P43403 (ZAP70_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › 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.16
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.35
Enzyme regulation	Activated by phosphorylation at Tyr-493 in the activation loop. Inhibited by staurosporine. Ref.35
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. Ref.1 Ref.10 Ref.15 Ref.17 Ref.19 Ref.22 Ref.31 Ref.32
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.25
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. Tyr-493 is dephosphorylated by PTN22. Ref.1 Ref.9 Ref.14 Ref.23 Ref.26
Involvement in disease	Selective T-cell defect (STCD) [MIM:269840]: A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T cells. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5 Ref.37 Ref.38 Ref.39 Ref.41
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.30. Source: UniProtKB T cell aggregation Traceable author statement Ref.30. Source: UniProtKB T cell migration Traceable author statement Ref.30. Source: UniProtKB T cell receptor signaling pathway Traceable author statement Ref.30. Source: UniProtKB adaptive immune response Traceable author statement Ref.30. Source: UniProtKB beta selection Inferred from electronic annotation. Source: Compara intracellular protein kinase cascade Non-traceable author statement Ref.1. Source: UniProtKB negative thymic T cell selection Inferred from electronic annotation. Source: Compara peptidyl-tyrosine phosphorylation Inferred from direct assay PubMed 22732588. Source: MGI positive regulation of T cell differentiation Inferred from direct assay PubMed 7630421. Source: MGI positive regulation of alpha-beta T cell differentiation Inferred from electronic annotation. Source: Compara positive regulation of alpha-beta T cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of calcium-mediated signaling Inferred from electronic annotation. Source: Compara positive thymic T cell selection Inferred from direct assay PubMed 7630421. Source: MGI protein autophosphorylation Inferred from electronic annotation. Source: Compara
Cellular_component	T cell receptor complex Inferred from direct assay PubMed 8176201. Source: MGI cytosol Traceable author statement. Source: Reactome immunological synapse Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Non-traceable author statement Ref.1. Source: UniProtKB non-membrane spanning protein tyrosine kinase activity Traceable author statement Ref.30. 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 Ref.35 Ref.36

Binding site

369

1

ATP

Amino acid modifications

Modified residue

248

1

Phosphotyrosine Ref.24

Modified residue

289

1

Phosphoserine Ref.21

Modified residue

292

1

Phosphotyrosine Ref.9 Ref.28

Modified residue

315

1

Phosphotyrosine; by LCK Ref.14

Modified residue

319

1

Phosphotyrosine Ref.14

Modified residue

492

1

Phosphotyrosine; by autocatalysis

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.40
Corresponds to variant rs55964305 [ dbSNP | Ensembl ].

VAR_041846

Natural variant

191

1

P → L. Ref.40
Corresponds to variant rs56403250 [ dbSNP | Ensembl ].

VAR_041847

Natural variant

337

1

L → R in STCD. Ref.41

VAR_065623

Natural variant

448

1

G → E in a head and neck squamous cell carcinoma sample; somatic mutation. Ref.40

VAR_041848

Natural variant

465

1

R → C in STCD. Ref.39

VAR_065624

Natural variant

465

1

R → H in STCD. Ref.38

VAR_015538

Natural variant

507

1

A → V in STCD. Ref.41

VAR_065625

Natural variant

518

1

S → R in STCD. Ref.37

VAR_006351

Natural variant

523

1

W → L. Ref.40
Corresponds to variant rs56189815 [ dbSNP | Ensembl ].

VAR_041849

Natural variant

541

1

K → KLEQ in STCD.

VAR_038688

Natural variant

564

1

C → R in STCD. Ref.41

VAR_065626

Experimental info

Mutagenesis

131

1

W → A: Increased constitutive kinase activity. Ref.36

Mutagenesis

133

1

L → A: Increased constitutive kinase activity. Ref.36

Mutagenesis

141

1

A → E: Increased constitutive kinase activity. Ref.36

Mutagenesis

144

1

S → A: Increased kinase activity after activation by LCK. Ref.36

Mutagenesis

145

1

Q → A: Increased kinase activity after activation by LCK. Ref.36

Mutagenesis

147

1

P → A: Increased kinase activity after activation by LCK. Ref.36

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. Ref.10 Ref.14 Ref.18 Ref.36

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. Ref.10 Ref.14 Ref.18 Ref.36

Mutagenesis

319

1

Y → A: Increased constitutive kinase activity; when associated with F-315. Ref.14 Ref.36

Mutagenesis

319

1

Y → F: Increased constitutive kinase activity; when associated with F-315. About 80% loss of TCR-induced NFAT activation. Ref.14 Ref.36

Mutagenesis

461

1

D → N: Abolishes kinase activity. Ref.36

Mutagenesis

479

1

D → N: Abolishes kinase activity. Ref.35

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. Ref.36

Mutagenesis

598

1

Y → A: Increased kinase activity after activation by LCK. Ref.36

Secondary structure

1

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619

Helix Strand Turn

Details...

Turn

4 – 7

4

Beta strand

11 – 14

4

Helix

17 – 26

10

Beta strand

34 – 38

5

Beta strand

40 – 42

3

Beta strand

46 – 52

7

Beta strand

55 – 63

9

Beta strand

69 – 71

3

Beta strand

77 – 79

3

Helix

80 – 89

10

Beta strand

94 – 96

3

Helix

114 – 131

18

Helix

135 – 156

22

Helix

157 – 160

4

Helix

170 – 178

9

Turn

179 – 181

3

Beta strand

186 – 191

6

Beta strand

197 – 204

8

Beta strand

207 – 215

9

Beta strand

221 – 223

3

Beta strand

229 – 231

3

Helix

232 – 241

10

Beta strand

246 – 248

3

Beta strand

316 – 320

5

Helix

334 – 336

3

Beta strand

337 – 345

9

Beta strand

350 – 357

8

Beta strand

364 – 371

8

Helix

377 – 392

16

Beta strand

401 – 415

15

Helix

422 – 426

5

Turn

430 – 432

3

Helix

435 – 454

20

Helix

464 – 466

3

Beta strand

467 – 471

5

Beta strand

474 – 477

4

Turn

482 – 485

4

Helix

503 – 505

3

Helix

508 – 513

6

Helix

518 – 533

16

Turn

539 – 542

4

Helix

546 – 553

8

Helix

566 – 574

9

Helix

580 – 582

3

Helix

586 – 601

16

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: D1E1A8EC66FA116F	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
	Isoform 2 (TZK) [UniParc]. Checksum: B1D7A63A61D63215	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
	Isoform 3 [UniParc]. Checksum: 14F1841C3F898EEF	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

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] [Europe PMC] [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] [Europe PMC] [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. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 521-547, VARIANT STCD 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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CBL AND SLA.
[16]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION IN CD3Z UBIQUITINATION.
[17]	"SPAP2, an Ig family receptor containing both ITIMs and ITAMs." Xu M.-J., Zhao R., Cao H., Zhao Z.J. Biochem. Biophys. Res. Commun. 293:1037-1046(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FCRL3.
[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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[21]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[22]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NFAM1.
[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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-248, MASS SPECTROMETRY.
[25]	"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] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[26]	"Identification of substrates of human protein-tyrosine phosphatase PTPN22." Wu J., Katrekar A., Honigberg L.A., Smith A.M., Conn M.T., Tang J., Jeffery D., Mortara K., Sampang J., Williams S.R., Buggy J., Clark J.M. J. Biol. Chem. 281:11002-11010(2006) [PubMed] [Europe PMC] [Abstract] Cited for: DEPHOSPHORYLATION BY PTN22.
[27]	"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] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-292, 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.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-603, MASS SPECTROMETRY.
[30]	"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] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION AND DOMAIN.
[31]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 3-256 IN COMPLEX WITH CD247, INTERACTION WITH CD247.
[32]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 286-297 IN COMPLEX WITH CBL, INTERACTION WITH CBL.
[33]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 289-297 IN COMPLEX WITH CBL AND UBE2L3.
[34]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-256.
[35]	"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] [Europe PMC] [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.
[36]	"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] [Europe PMC] [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.
[37]	"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] [Europe PMC] [Abstract] Cited for: VARIANT STCD ARG-518.
[38]	"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] [Europe PMC] [Abstract] Cited for: VARIANT STCD HIS-465.
[39]	"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] [Europe PMC] [Abstract] Cited for: VARIANT STCD CYS-465.
[40]	"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. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-175; LEU-191; GLU-448 AND LEU-523.
[41]	"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] [Europe PMC] [Abstract] Cited for: VARIANTS STCD 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	[»]
2Y1N	X-ray	2.00	B/D	286-297	[»]
4A4B	X-ray	2.79	B	286-297	[»]
4A4C	X-ray	2.70	B	286-297	[»]

ProteinModelPortal

P43403.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-38781N.

IntAct

P43403. 8 interactions.

MINT

MINT-110540.

STRING

9606.ENSP00000264972.

PTM databases

PhosphoSite

P43403.

Polymorphism databases

DMDM

1177044.

Proteomic databases

PaxDb

P43403.

PRIDE

P43403.

Protocols and materials databases

DNASU

7535.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264972; ENSP00000264972; ENSG00000115085.
ENST00000442208; ENSP00000411141; ENSG00000115085.
ENST00000451498; ENSP00000400475; ENSG00000115085.

GeneID

7535.

KEGG

hsa:7535.

UCSC

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

Organism-specific databases

CTD

7535.

GeneCards

GC02P098331.

HGNC

HGNC:12858. ZAP70.

HPA

CAB002625.
HPA003134.

MIM

176947. gene.
269840. phenotype.

neXtProt

NX_P43403.

Orphanet

911. Combined immunodeficiency due to ZAP70 deficiency.

PharmGKB

PA37447.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000113264.

HOVERGEN

HBG001540.

InParanoid

P43403.

KO

K07360.

OMA

PAHPSTF.

OrthoDB

EOG4NZTSX.

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

Gene3D

1.10.930.10. 1 hit.
3.30.505.10. 2 hits.

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.
[Graphical view]

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

BindingDB

P43403.

ChEMBL

CHEMBL2803.

EvolutionaryTrace

P43403.

GenomeRNAi

7535.

NextBio

29481.

PMAP-CutDB

P43403.

SOURCE

Search...

Entry information

Entry name

ZAP70_HUMAN

Accession

Primary (citable) accession number: P43403
Secondary accession number(s): A6NFP4 , Q6PIA4, Q8IXD6, Q9UBS6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	May 1, 2013
This is version 159 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.