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Protein

Tyrosine-protein kinase ZAP-70

Gene

Zap70

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 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-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).5 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Enzyme regulationi

Activated by phosphorylation at Tyr-492 in the activation loop.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei368ATPPROSITE-ProRule annotation1
Active sitei460Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi343 – 351ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: MGI
  • non-membrane spanning protein tyrosine kinase activity Source: GO_Central
  • protein kinase activity Source: MGI
  • protein tyrosine kinase activity Source: MGI
  • receptor binding Source: GO_Central

GO - Biological processi

  • adaptive immune response Source: UniProtKB-KW
  • beta selection Source: MGI
  • cell migration Source: GO_Central
  • immune response Source: MGI
  • innate immune response Source: GO_Central
  • intracellular signal transduction Source: MGI
  • negative thymic T cell selection Source: MGI
  • peptidyl-tyrosine autophosphorylation Source: GO_Central
  • peptidyl-tyrosine phosphorylation Source: MGI
  • positive regulation of alpha-beta T cell differentiation Source: MGI
  • positive regulation of alpha-beta T cell proliferation Source: MGI
  • positive regulation of calcium-mediated signaling Source: MGI
  • positive regulation of T cell differentiation Source: MGI
  • positive thymic T cell selection Source: MGI
  • protein autophosphorylation Source: MGI
  • protein phosphorylation Source: MGI
  • T cell receptor signaling pathway Source: MGI
  • thymic T cell selection Source: MGI
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processAdaptive immunity, Immunity
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-202430. Translocation of ZAP-70 to Immunological synapse.
R-MMU-202433. Generation of second messenger molecules.

Names & Taxonomyi

Protein namesi
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 namesi
Name:Zap70
Synonyms:Srk, Zap-70
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 1

Organism-specific databases

MGIiMGI:99613. Zap70.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Disruption phenotypei

Mice lack both CD4 and CD8 positive mature T-lymphocytes. Displays a complete block in B-Cell development at the pro-B cell stage in the absence of both SYK and ZAP70.2 Publications

Chemistry databases

ChEMBLiCHEMBL2034801.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000881691 – 618Tyrosine-protein kinase ZAP-70Add BLAST618

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei248PhosphotyrosineBy similarity1
Modified residuei287PhosphoserineBy similarity1
Modified residuei290PhosphotyrosineBy similarity1
Modified residuei314Phosphotyrosine; by LCKBy similarity1
Modified residuei318PhosphotyrosineBy similarity1
Modified residuei491PhosphotyrosineBy similarity1
Modified residuei492PhosphotyrosineBy similarity1
Cross-linki543Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity

Post-translational modificationi

Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Phosphorylation of Tyr-314 and Tyr-314 are essential for ZAP70 positive function on T-lymphocyte activation whereas Tyr-290 has a negative regulatory role. Within the C-terminal kinase domain, Tyr-491 and Tyr-492 are phosphorylated after TCR induction, Tyr-491 playing a negative regulatory role and Tyr-492 a positive. Tyr-492 is dephosphorylated by PTN22.
Ubiquitinated in response to T cell activation. Deubiquitinated by OTUD7B.1 Publication

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP43404.
MaxQBiP43404.
PaxDbiP43404.
PRIDEiP43404.

PTM databases

iPTMnetiP43404.
PhosphoSitePlusiP43404.

Expressioni

Tissue specificityi

Isoform 1 and isoform 2 are expressed in thymus, spleen and lymph nodes.1 Publication

Developmental stagei

Isoform 2 is expressed in developing thymocytes from the CD44+CD25- stage up to mature T-cells. Isoform 1 is not expressed in thymocytes at the CD44+CD25- or CD44+CD25+ stages.1 Publication

Gene expression databases

BgeeiENSMUSG00000026117.
CleanExiMM_ZAP70.
ExpressionAtlasiP43404. baseline and differential.
GenevisibleiP43404. MM.

Interactioni

Subunit structurei

Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR (By similarity). Interacts with NFAM1 (PubMed:15143214). Interacts with adapter protein SLA; this interaction negatively regulates T-cell receptor signaling (PubMed:10662792). Interacts with VAV1 (By similarity). Interacts with CBL; this interaction promotes ubiquitination, internalization and subsequent degradation of CD247/CD3Z (By similarity). Identified in a complex with CBL and UBE2L3 (By similarity). Interacts with SHB (By similarity). Interacts with adapter protein SLA2; this interaction negatively regulates T-cell receptor signaling (PubMed:11891219). Interacts with CBLB (PubMed:10646608). Interacts (via SH2 domains) with RHOH; this interaction regulates ZAP70 subcellular localization (PubMed:17028588). Interacts with DEF6 (PubMed:12648457). Interacts (ubiquitinated form) with OTUD7B and UBASH3B (PubMed:26903241).By similarity7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Cd247P241614EBI-3862932,EBI-7803400

GO - Molecular functioni

Protein-protein interaction databases

BioGridi204628. 10 interactors.
IntActiP43404. 39 interactors.
STRINGi10090.ENSMUSP00000027291.

Chemistry databases

BindingDBiP43404.

Structurei

3D structure databases

ProteinModelPortaliP43404.
SMRiP43404.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini10 – 102SH2 1PROSITE-ProRule annotationAdd BLAST93
Domaini163 – 254SH2 2PROSITE-ProRule annotationAdd BLAST92
Domaini337 – 597Protein kinasePROSITE-ProRule annotationAdd BLAST261

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni103 – 162Interdomain AAdd BLAST60
Regioni255 – 336Interdomain BAdd BLAST82

Domaini

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 has 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 (By similarity).By similarity

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, SH2 domain

Phylogenomic databases

eggNOGiENOG410IH0T. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118799.
HOGENOMiHOG000113264.
HOVERGENiHBG001540.
InParanoidiP43404.
KOiK07360.
OMAiADKDEMM.
OrthoDBiEOG091G07KU.
TreeFamiTF351629.

Family and domain databases

CDDicd09938. SH2_N-SH2_Zap70_Syk_like. 1 hit.
Gene3Di1.10.930.10. 1 hit.
3.30.505.10. 2 hits.
InterProiView protein in InterPro
IPR011009. Kinase-like_dom_sf.
IPR023420. Kinase_SYK/ZAP-70_inter-SH2_sf.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR036860. SH2_dom_sf.
IPR035838. SYK/ZAP-70_N_SH2.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR012234. Tyr_kinase_non-rcpt_SYK/ZAP70.
PfamiView protein in Pfam
PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 2 hits.
PIRSFiPIRSF000604. TyrPK_SYK. 1 hit.
PRINTSiPR00401. SH2DOMAIN.
PR00109. TYRKINASE.
SMARTiView protein in SMART
SM00252. SH2. 2 hits.
SM00219. TyrKc. 1 hit.
SUPFAMiSSF55550. SSF55550. 2 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 2 hits.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P43404-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MPDPAAHLPF FYGSISRAEA EEHLKLAGMA DGLFLLRQCL RSLGGYVLSL
60 70 80 90 100
VHDVRFHHFP IERQLNGTYA IAGGKAHCGP AELCQFYSQD PDGLPCNLRK
110 120 130 140 150
PCNRPPGLEP QPGVFDCLRD AMVRDYVRQT WKLEGDALEQ AIISQAPQVE
160 170 180 190 200
KLIATTAHER MPWYHSSLTR EEAERKLYSG QQTDGKFLLR PRKEQGTYAL
210 220 230 240 250
SLVYGKTVYH YLISQDKAGK YCIPEGTKFD TLWQLVEYLK LKADGLIYRL
260 270 280 290 300
KEVCPNSSAS AAVAAPTLPA HPSTFTQPQR RVDTLNSDGY TPEPARLASS
310 320 330 340 350
TDKPRPMPMD TSVYESPYSD PEELKDKKLF LKRENLLVAD IELGCGNFGS
360 370 380 390 400
VRQGVYRMRK KQIDVAIKVL KQGTEKADKD EMMREAQIMH QLDNPYIVRL
410 420 430 440 450
IGVCQAEALM LVMEMAGGGP LHKFLLGKKE EIPVSNVAEL LHQVAMGMKY
460 470 480 490 500
LEEKNFVHRD LAARNVLLVN RHYAKISDFG LSKALGADDS YYTARSAGKW
510 520 530 540 550
PLKWYAPECI NFRKFSSRSD VWSYGVTMWE AFSYGQKPYK KMKGPEVLDF
560 570 580 590 600
IKQGKRMECP PECPPEMYAL MSDCWIYKWE DRPDFLTVEQ RMRNYYYSLA
610
SRAEGPPQCE QVAEAACG
Length:618
Mass (Da):70,112
Last modified:December 14, 2011 - v3
Checksum:i9E0D18B240B28392
GO
Isoform 2 (identifier: P43404-2) [UniParc]FASTAAdd to basket
Also known as: TZK

The sequence of this isoform differs from the canonical sequence as follows:
     1-306: Missing.

Show »
Length:312
Mass (Da):35,883
Checksum:i12CCA3AA2C3B1CF2
GO
Isoform 3 (identifier: P43404-3) [UniParc]FASTAAdd to basket
Also known as: TZK-2

The sequence of this isoform differs from the canonical sequence as follows:
     1-309: Missing.
     310-360: DTSVYESPYS...VRQGVYRMRK → MAYGRVSGVS...MLSVASHLGR

Note: No experimental confirmation available.
Show »
Length:309
Mass (Da):35,255
Checksum:iD1A230395CA2AFE4
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti124R → C in AAA19250 (PubMed:8196616).Curated1
Sequence conflicti526 – 529VTMW → GHHV in BAC67015 (Ref. 4) Curated4
Sequence conflicti546E → Q in AAA19250 (PubMed:8196616).Curated1
Sequence conflicti599L → P in AAA19250 (PubMed:8196616).Curated1
Sequence conflicti599L → P in AAB36538 (PubMed:9208839).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti464R → C in ST; causes an absence of mature T-cells due to thymocyte development being arrested at the CD4+CD8+ stage. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0311601 – 309Missing in isoform 3. 1 PublicationAdd BLAST309
Alternative sequenceiVSP_0311591 – 306Missing in isoform 2. 1 PublicationAdd BLAST306
Alternative sequenceiVSP_031161310 – 360DTSVY…YRMRK → MAYGRVSGVSELSRVLYVPF PPPPFLSNPGVHDTRMYTQH AMLSVASHLGR in isoform 3. 1 PublicationAdd BLAST51

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U04379 mRNA. Translation: AAA19250.1.
U77667 mRNA. Translation: AAB36538.1.
AB083210 mRNA. Translation: BAC43746.1.
AB084383 mRNA. Translation: BAC67015.1.
AK039883 mRNA. Translation: BAC30471.1.
AC084389 mRNA. No translation available.
BC029727 mRNA. Translation: AAH29727.1.
CCDSiCCDS14888.1. [P43404-1]
PIRiI48914.
RefSeqiNP_001276541.1. NM_001289612.1. [P43404-2]
NP_001276694.1. NM_001289765.1. [P43404-1]
NP_033565.2. NM_009539.3. [P43404-1]
XP_006495959.1. XM_006495896.2. [P43404-1]
UniGeneiMm.8038.

Genome annotation databases

EnsembliENSMUST00000027291; ENSMUSP00000027291; ENSMUSG00000026117. [P43404-1]
GeneIDi22637.
KEGGimmu:22637.
UCSCiuc007aqz.2. mouse. [P43404-1]
uc007arb.2. mouse. [P43404-3]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiZAP70_MOUSE
AccessioniPrimary (citable) accession number: P43404
Secondary accession number(s): P97455, Q80VV2, Q8CHJ3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: December 14, 2011
Last modified: November 22, 2017
This is version 169 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families