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P43403 (ZAP70_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 170. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length619 AA.
Sequence statusComplete.
Protein existenceEvidence 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 Ref.30

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. Colocalizes 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. Ref.30

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 processAdaptive immunity
Immunity
   Cellular componentCell membrane
Cytoplasm
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
SCID
   DomainRepeat
SH2 domain
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Transferase
Tyrosine-protein kinase
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell activation

Traceable author statement Ref.30. Source: UniProtKB

T cell activation

Traceable author statement Ref.30. Source: UniProtKB

T cell aggregation

Traceable author statement Ref.30. Source: UniProtKB

T cell differentiation

Non-traceable author statement PubMed 8613493. 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: Ensembl

immune response

Inferred from direct assay Ref.1. Source: UniProtKB

intracellular signal transduction

Non-traceable author statement Ref.1. Source: UniProtKB

negative thymic T cell selection

Inferred from electronic annotation. Source: Ensembl

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: Ensembl

positive regulation of alpha-beta T cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of calcium-mediated signaling

Inferred from electronic annotation. Source: Ensembl

positive thymic T cell selection

Inferred from direct assay PubMed 7630421. Source: MGI

protein autophosphorylation

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from direct assay PubMed 12447358. Source: UniProtKB

   Cellular_componentT cell receptor complex

Inferred from direct assay PubMed 8176201. Source: MGI

cytoplasm

Traceable author statement PubMed 12359715. Source: HGNC

cytosol

Traceable author statement. Source: Reactome

immunological synapse

Inferred from electronic annotation. Source: Ensembl

plasma membrane

Traceable author statement Ref.30. Source: UniProtKB

   Molecular_functionATP binding

Non-traceable author statement Ref.1. Source: UniProtKB

non-membrane spanning protein tyrosine kinase activity

Traceable author statement Ref.30. Source: UniProtKB

protein tyrosine kinase activity

Inferred from direct assay PubMed 12447358. Source: UniProtKB

Complete GO annotation...

Binary interactions

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 619619Tyrosine-protein kinase ZAP-70
PRO_0000088168

Regions

Domain10 – 10293SH2 1
Domain163 – 25492SH2 2
Domain338 – 600263Protein kinase
Nucleotide binding345 – 3528ATP
Region103 – 16260Interdomain A
Region255 – 33783Interdomain B

Sites

Active site4611Proton acceptor Ref.35 Ref.36
Binding site3691ATP

Amino acid modifications

Modified residue2481Phosphotyrosine Ref.24
Modified residue2891Phosphoserine Ref.21
Modified residue2921Phosphotyrosine Ref.9 Ref.28
Modified residue3151Phosphotyrosine; by LCK Ref.14
Modified residue3191Phosphotyrosine Ref.14
Modified residue4921Phosphotyrosine; by autocatalysis
Modified residue6031N6-acetyllysine Ref.29

Natural variations

Alternative sequence1 – 307307Missing in isoform 2.
VSP_031156
Alternative sequence1 – 126126Missing in isoform 3.
VSP_031157
Alternative sequence127 – 1348VRQTWKLE → MRLGPRWK in isoform 3.
VSP_031158
Natural variant1751R → L. Ref.40
Corresponds to variant rs55964305 [ dbSNP | Ensembl ].
VAR_041846
Natural variant1911P → L. Ref.40
Corresponds to variant rs56403250 [ dbSNP | Ensembl ].
VAR_041847
Natural variant3371L → R in STCD. Ref.41
VAR_065623
Natural variant4481G → E in a head and neck squamous cell carcinoma sample; somatic mutation. Ref.40
VAR_041848
Natural variant4651R → C in STCD. Ref.39
VAR_065624
Natural variant4651R → H in STCD. Ref.38
VAR_015538
Natural variant5071A → V in STCD. Ref.41
VAR_065625
Natural variant5181S → R in STCD. Ref.37
VAR_006351
Natural variant5231W → L. Ref.40
Corresponds to variant rs56189815 [ dbSNP | Ensembl ].
VAR_041849
Natural variant5411K → KLEQ in STCD.
VAR_038688
Natural variant5641C → R in STCD. Ref.41
VAR_065626

Experimental info

Mutagenesis1311W → A: Increased constitutive kinase activity. Ref.36
Mutagenesis1331L → A: Increased constitutive kinase activity. Ref.36
Mutagenesis1411A → E: Increased constitutive kinase activity. Ref.36
Mutagenesis1441S → A: Increased kinase activity after activation by LCK. Ref.36
Mutagenesis1451Q → A: Increased kinase activity after activation by LCK. Ref.36
Mutagenesis1471P → A: Increased kinase activity after activation by LCK. Ref.36
Mutagenesis2921Y → F: Induces constitutive TCR stimulation-independent NFAT induction. Ref.9
Mutagenesis3141V → A: Increased constitutive kinase activity.
Mutagenesis3151Y → A: Increased constitutive kinase activity; when associated with F-319. Ref.10 Ref.14 Ref.18 Ref.36
Mutagenesis3151Y → 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
Mutagenesis3191Y → A: Increased constitutive kinase activity; when associated with F-315. Ref.14 Ref.36
Mutagenesis3191Y → F: Increased constitutive kinase activity; when associated with F-315. About 80% loss of TCR-induced NFAT activation. Ref.14 Ref.36
Mutagenesis4611D → N: Abolishes kinase activity. Ref.36
Mutagenesis4791D → N: Abolishes kinase activity. Ref.35
Mutagenesis4921Y → F: Increases kinase activity. Ref.7
Mutagenesis4931Y → F: Impairs kinase activity. Ref.7
Mutagenesis5971Y → A: Increased kinase activity after activation by LCK. Ref.36
Mutagenesis5981Y → A: Increased kinase activity after activation by LCK. Ref.36

Secondary structure

.......................................................................................... 619
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1995. Version 1.
Checksum: D1E1A8EC66FA116F

FASTA61969,872
        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 »

FASTA31235,647
Isoform 3 [UniParc].

Checksum: 14F1841C3F898EEF
Show »

FASTA49355,873

References

« Hide '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. expand/collapse author list , 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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[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: FUNCTION, 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. expand/collapse author list , 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.
PIRA44266.
A49955.
RefSeqNP_001070.2. NM_001079.3.
NP_997402.1. NM_207519.1.
UniGeneHs.234569.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1FBVX-ray2.90B289-297[»]
1M61X-ray2.50A1-256[»]
1U59X-ray2.30A327-606[»]
2CBLX-ray2.10B286-297[»]
2OQ1X-ray1.90A3-256[»]
2OZOX-ray2.60A1-606[»]
2Y1NX-ray2.00B/D286-297[»]
3ZNIX-ray2.21B/F/J/N286-297[»]
4A4BX-ray2.79B286-297[»]
4A4CX-ray2.70B286-297[»]
4K2RX-ray3.00A1-606[»]
ProteinModelPortalP43403.
SMRP43403. Positions 1-609.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid113367. 49 interactions.
DIPDIP-38781N.
IntActP43403. 17 interactions.
MINTMINT-110540.
STRING9606.ENSP00000264972.

Chemistry

BindingDBP43403.
ChEMBLCHEMBL2803.
GuidetoPHARMACOLOGY2285.

PTM databases

PhosphoSiteP43403.

Polymorphism databases

DMDM1177044.

Proteomic databases

PaxDbP43403.
PRIDEP43403.

Protocols and materials databases

DNASU7535.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000264972; ENSP00000264972; ENSG00000115085. [P43403-1]
ENST00000442208; ENSP00000411141; ENSG00000115085. [P43403-3]
ENST00000451498; ENSP00000400475; ENSG00000115085. [P43403-2]
GeneID7535.
KEGGhsa:7535.
UCSCuc002syd.1. human. [P43403-1]
uc002sye.1. human. [P43403-3]

Organism-specific databases

CTD7535.
GeneCardsGC02P098331.
HGNCHGNC:12858. ZAP70.
HPACAB002625.
HPA003134.
MIM176947. gene.
269840. phenotype.
neXtProtNX_P43403.
Orphanet911. Combined immunodeficiency due to ZAP70 deficiency.
PharmGKBPA37447.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000113264.
HOVERGENHBG001540.
InParanoidP43403.
KOK07360.
OMAMKGPEVI.
OrthoDBEOG7MWGWD.
PhylomeDBP43403.
TreeFamTF351629.

Enzyme and pathway databases

BRENDA2.7.10.2. 2681.
ReactomeREACT_6900. Immune System.
SignaLinkP43403.

Gene expression databases

ArrayExpressP43403.
BgeeP43403.
CleanExHS_ZAP70.
GenevestigatorP43403.

Family and domain databases

Gene3D1.10.930.10. 1 hit.
3.30.505.10. 2 hits.
InterProIPR011009. Kinase-like_dom.
IPR023420. Kinase_SYK/ZAP-70_inter-SH2.
IPR000719. Prot_kinase_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]
PfamPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 2 hits.
[Graphical view]
PIRSFPIRSF000604. TyrPK_SYK. 1 hit.
PRINTSPR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTSM00252. SH2. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF55550. SSF55550. 2 hits.
SSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP43403.
GeneWikiZAP70.
GenomeRNAi7535.
NextBio29481.
PMAP-CutDBP43403.
PROP43403.
SOURCESearch...

Entry information

Entry nameZAP70_HUMAN
AccessionPrimary (citable) accession number: P43403
Secondary accession number(s): A6NFP4 expand/collapse secondary AC list , Q6PIA4, Q8IXD6, Q9UBS6
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: April 16, 2014
This is version 170 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

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

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

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