive kinase activity.

Mutagenesis

133

1

L → A: Increased constitutive kinase activity.

Mutagenesis

141

1

A → E: Increased constitutive kinase activity.

Mutagenesis

144

1

S → A: Increased kinase activity after activation by LCK.

Mutagenesis

145

1

Q → A: Increased kinase activity after activation by LCK.

Mutagenesis

147

1

P → A: Increased kinase activity after activation by LCK.

Mutagenesis

292

1

Y → F: Induces constitutive TCR stimulation-independent NFAT induction. Ref.9

Mutagenesis

314

1

V → A: Increased constitutive kinase activity.

Mutagenesis

315

1

Y → A: Increased constitutive kinase activity; when associated with F-319.

Mutagenesis

315

1

Y → F: Increased constitutive kinase activity; when associated with F-319. About 75% loss of CD247/CD3Z-binding in stimulated TCR and complete loss of VAV1 interaction.

Mutagenesis

319

1

Y → A: Increased constitutive kinase activity; when associated with F-315.

Mutagenesis

319

1

Y → F: Increased constitutive kinase activity; when associated with F-315. About 80% loss of TCR-induced NFAT activation.

Mutagenesis

461

1

D → N: Abolishes kinase activity.

Mutagenesis

479

1

D → N: Abolishes kinase activity.

Mutagenesis

492

1

Y → F: Increases kinase activity. Ref.7

Mutagenesis

493

1

Y → F: Impairs kinase activity. Ref.7

Mutagenesis

597

1

Y → A: Increased kinase activity after activation by LCK.

Mutagenesis

598

1

Y → A: Increased kinase activity after activation by LCK.

Secondary structure

1

.

619

Helix Strand Turn

Details...

Sequences

Sequence		Length	Mass (Da)
Isoform 1 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: D1E1A8EC66FA116F Show »	FASTA	619	69,872
10 20 30 40 50 60 MPDPAAHLPF FYGSISRAEA EEHLKLAGMA DGLFLLRQCL RSLGGYVLSL VHDVRFHHFP 70 80 90 100 110 120 IERQLNGTYA IAGGKAHCGP AELCEFYSRD PDGLPCNLRK PCNRPSGLEP QPGVFDCLRD 130 140 150 160 170 180 AMVRDYVRQT WKLEGEALEQ AIISQAPQVE KLIATTAHER MPWYHSSLTR EEAERKLYSG 190 200 210 220 230 240 AQTDGKFLLR PRKEQGTYAL SLIYGKTVYH YLISQDKAGK YCIPEGTKFD TLWQLVEYLK 250 260 270 280 290 300 LKADGLIYCL KEACPNSSAS NASGAAAPTL PAHPSTLTHP QRRIDTLNSD GYTPEPARIT 310 320 330 340 350 360 SPDKPRPMPM DTSVYESPYS DPEELKDKKL FLKRDNLLIA DIELGCGNFG SVRQGVYRMR 370 380 390 400 410 420 KKQIDVAIKV LKQGTEKADT EEMMREAQIM HQLDNPYIVR LIGVCQAEAL MLVMEMAGGG 430 440 450 460 470 480 PLHKFLVGKR EEIPVSNVAE LLHQVSMGMK YLEEKNFVHR DLAARNVLLV NRHYAKISDF 490 500 510 520 530 540 GLSKALGADD SYYTARSAGK WPLKWYAPEC INFRKFSSRS DVWSYGVTMW EALSYGQKPY 550 560 570 580 590 600 KKMKGPEVMA FIEQGKRMEC PPECPPELYA LMSDCWIYKW EDRPDFLTVE QRMRACYYSL 610 ASKVEGPPGS TQKAEAACA « Hide
Isoform 2 (TZK) [UniParc]. Checksum: B1D7A63A61D63215 Show »	FASTA	312	35,647
10 20 30 40 50 60 MPMDTSVYES PYSDPEELKD KKLFLKRDNL LIADIELGCG NFGSVRQGVY RMRKKQIDVA 70 80 90 100 110 120 IKVLKQGTEK ADTEEMMREA QIMHQLDNPY IVRLIGVCQA EALMLVMEMA GGGPLHKFLV 130 140 150 160 170 180 GKREEIPVSN VAELLHQVSM GMKYLEEKNF VHRDLAARNV LLVNRHYAKI SDFGLSKALG 190 200 210 220 230 240 ADDSYYTARS AGKWPLKWYA PECINFRKFS SRSDVWSYGV TMWEALSYGQ KPYKKMKGPE 250 260 270 280 290 300 VMAFIEQGKR MECPPECPPE LYALMSDCWI YKWEDRPDFL TVEQRMRACY YSLASKVEGP 310 PGSTQKAEAA CA « Hide
Isoform 3 [UniParc]. Checksum: 14F1841C3F898EEF Show »	FASTA	493	55,873
10 20 30 40 50 60 MRLGPRWKGE ALEQAIISQA PQVEKLIATT AHERMPWYHS SLTREEAERK LYSGAQTDGK 70 80 90 100 110 120 FLLRPRKEQG TYALSLIYGK TVYHYLISQD KAGKYCIPEG TKFDTLWQLV EYLKLKADGL 130 140 150 160 170 180 IYCLKEACPN SSASNASGAA APTLPAHPST LTHPQRRIDT LNSDGYTPEP ARITSPDKPR 190 200 210 220 230 240 PMPMDTSVYE SPYSDPEELK DKKLFLKRDN LLIADIELGC GNFGSVRQGV YRMRKKQIDV 250 260 270 280 290 300 AIKVLKQGTE KADTEEMMRE AQIMHQLDNP YIVRLIGVCQ AEALMLVMEM AGGGPLHKFL 310 320 330 340 350 360 VGKREEIPVS NVAELLHQVS MGMKYLEEKN FVHRDLAARN VLLVNRHYAK ISDFGLSKAL 370 380 390 400 410 420 GADDSYYTAR SAGKWPLKWY APECINFRKF SSRSDVWSYG VTMWEALSYG QKPYKKMKGP 430 440 450 460 470 480 EVMAFIEQGK RMECPPECPP ELYALMSDCW IYKWEDRPDF LTVEQRMRAC YYSLASKVEG 490 PPGSTQKAEA ACA « Hide

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain." Chan A.C., Iwashima M., Turck C.W., Weiss A. Cell 71:649-662(1992) [PubMed: 1423621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH CD3Z, TISSUE SPECIFICITY, PHOSPHORYLATION.
[2]	"Identification of a novel isoform of ZAP-70, truncated ZAP kinase." Kuroyama H., Ikeda T., Kasai M., Yamasaki S., Tatsumi M., Utsuyama M., Saito T., Hirokawa K. Biochem. Biophys. Res. Commun. 315:935-941(2004) [PubMed: 14985102] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Leukocyte.
[3]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). Tissue: Blood and Brain.
[5]	"Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase." Arpaia E., Shahar M., Dadi H., Cohen A., Roifman C.M. Cell 76:947-958(1994) [PubMed: 8124727] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 521-547, VARIANT STD LEU-GLU-GLN-541 INS, FUNCTION. Tissue: Lymphoid tissue.
[6]	"ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity." Isakov N., Wange R.L., Burgess W.H., Watts J.D., Aebersold R., Samelson L.E. J. Exp. Med. 181:375-380(1995) [PubMed: 7528772] [Abstract] Cited for: CHARACTERIZATION OF TAM-BINDING.
[7]	"Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function." Chan A.C., Dalton M., Johnson R., Kong G.H., Wang T., Thoma R., Kurosaki T. EMBO J. 14:2499-2508(1995) [PubMed: 7781602] [Abstract] Cited for: MUTAGENESIS OF TYR-492 AND TYR-493.
[8]	"Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function." Bubeck Wardenburg J., Fu C., Jackman J.K., Flotow H., Wilkinson S.E., Williams D.H., Johnson R., Kong G., Chan A.C., Findell P.R. J. Biol. Chem. 271:19641-19644(1996) [PubMed: 8702662] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF LCP2.
[9]	"Enhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70." Zhao Q., Weiss A. Mol. Cell. Biol. 16:6765-6774(1996) [PubMed: 8943331] [Abstract] Cited for: PHOSPHORYLATION AT TYR-292, MUTAGENESIS OF TYR-292.
[10]	"The Vav binding site (Y315) in ZAP-70 is critical for antigen receptor-mediated signal transduction." Wu J., Zhao Q., Kurosaki T., Weiss A. J. Exp. Med. 185:1877-1882(1997) [PubMed: 9151714] [Abstract] Cited for: INTERACTION WITH VAV1, MUTAGENESIS OF TYR-315.
[11]	"In vivo association of CD5 with tyrosine-phosphorylated ZAP-70 and p21 phospho-zeta molecules in human CD3+ thymocytes." Gary-Gouy H., Lang V., Sarun S., Boumsell L., Bismuth G. J. Immunol. 159:3739-3747(1997) [PubMed: 9378960] [Abstract] Cited for: TISSUE SPECIFICITY.
[12]	"LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation." Zhang W., Sloan-Lancaster J., Kitchen J., Trible R.P., Samelson L.E. Cell 92:83-92(1998) [PubMed: 9489702] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF LAT.
[13]	"ZAP-70 association with T cell receptor zeta (TCRzeta): fluorescence imaging of dynamic changes upon cellular stimulation." Sloan-Lancaster J., Presley J., Ellenberg J., Yamazaki T., Lippincott-Schwartz J., Samelson L.E. J. Cell Biol. 143:613-624(1998) [PubMed: 9813084] [Abstract] Cited for: SUBCELLULAR LOCATION.
[14]	"Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling." Di Bartolo V., Mege D., Germain V., Pelosi M., Dufour E., Michel F., Magistrelli G., Isacchi A., Acuto O. J. Biol. Chem. 274:6285-6294(1999) [PubMed: 10037717] [Abstract] Cited for: PHOSPHORYLATION AT TYR-315 AND TYR-319, MUTAGENESIS OF TYR-315 AND TYR-319.
[15]	"SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling." Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J. Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999) [PubMed: 10449770] [Abstract] Cited for: INTERACTION WITH CBL AND SLA.
[16]	"Molecular cloning and characterization of SPAP1, an inhibitory receptor." Xu M.-J., Zhao R., Zhao Z.J. Biochem. Biophys. Res. Commun. 280:768-775(2001) [PubMed: 11162587] [Abstract] Cited for: INTERACTION WITH FCRL3.
[17]	"Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70." Wang H.Y., Altman Y., Fang D., Elly C., Dai Y., Shao Y., Liu Y.C. J. Biol. Chem. 276:26004-26011(2001) [PubMed: 11353765] [Abstract] Cited for: FUNCTION IN CD3Z UBIQUITINATION.
[18]	"Tyrosine 315 determines optimal recruitment of ZAP-70 to the T cell antigen receptor." Di Bartolo V., Malissen M., Dufour E., Sechet E., Malissen B., Acuto O. Eur. J. Immunol. 32:568-575(2002) [PubMed: 11828374] [Abstract] Cited for: MUTAGENESIS OF TYR-315.
[19]	"Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells." Lindholm C.K., Henriksson M.L., Hallberg B., Welsh M. Eur. J. Biochem. 269:3279-3288(2002) [PubMed: 12084069] [Abstract] Cited for: INTERACTION WITH SHB.
[20]	"Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry." Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T., Ericson C., Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C. Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003) [PubMed: 12522270] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-292; TYR-315; TYR-319; TYR-492 AND TYR-493, MASS SPECTROMETRY.
[21]	"NFAM1, an immunoreceptor tyrosine-based activation motif-bearing molecule that regulates B cell development and signaling." Ohtsuka M., Arase H., Takeuchi A., Yamasaki S., Shiina R., Suenaga T., Sakurai D., Yokosuka T., Arase N., Iwashima M., Kitamura T., Moriya H., Saito T. Proc. Natl. Acad. Sci. U.S.A. 101:8126-8131(2004) [PubMed: 15143214] [Abstract] Cited for: INTERACTION WITH NFAM1.
[22]	"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry." Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C. Anal. Chem. 76:2763-2772(2004) [PubMed: 15144186] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[23]	"T cell activation-induced CrkII binding to the Zap70 protein tyrosine kinase is mediated by Lck-dependent phosphorylation of Zap70 tyrosine 315." Gelkop S., Gish G.D., Babichev Y., Pawson T., Isakov N. J. Immunol. 175:8123-8132(2005) [PubMed: 16339550] [Abstract] Cited for: PHOSPHORYLATION BY LCK.
[24]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-248; TYR-292; TYR-315; TYR-319; TYR-492 AND TYR-493, MASS SPECTROMETRY.
[25]	"Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry." Tao W.A., Wollscheid B., O'Brien R., Eng J.K., Li X.-J., Bodenmiller B., Watts J.D., Hood L., Aebersold R. Nat. Methods 2:591-598(2005) [PubMed: 16094384] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-292; TYR-315; TYR-319; TYR-492 AND TYR-493, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[26]	"ZAP-70 expression in normal pro/pre B cells, mature B cells, and in B-cell acute lymphoblastic leukemia." Crespo M., Villamor N., Gine E., Muntanola A., Colomer D., Marafioti T., Jones M., Camos M., Campo E., Montserrat E., Bosch F. Clin. Cancer Res. 12:726-734(2006) [PubMed: 16467082] [Abstract] Cited for: TISSUE SPECIFICITY.
[27]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-248; TYR-292 AND TYR-492, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[28]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-292 AND TYR-492, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[29]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-603, MASS SPECTROMETRY.
[30]	"The structure, regulation, and function of ZAP-70." Au-Yeung B.B., Deindl S., Hsu L.Y., Palacios E.H., Levin S.E., Kuriyan J., Weiss A. Immunol. Rev. 228:41-57(2009) [PubMed: 19290920] [Abstract] Cited for: REVIEW ON FUNCTION.
[31]	"ZAP70: a master regulator of adaptive immunity." Fischer A., Picard C., Chemin K., Dogniaux S., le Deist F., Hivroz C. Semin. Immunopathol. 32:107-116(2010) [PubMed: 20135127] [Abstract] Cited for: REVIEW ON FUNCTION AND DOMAIN.
[32]	"Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor." Hatada M.H., Lu X., Laird E.R., Green J., Morgenstern J.P., Lou M., Marr C.S., Phillips T.B., Ram M.K., Theriault K., Zoller M.J., Karas L.K. Nature 377:32-38(1995) [PubMed: 7659156] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 3-256 IN COMPLEX WITH CD247, INTERACTION WITH CD247.
[33]	"Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase." Meng W., Sawasdikosol S., Burakoff S.J., Eck M.J. Nature 398:84-90(1999) [PubMed: 10078535] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 286-297 IN COMPLEX WITH CBL, INTERACTION WITH CBL.
[34]	"Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases." Zheng N., Wang P., Jeffrey P.D., Pavletich N.P. Cell 102:533-539(2000) [PubMed: 10966114] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 289-297 IN COMPLEX WITH CBL AND UBE2L3.
[35]	"Crystal structure and NMR studies of the apo SH2 domains of ZAP-70: two bikes rather than a tandem." Folmer R.H., Geschwindner S., Xue Y. Biochemistry 41:14176-14184(2002) [PubMed: 12450381] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-256.
[36]	"The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors." Jin L., Pluskey S., Petrella E.C., Cantin S.M., Gorga J.C., Rynkiewicz M.J., Pandey P., Strickler J.E., Babine R.E., Weaver D.T., Seidl K.J. J. Biol. Chem. 279:42818-42825(2004) [PubMed: 15292186] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 327-606 IN COMPLEX WITH STAUROSPORINE, CATALYTIC ACTIVITY, ACTIVE SITE, MUTAGENESIS OF ASP-479, ENZYME REGULATION.
[37]	"Structural basis for the inhibition of tyrosine kinase activity of ZAP-70." Deindl S., Kadlecek T.A., Brdicka T., Cao X., Weiss A., Kuriyan J. Cell 129:735-746(2007) [PubMed: 17512407] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 1-606 OF MUTANT ASN-461 IN COMPLEX WITH MAGNESIUM AND ATP ANALOG, ACTIVE SITE, MUTAGENESIS OF TRP-131; LEU-133; ALA-141; SER-144; GLN-145; PRO-147; TYR-315; TYR-319; ASP-461; TYR-597 AND TYR-598.
[38]	"ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency." Chan A.C., Kadlecek T.A., Elder M.E., Filipovich A.H., Kuo W.-L., Iwashima M., Parslow T.G., Weiss A. Science 264:1599-1601(1994) [PubMed: 8202713] [Abstract] Cited for: VARIANT STD ARG-518.
[39]	"Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling." Toyabe S., Watanabe A., Harada W., Karasawa T., Uchiyama M. Immunology 103:164-171(2001) [PubMed: 11412303] [Abstract] Cited for: VARIANT STD HIS-465.
[40]	"Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70." Elder M.E., Skoda-Smith S., Kadlecek T.A., Wang F., Wu J., Weiss A. J. Immunol. 166:656-661(2001) [PubMed: 11123350] [Abstract] Cited for: VARIANT STD CYS-465.
[41]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-175; LEU-191; GLU-448 AND LEU-523.
[42]	"Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency." Turul T., Tezcan I., Artac H., de Bruin-Versteeg S., Barendregt B.H., Reisli I., Sanal O., van Dongen J.J., van der Burg M. Eur. J. Pediatr. 168:87-93(2009) [PubMed: 18509675] [Abstract] Cited for: VARIANTS STD ARG-337; VAL-507 AND ARG-564.
+	Additional computationally mapped references.

Web resources

ZAP70base

ZAP70 mutation db

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L05148 mRNA. No translation available.
AB083211 mRNA. Translation: BAC43747.1.
AC016699 Genomic DNA. Translation: AAX93187.1.
BC039039 mRNA. Translation: AAH39039.1.
BC053878 mRNA. Translation: AAH53878.1.

IPI

IPI00329789.
IPI00410185.
IPI00885038.

PIR

A44266.
A49955.

RefSeq

NP_001070.2. NM_001079.3.
NP_997402.1. NM_207519.1.

UniGene

Hs.234569.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1FBV	X-ray	2.90	B	289-297	[»]
1M61	X-ray	2.50	A	1-256	[»]
1U59	X-ray	2.30	A	327-606	[»]
2CBL	X-ray	2.10	B	286-297	[»]
2OQ1	X-ray	1.90	A	3-256	[»]
2OZO	X-ray	2.60	A	1-606	[»]

ProteinModelPortal

P43403.

SMR

P43403. Positions 1-606.

ModBase

Search...

Protein-protein interaction databases

IntAct

P43403. 8 interactions.

MINT

MINT-110540.

STRING

P43403.

PTM databases

PhosphoSite

P43403.

Polymorphism databases

DMDM

1177044.

Proteomic databases

PRIDE

P43403.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264972; ENSP00000264972; ENSG00000115085.

GeneID

7535.

KEGG

hsa:7535.

UCSC

uc002syd.1. human.
uc002sye.1. human.

Organism-specific databases

CTD

7535.

GeneCards

GC02P098331.

H-InvDB

HIX0002292.

HGNC

HGNC:12858. ZAP70.

HPA

CAB002625.
HPA003134.

MIM

176947. gene+phenotype.

neXtProt

NX_P43403.

Orphanet

911. Combined immunodeficiency due to ZAP70 deficiency.

PharmGKB

PA37447.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG17394.

GeneTree

ENSGT00600000084269.

HOGENOM

HBG714705.

HOVERGEN

HBG001540.

InParanoid

P43403.

OMA

FIEQGKR.

OrthoDB

EOG4NZTSX.

PhylomeDB

P43403.

Enzyme and pathway databases

BRENDA

2.7.10.2. 2681.

Pathway_Interaction_DB

pi3kcipathway. Class I PI3K signaling events.
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P43403.

Bgee

P43403.

CleanEx

HS_ZAP70.

Genevestigator

P43403.

GermOnline

ENSG00000115085. Homo sapiens.

Family and domain databases

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.
IPR000980. SH2.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR012234. Tyr_kinase_non-rcpt_SYK/ZAP70.
[Graphical view]

Gene3D

G3DSA:1.10.930.10. G3DSA:1.10.930.10. 1 hit.
G3DSA:3.30.505.10. SH2. 2 hits.

KO

K07360.

Pfam

PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 2 hits.
[Graphical view]

PIRSF

PIRSF000604. TyrPK_SYK. 1 hit.

PRINTS

PR00401. SH2DOMAIN.
PR00109. TYRKINASE.

SMART

SM00252. SH2. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

NextBio

29481.

PMAP-CutDB

P43403.

SOURCE

Search...

Entry information

Entry name

ZAP70_HUMAN

Accession

Primary (citable) accession number: P43403
Secondary accession number(s): A6NFP4

Q9UBS6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	January 25, 2012
This is version 145 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Secondary structure

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Polymorphism databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents