DB code: M00333

RLCP classification 3.103.130000.1162 : Transfer
CATH domain 3.30.505.10 : SHC Adaptor Protein
1.10.930.10 : Syk Kinase; Chain A, domain 2
3.30.505.10 : SHC Adaptor Protein
-.-.-.- :
3.30.200.20 : Phosphorylase Kinase; domain 1
1.10.510.10 : Transferase(Phosphotransferase); domain 1 Catalytic domain
E.C. 2.7.10.2
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1 M00125 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 2 M00148
3.30.200.20 : Phosphorylase Kinase; domain 1 M00125 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 Protein M00183 M00043 M00130 M00148 T00256 M00304 M00339 M00344 T00221

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P43403 Tyrosine-protein kinase ZAP-70
EC 2.7.10.2
70 kDa zeta-chain associated protein
Syk-related tyrosine kinase
NP_001070.2 (Protein)
NM_001079.3 (DNA/RNA sequence)
NP_997402.1 (Protein)
NM_207519.1 (DNA/RNA sequence)
PF07714 (Pkinase_Tyr)
PF00017 (SH2)
[Graphical View]

KEGG enzyme name
Non-specific protein-tyrosine kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
Cytoplasmic protein tyrosine kinase
Protein-tyrosine kinase (ambiguous)
SRK
SYK
ZAP70

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P43403 ZAP70_HUMAN ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. 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. 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).

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00002 C00585 C00008 C01167
E.C.
Compound Magnesium ATP [protein]-L-tyrosine ADP [protein]-L-tyrosine phosphate
Type divalent metal (Ca2+, Mg2+) amine group,nucleotide aromatic ring (only carbon atom),peptide/protein amine group,nucleotide aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion
ChEBI 18420
 18420
 		15422
 15422
 		16761
 16761
PubChem 888
 888
 		5957
 5957
 		6022
 6022
1m61A01 Unbound Unbound Unbound Unbound Unbound
2oq1A01 Unbound Unbound Unbound Unbound Unbound
2ozoA01 Unbound Unbound Unbound Unbound Unbound
1m61A02 Unbound Unbound Unbound Unbound Unbound
2oq1A02 Unbound Unbound Unbound Unbound Unbound
2ozoA02 Unbound Unbound Unbound Unbound Unbound
1m61A03 Unbound Unbound Unbound Unbound Unbound
2oq1A03 Unbound Unbound Unbound Unbound Unbound
2ozoA03 Unbound Unbound Unbound Unbound Unbound
1u59A01 Unbound Unbound Unbound Unbound Unbound
2ozoA04 Unbound Unbound Unbound Unbound Unbound
1u59A02 Unbound Unbound Unbound Unbound Unbound
2ozoA05 Bound:_MG Analogue:ANP Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Literature [21] & Swiss-prot;P43403

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
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
1u59A02 ASP 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
References Sections No. of steps in catalysis
[23]
Figure 7
[28]
FIGURE 9

References
[1]
Resource
Comments
Medline ID
PubMed ID 1717999
Journal Proc Natl Acad Sci U S A
Year 1991
Volume 88
Pages 9166-70
Authors Chan AC, Irving BA, Fraser JD, Weiss A
Title The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 1423621
Journal Cell
Year 1992
Volume 71
Pages 649-62
Authors Chan AC, Iwashima M, Turck CW, Weiss A
Title ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8366117
Journal J Biol Chem
Year 1993
Volume 268
Pages 19797-801
Authors Wange RL, Malek SN, Desiderio S, Samelson LE
Title Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 7509083
Journal Science
Year 1994
Volume 263
Pages 1136-9
Authors Iwashima M, Irving BA, van Oers NS, Chan AC, Weiss A
Title Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases.
Related PDB
Related UniProtKB
[5]
Resource
Comments MUTAGENESIS OF TYR-492 AND TYR-493.
Medline ID
PubMed ID 7781602
Journal EMBO J
Year 1995
Volume 14
Pages 2499-508
Authors Chan AC, Dalton M, Johnson R, Kong GH, Wang T, Thoma R, Kurosaki T
Title Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 7642520
Journal J Biol Chem
Year 1995
Volume 270
Pages 18730-3
Authors Wange RL, Guitian R, Isakov N, Watts JD, Aebersold R, Samelson LE
Title Activating and inhibitory mutations in adjacent tyrosines in the kinase domain of ZAP-70.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 7760813
Journal Mol Cell Biol
Year 1995
Volume 15
Pages 3171-8
Authors Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS
Title Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 7659156
Journal Nature
Year 1995
Volume 377
Pages 32-8
Authors Hatada MH, Lu X, Laird ER, Green J, Morgenstern JP, Lou M, Marr CS, Phillips TB, Ram MK, Theriault K, et al
Title Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor.
Related PDB 2oq1
Related UniProtKB P43403
[9]
Resource
Comments
Medline ID
PubMed ID 8663155
Journal J Biol Chem
Year 1996
Volume 271
Pages 15753-61
Authors Isakov N, Wange RL, Watts JD, Aebersold R, Samelson LE
Title Purification and characterization of human ZAP-70 protein-tyrosine kinase from a baculovirus expression system.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 8642247
Journal J Exp Med
Year 1996
Volume 183
Pages 1053-62
Authors van Oers NS, Killeen N, Weiss A
Title Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 8756661
Journal Mol Cell Biol
Year 1996
Volume 16
Pages 5026-35
Authors Kong G, Dalton M, Bubeck Wardenburg J, Straus D, Kurosaki T, Chan AC
Title Distinct tyrosine phosphorylation sites in ZAP-70 mediate activation and negative regulation of antigen receptor function.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 8943331
Journal Mol Cell Biol
Year 1996
Volume 16
Pages 6765-74
Authors Zhao Q, Weiss A
Title Enhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 8901551
Journal Proc Natl Acad Sci U S A
Year 1996
Volume 93
Pages 12165-70
Authors LoGrasso PV, Hawkins J, Frank LJ, Wisniewski D, Marcy A
Title Mechanism of activation for Zap-70 catalytic activity.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 9185620
Journal Arch Biochem Biophys
Year 1997
Volume 342
Pages 117-25
Authors Labadia ME, Jakes S, Grygon CA, Greenwood DJ, Schembri-King J, Lukas SM, Warren TC, Ingraham RH
Title Interaction between the SH2 domains of ZAP-70 and the tyrosine-based activation motif 1 sequence of the zeta subunit of the T-cell receptor.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 9535874
Journal J Biol Chem
Year 1998
Volume 273
Pages 8916-21
Authors Grazioli L, Germain V, Weiss A, Acuto O
Title Anti-peptide antibodies detect conformational changes of the inter-SH2 domain of ZAP-70 due to binding to the zeta chain and to intramolecular interactions.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 10583414
Journal Eur J Biochem
Year 1999
Volume 266
Pages 1166-73
Authors Magistrelli G, Bosotti R, Valsasina B, Visco C, Perego R, Toma S, Acuto O, Isacchi A
Title Role of the Src homology 2 domains and interdomain regions in ZAP-70 phosphorylation and enzymatic activity.
Related PDB
Related UniProtKB
[17]
Resource
Comments PHOSPHORYLATION AT TYR-315 AND TYR-319, MUTAGENESIS OF TYR-315 AND TYR-319.
Medline ID
PubMed ID 10037717
Journal J Biol Chem
Year 1999
Volume 274
Pages 6285-94
Authors Di Bartolo V, Mege D, Germain V, Pelosi M, Dufour E, Michel F, Magistrelli G, Isacchi A, Acuto O
Title Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 9858619
Journal Mol Cell Biol
Year 1999
Volume 19
Pages 948-56
Authors Zhao Q, Williams BL, Abraham RT, Weiss A
Title Interdomain B in ZAP-70 regulates but is not required for ZAP-70 signaling function in lymphocytes.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 10704231
Journal Biochemistry
Year 2000
Volume 39
Pages 2784-91
Authors Visco C, Magistrelli G, Bosotti R, Perego R, Rusconi L, Toma S, Zamai M, Acuto O, Isacchi A
Title Activation of Zap-70 tyrosine kinase due to a structural rearrangement induced by tyrosine phosphorylation and/or ITAM binding.
Related PDB
Related UniProtKB
[20]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-256.
Medline ID
PubMed ID 12450381
Journal Biochemistry
Year 2002
Volume 41
Pages 14176-84
Authors Folmer RH, Geschwindner S, Xue Y
Title Crystal structure and NMR studies of the apo SH2 domains of ZAP-70: two bikes rather than a tandem.
Related PDB 1m61
Related UniProtKB P43403
[21]
Resource
Comments
Medline ID
PubMed ID 15292186
Journal J Biol Chem
Year 2004
Volume 279
Pages 42818-25
Authors Jin L, Pluskey S, Petrella EC, Cantin SM, Gorga JC, Rynkiewicz MJ, Pandey P, Strickler JE, Babine RE, Weaver DT, Seidl KJ
Title The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors.
Related PDB 1u59
Related UniProtKB P43403
[22]
Resource
Comments
Medline ID
PubMed ID 15923611
Journal Mol Cell Biol
Year 2005
Volume 25
Pages 4924-33
Authors Brdicka T, Kadlecek TA, Roose JP, Pastuszak AW, Weiss A
Title Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 17512407
Journal Cell
Year 2007
Volume 129
Pages 735-46
Authors Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J
Title Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.
Related PDB 2ozo
Related UniProtKB P43403
[24]
Resource
Comments REVIEW ON FUNCTION.
Medline ID
PubMed ID 19290920
Journal Immunol Rev
Year 2009
Volume 228
Pages 41-57
Authors Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, Weiss A
Title The structure, regulation, and function of ZAP-70.
Related PDB
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 19920178
Journal Proc Natl Acad Sci U S A
Year 2009
Volume 106
Pages 20699-704
Authors Deindl S, Kadlecek TA, Cao X, Kuriyan J, Weiss A
Title Stability of an autoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 20206686
Journal Cell Signal
Year 2010
Volume 22
Pages 1175-84
Authors Bradshaw JM
Title The Src, Syk, and Tec family kinases: distinct types of molecular switches.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 20452964
Journal Cold Spring Harb Perspect Biol
Year 2010
Volume 2
Pages a002279
Authors Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A
Title ZAP-70: an essential kinase in T-cell signaling.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 21602568
Journal J Biol Chem
Year 2011
Volume 286
Pages 25872-81
Authors Bond PJ, Faraldo-Gomez JD
Title Molecular mechanism of selective recruitment of Syk kinases by the membrane antigen-receptor complex.
Related PDB
Related UniProtKB

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.

Created Updated
2011-12-07 2013-02-08