EzCatDB: M00333
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DB codeM00333
RLCP classification3.103.130000.1162 : Transfer
CATH domainDomain 13.30.505.10 : SHC Adaptor Protein
Domain 21.10.930.10 : Syk Kinase; Chain A, domain 2
Domain 33.30.505.10 : SHC Adaptor Protein
Domain 4-.-.-.-
Domain 53.30.200.20 : Phosphorylase Kinase; domain 1
Domain 61.10.510.10 : Transferase(Phosphotransferase); domain 1Catalytic domain
E.C.2.7.10.2

CATH domainRelated DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00335,M00339,M00344
1.10.930.10 : Syk Kinase; Chain A, domain 2M00148
3.30.200.20 : Phosphorylase Kinase; domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00335,M00339,M00344,D00298
3.30.505.10 : SHC Adaptor ProteinM00183,M00043,M00130,M00148,T00256,M00304,M00339,M00344,T00221

Enzyme Name
UniProtKBKEGG

P43403
Protein nameTyrosine-protein kinase ZAP-70Non-specific protein-tyrosine kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
Cytoplasmic protein tyrosine kinase
Protein-tyrosine kinase (ambiguous)
SRK
SYK
ZAP70
SynonymsEC 2.7.10.2
70 kDa zeta-chain associated protein
Syk-related tyrosine kinase
RefSeqNP_001070.2 (Protein)
NM_001079.3 (DNA/RNA sequence)
NP_997402.1 (Protein)
NM_207519.1 (DNA/RNA sequence)
PfamPF07714 (Pkinase_Tyr)
PF00017 (SH2)
[Graphical view]


UniProtKB:Accession NumberP43403
Entry nameZAP70_HUMAN
ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SubunitInteracts 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 locationCytoplasm. 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).
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00002C00585C00008C01167
CompoundMagnesiumATP[protein]-L-tyrosineADP[protein]-L-tyrosine phosphate
Typedivalent metal (Ca2+, Mg2+)amine group,nucleotidearomatic ring (only carbon atom),peptide/proteinamine group,nucleotidearomatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion
ChEBI18420
15422

16761

PubChem888
5957

6022

             
1m61A01UnboundUnboundUnboundUnboundUnbound
2oq1A01UnboundUnboundUnboundUnboundUnbound
2ozoA01UnboundUnboundUnboundUnboundUnbound
1m61A02UnboundUnboundUnboundUnboundUnbound
2oq1A02UnboundUnboundUnboundUnboundUnbound
2ozoA02UnboundUnboundUnboundUnboundUnbound
1m61A03UnboundUnboundUnboundUnboundUnbound
2oq1A03UnboundUnboundUnboundUnboundUnbound
2ozoA03UnboundUnboundUnboundUnboundUnbound
1u59A01UnboundUnboundUnboundUnboundUnbound
2ozoA04UnboundUnboundUnboundUnboundUnbound
1u59A02UnboundUnboundUnboundUnboundUnbound
2ozoA05Bound:_MGAnalogue:ANPUnboundUnboundUnbound

Active-site residues
resource
Literature [21] & Swiss-prot;P43403
pdbCatalytic residuesCofactor-binding residuesModified residuescomment
            
1m61A01               
ARG  17;ARG  37(phosphotyrosine-2 binding)
 
 
2oq1A01               
ARG  19;ARG  39(phosphotyrosine-2 binding)
 
 
2ozoA01               
ARG  17;ARG  37(phosphotyrosine-2 binding)
 
 
1m61A02               
 
 
 
2oq1A02               
 
 
 
2ozoA02               
 
 
 
1m61A03               
ARG 170;ARG 190(phosphotyrosine-1 binding);LYS 242(phosphotyrosine-2)
 
 
2oq1A03               
ARG 172;ARG 192(phosphotyrosine-1 binding);LYS 244(phosphotyrosine-2)
 
 
2ozoA03               
ARG 170;ARG 190(phosphotyrosine-1 binding);LYS 242(phosphotyrosine-2)
 
 
1u59A01               
 
 
 
2ozoA04               
 
 
mutant Y315F, Y319F
1u59A02ASP 461;ARG 465
ASN 466;ASP 479(Magnesium binding)
TYR 492;TYR 493(phosphorylation)
 
2ozoA05       ;ARG 465
ASN 466;ASP 479(Magnesium binding)
                                
mutant D461N, invisible 488-501

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[23]Figure 7
[28]FIGURE 9

references
[1]
PubMed ID1717999
JournalProc Natl Acad Sci U S A
Year1991
Volume88
Pages9166-70
AuthorsChan AC, Irving BA, Fraser JD, Weiss A
TitleThe zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein.
[2]
PubMed ID1423621
JournalCell
Year1992
Volume71
Pages649-62
AuthorsChan AC, Iwashima M, Turck CW, Weiss A
TitleZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.
[3]
PubMed ID8366117
JournalJ Biol Chem
Year1993
Volume268
Pages19797-801
AuthorsWange RL, Malek SN, Desiderio S, Samelson LE
TitleTandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells.
[4]
PubMed ID7509083
JournalScience
Year1994
Volume263
Pages1136-9
AuthorsIwashima M, Irving BA, van Oers NS, Chan AC, Weiss A
TitleSequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases.
[5]
CommentsMUTAGENESIS OF TYR-492 AND TYR-493.
PubMed ID7781602
JournalEMBO J
Year1995
Volume14
Pages2499-508
AuthorsChan AC, Dalton M, Johnson R, Kong GH, Wang T, Thoma R, Kurosaki T
TitleActivation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function.
[6]
PubMed ID7642520
JournalJ Biol Chem
Year1995
Volume270
Pages18730-3
AuthorsWange RL, Guitian R, Isakov N, Watts JD, Aebersold R, Samelson LE
TitleActivating and inhibitory mutations in adjacent tyrosines in the kinase domain of ZAP-70.
[7]
PubMed ID7760813
JournalMol Cell Biol
Year1995
Volume15
Pages3171-8
AuthorsNeumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS
TitleBinding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins.
[8]
PubMed ID7659156
JournalNature
Year1995
Volume377
Pages32-8
AuthorsHatada MH, Lu X, Laird ER, Green J, Morgenstern JP, Lou M, Marr CS, Phillips TB, Ram MK, Theriault K, et al
TitleMolecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor.
Related PDB2oq1
Related UniProtKBP43403
[9]
PubMed ID8663155
JournalJ Biol Chem
Year1996
Volume271
Pages15753-61
AuthorsIsakov N, Wange RL, Watts JD, Aebersold R, Samelson LE
TitlePurification and characterization of human ZAP-70 protein-tyrosine kinase from a baculovirus expression system.
[10]
PubMed ID8642247
JournalJ Exp Med
Year1996
Volume183
Pages1053-62
Authorsvan Oers NS, Killeen N, Weiss A
TitleLck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes.
[11]
PubMed ID8756661
JournalMol Cell Biol
Year1996
Volume16
Pages5026-35
AuthorsKong G, Dalton M, Bubeck Wardenburg J, Straus D, Kurosaki T, Chan AC
TitleDistinct tyrosine phosphorylation sites in ZAP-70 mediate activation and negative regulation of antigen receptor function.
[12]
PubMed ID8943331
JournalMol Cell Biol
Year1996
Volume16
Pages6765-74
AuthorsZhao Q, Weiss A
TitleEnhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70.
[13]
PubMed ID8901551
JournalProc Natl Acad Sci U S A
Year1996
Volume93
Pages12165-70
AuthorsLoGrasso PV, Hawkins J, Frank LJ, Wisniewski D, Marcy A
TitleMechanism of activation for Zap-70 catalytic activity.
[14]
PubMed ID9185620
JournalArch Biochem Biophys
Year1997
Volume342
Pages117-25
AuthorsLabadia ME, Jakes S, Grygon CA, Greenwood DJ, Schembri-King J, Lukas SM, Warren TC, Ingraham RH
TitleInteraction between the SH2 domains of ZAP-70 and the tyrosine-based activation motif 1 sequence of the zeta subunit of the T-cell receptor.
[15]
PubMed ID9535874
JournalJ Biol Chem
Year1998
Volume273
Pages8916-21
AuthorsGrazioli L, Germain V, Weiss A, Acuto O
TitleAnti-peptide antibodies detect conformational changes of the inter-SH2 domain of ZAP-70 due to binding to the zeta chain and to intramolecular interactions.
[16]
PubMed ID10583414
JournalEur J Biochem
Year1999
Volume266
Pages1166-73
AuthorsMagistrelli G, Bosotti R, Valsasina B, Visco C, Perego R, Toma S, Acuto O, Isacchi A
TitleRole of the Src homology 2 domains and interdomain regions in ZAP-70 phosphorylation and enzymatic activity.
[17]
CommentsPHOSPHORYLATION AT TYR-315 AND TYR-319, MUTAGENESIS OF TYR-315 AND TYR-319.
PubMed ID10037717
JournalJ Biol Chem
Year1999
Volume274
Pages6285-94
AuthorsDi Bartolo V, Mege D, Germain V, Pelosi M, Dufour E, Michel F, Magistrelli G, Isacchi A, Acuto O
TitleTyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling.
[18]
PubMed ID9858619
JournalMol Cell Biol
Year1999
Volume19
Pages948-56
AuthorsZhao Q, Williams BL, Abraham RT, Weiss A
TitleInterdomain B in ZAP-70 regulates but is not required for ZAP-70 signaling function in lymphocytes.
[19]
PubMed ID10704231
JournalBiochemistry
Year2000
Volume39
Pages2784-91
AuthorsVisco C, Magistrelli G, Bosotti R, Perego R, Rusconi L, Toma S, Zamai M, Acuto O, Isacchi A
TitleActivation of Zap-70 tyrosine kinase due to a structural rearrangement induced by tyrosine phosphorylation and/or ITAM binding.
[20]
CommentsX-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-256.
PubMed ID12450381
JournalBiochemistry
Year2002
Volume41
Pages14176-84
AuthorsFolmer RH, Geschwindner S, Xue Y
TitleCrystal structure and NMR studies of the apo SH2 domains of ZAP-70: two bikes rather than a tandem.
Related PDB1m61
Related UniProtKBP43403
[21]
PubMed ID15292186
JournalJ Biol Chem
Year2004
Volume279
Pages42818-25
AuthorsJin L, Pluskey S, Petrella EC, Cantin SM, Gorga JC, Rynkiewicz MJ, Pandey P, Strickler JE, Babine RE, Weaver DT, Seidl KJ
TitleThe three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors.
Related PDB1u59
Related UniProtKBP43403
[22]
PubMed ID15923611
JournalMol Cell Biol
Year2005
Volume25
Pages4924-33
AuthorsBrdicka T, Kadlecek TA, Roose JP, Pastuszak AW, Weiss A
TitleIntramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases.
[23]
PubMed ID17512407
JournalCell
Year2007
Volume129
Pages735-46
AuthorsDeindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J
TitleStructural basis for the inhibition of tyrosine kinase activity of ZAP-70.
Related PDB2ozo
Related UniProtKBP43403
[24]
CommentsREVIEW ON FUNCTION.
PubMed ID19290920
JournalImmunol Rev
Year2009
Volume228
Pages41-57
AuthorsAu-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, Weiss A
TitleThe structure, regulation, and function of ZAP-70.
[25]
PubMed ID19920178
JournalProc Natl Acad Sci U S A
Year2009
Volume106
Pages20699-704
AuthorsDeindl S, Kadlecek TA, Cao X, Kuriyan J, Weiss A
TitleStability of an autoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response.
[26]
PubMed ID20206686
JournalCell Signal
Year2010
Volume22
Pages1175-84
AuthorsBradshaw JM
TitleThe Src, Syk, and Tec family kinases: distinct types of molecular switches.
[27]
PubMed ID20452964
JournalCold Spring Harb Perspect Biol
Year2010
Volume2
Pagesa002279
AuthorsWang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A
TitleZAP-70: an essential kinase in T-cell signaling.
[28]
PubMed ID21602568
JournalJ Biol Chem
Year2011
Volume286
Pages25872-81
AuthorsBond PJ, Faraldo-Gomez JD
TitleMolecular mechanism of selective recruitment of Syk kinases by the membrane antigen-receptor complex.

comments
This enzyme belongs to Syk kinase family of non-receptor tyrosine kinases. This enzyme plays a critical role in T cell activation and the immune response.
This enzyme is composed of two SH2 domains in the N-terminal region, interdomain-A, which is inserted between the two SH2 domains, interdomain-B, and the catalytic domain. The interdomain-B is located between the second SH2 domain and the catalytic domain.
The two SH2 domains interact with the phosphotyrosines in the immunoreceptor tyrosine activation motifs (ITAMs) of the zeta-chains of T-cell antigen receptor (TCR) (see [8]). The interaction of the SH2 domains with ITAMs induces the conformational reorientation, which can lead to the activation of the catalytic domain (see [20]). Without the interaction with ITAMs, both the SH2 domains may down-regulate the catalytic domain (see [20]).
The catalytic domain of this enzyme is homologous to Proto-oncogene tyrosine-protein kinase ABL1 (M00130 in EzCatDB), with common active-site residues.

createdupdated
2011-12-072013-02-08


Copyright: Nozomi Nagano, JST & CBRC-AIST
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Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
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Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
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