EzCatDB: M00304
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DB codeM00304
RLCP classification3.103.130000.1162 : Transfer
CATH domainDomain 12.30.30.40 : SH3 type barrels.
Domain 23.30.505.10 : SHC Adaptor Protein
Domain 33.30.200.20 : Phosphorylase Kinase; domain 1
Domain 41.10.510.10 : 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,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344
2.30.30.40 : SH3 type barrels.M00183,M00043,M00130,T00256,M00335
3.30.200.20 : Phosphorylase Kinase; domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344,D00298
3.30.505.10 : SHC Adaptor ProteinM00183,M00043,M00130,M00148,T00256,M00333,M00339,M00344,T00221

Enzyme Name
UniProtKBKEGG

P32577P41241P41240
Protein nameTyrosine-protein kinase CSKTyrosine-protein kinase CSKTyrosine-protein kinase CSKNon-specific protein-tyrosine kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
CSK
CYL
Cytoplasmic protein tyrosine kinase
MATK
Protein-tyrosine kinase (ambiguous)
SRC
SRC2
SynonymsEC 2.7.10.2
C-Src kinase
EC 2.7.10.2
C-Src kinase
Protein-tyrosine kinase MPK-2
p50CSK
EC 2.7.10.2
C-Src kinase
Protein-tyrosine kinase CYL
RefSeqNP_001025210.1 (Protein)
NM_001030039.1 (DNA/RNA sequence)
NP_031809.2 (Protein)
NM_007783.2 (DNA/RNA sequence)
NP_001120662.1 (Protein)
NM_001127190.1 (DNA/RNA sequence)
NP_004374.1 (Protein)
NM_004383.2 (DNA/RNA sequence)
PfamPF07714 (Pkinase_Tyr)
PF00017 (SH2)
PF00018 (SH3_1)
[Graphical view]
PF07714 (Pkinase_Tyr)
PF00017 (SH2)
PF00018 (SH3_1)
[Graphical view]
PF07714 (Pkinase_Tyr)
PF00017 (SH2)
PF00018 (SH3_1)
[Graphical view]


UniProtKB:Accession NumberP32577P41241P41240
Entry nameCSK_RATCSK_MOUSECSK_HUMAN
ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SubunitHomodimer (via SH3-domain). Interacts with PTPN8. Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1, these interactions serve to recruit CSK to the membrane where it can phosphorylate and inhibit Src-family kinases. Interacts with SRCIN1. Interacts with RHOH (By similarity).Homodimer (via SH3-domain). Interacts with PTPN8. Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1, these interactions serve to recruit CSK to the membrane where it can phosphorylate and inhibit Src-family kinases. Interacts with SRCIN1. Interacts with RHOH (By similarity).Homodimer (via SH3-domain). Interacts with PTPN8 (By similarity). Interacts with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1, these interactions serve to recruit CSK to the membrane where it can phosphorylate and inhibit Src-family kinases. Interacts with SRCIN1. Interacts with RHOH.
Subcellular locationCytoplasm (By similarity). Cell membrane (By similarity). Note: Mainly cytoplasmic, also present in lipid rafts (By similarity).Cytoplasm. Cell membrane. Note: Mainly cytoplasmic, also present in lipid rafts.Cytoplasm (By similarity). Cell membrane (By similarity). Note: Mainly cytoplasmic, also present in lipid rafts (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

             
1k9aA01UnboundUnboundUnboundUnboundUnbound
1k9aB01UnboundUnboundUnboundUnboundUnbound
1k9aC01UnboundUnboundUnboundUnboundUnbound
1k9aD01UnboundUnboundUnboundUnboundUnbound
1k9aE01UnboundUnboundUnboundUnboundUnbound
1k9aF01UnboundUnboundUnboundUnboundUnbound
1jegA00UnboundUnboundUnboundUnboundUnbound
1cskA00UnboundUnboundUnboundUnboundUnbound
1cskB00UnboundUnboundUnboundUnboundUnbound
1cskC00UnboundUnboundUnboundUnboundUnbound
1cskD00UnboundUnboundUnboundUnboundUnbound
1k9aA02UnboundUnboundUnboundUnboundUnbound
1k9aB02UnboundUnboundUnboundUnboundUnbound
1k9aC02UnboundUnboundUnboundUnboundUnbound
1k9aD02UnboundUnboundUnboundUnboundUnbound
1k9aE02UnboundUnboundUnboundUnboundUnbound
1k9aF02UnboundUnboundUnboundUnboundUnbound
3eacA00UnboundUnboundUnboundUnboundUnbound
3eazA00UnboundUnboundUnboundUnboundUnbound
1k9aA03UnboundUnboundUnboundUnboundUnbound
1k9aB03UnboundUnboundUnboundUnboundUnbound
1k9aC03UnboundUnboundUnboundUnboundUnbound
1k9aD03UnboundUnboundUnboundUnboundUnbound
1k9aE03UnboundUnboundUnboundUnboundUnbound
1k9aF03UnboundUnboundUnboundUnboundUnbound
1bygA01UnboundUnboundUnboundUnboundUnbound
3d7tA01UnboundUnboundUnboundUnboundUnbound
3d7uA01UnboundUnboundUnboundUnboundUnbound
3d7uC01UnboundUnboundUnboundUnboundUnbound
1k9aA04UnboundUnboundUnboundUnboundUnbound
1k9aB04UnboundUnboundUnboundUnboundUnbound
1k9aC04UnboundUnboundUnboundUnboundUnbound
1k9aD04UnboundUnboundUnboundUnboundUnbound
1k9aE04UnboundUnboundUnboundUnboundUnbound
1k9aF04UnboundUnboundUnboundUnboundUnbound
1bygA02UnboundUnboundUnboundUnboundUnbound
3d7tA02UnboundUnboundUnboundUnboundUnbound
3d7uA02UnboundUnboundUnboundUnboundUnbound
3d7uC02UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
literature [6], [34]
pdbCatalytic residuesCofactor-binding residues
          
1k9aA01               
 
1k9aB01               
 
1k9aC01               
 
1k9aD01               
 
1k9aE01               
 
1k9aF01               
 
1jegA00               
 
1cskA00               
 
1cskB00               
 
1cskC00               
 
1cskD00               
 
1k9aA02               
 
1k9aB02               
 
1k9aC02               
 
1k9aD02               
 
1k9aE02               
 
1k9aF02               
 
3eacA00               
 
3eazA00               
 
1k9aA03               
 
1k9aB03               
 
1k9aC03               
 
1k9aD03               
 
1k9aE03               
 
1k9aF03               
 
1bygA01               
 
3d7tA01               
 
3d7uA01               
 
3d7uC01               
 
1k9aA04ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
1k9aB04ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
1k9aC04ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
1k9aD04ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
1k9aE04ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
1k9aF04ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
1bygA02ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
3d7tA02ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
3d7uA02ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)
3d7uC02ASP 314;ARG 318
ASN 319;ASP 332(Magnesium binding)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[6]FIG.4
[8]Figure 2
[34]Figure 7, p.344-345

references
[1]
CommentsFUNCTION IN PHOSPHORYLATION OF LYN AND FYN.
PubMed ID1722201
JournalJ Biol Chem
Year1991
Volume266
Pages24249-52
AuthorsOkada M, Nada S, Yamanashi Y, Yamamoto T, Nakagawa H
TitleCSK: a protein-tyrosine kinase involved in regulation of src family kinases.
[2]
CommentsX-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-71.
PubMed ID7511113
JournalFEBS Lett
Year1994
Volume341
Pages79-85
AuthorsBorchert TV, Mathieu M, Zeelen JP, Courtneidge SA, Wierenga RK
TitleThe crystal structure of human CskSH3: structural diversity near the RT-Src and n-Src loop.
Related PDB1csk
Related UniProtKBP41240
[3]
PubMed ID7527038
JournalJ Biol Chem
Year1994
Volume269
Pages30880-7
AuthorsCole PA, Burn P, Takacs B, Walsh CT
TitleEvaluation of the catalytic mechanism of recombinant human Csk (C-terminal Src kinase) using nucleotide analogs and viscosity effects.
[4]
PubMed ID7518562
JournalMol Cell Biol
Year1994
Volume14
Pages5402-11
AuthorsHowell BW, Cooper JA
TitleCsk suppression of Src involves movement of Csk to sites of Src activity.
[5]
PubMed ID7513429
JournalProc Natl Acad Sci U S A
Year1994
Volume91
Pages3984-8
AuthorsSabe H, Hata A, Okada M, Nakagawa H, Hanafusa H
TitleAnalysis of the binding of the Src homology 2 domain of Csk to tyrosine-phosphorylated proteins in the suppression and mitotic activation of c-Src.
[6]
PubMed ID7673185
JournalJ Biol Chem
Year1995
Volume270
Pages22105-8
AuthorsCole PA, Grace MR, Phillips RS, Burn P, Walsh CT
TitleThe role of the catalytic base in the protein tyrosine kinase Csk.
[7]
PubMed ID9048573
JournalBiochemistry
Year1997
Volume36
Pages1874-81
AuthorsGrace MR, Walsh CT, Cole PA
TitleDivalent ion effects and insights into the catalytic mechanism of protein tyrosine kinase Csk.
[8]
JournalJ Am Chem Soc
Year1998
Volume120
Pages9851-8
AuthorsKim K, Cole PA
TitleKinetic analysis of a protein tyrosine kinase reaction transition state in the forward and reverse directions.
[9]
PubMed ID10395732
JournalArch Biochem Biophys
Year1999
Volume367
Pages167-72
AuthorsSun G, Budde RJ
TitleMutations in the N-terminal regulatory region reduce the catalytic activity of Csk, but do not affect its recognition of Src.
[10]
PubMed ID10460171
JournalBiochemistry
Year1999
Volume38
Pages11147-55
AuthorsSondhi D, Cole PA
TitleDomain interactions in protein tyrosine kinase Csk.
[11]
PubMed ID9878439
JournalJ Mol Biol
Year1999
Volume285
Pages713-25
AuthorsLamers MB, Antson AA, Hubbard RE, Scott RK, Williams DH
TitleStructure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine.
Related PDB1byg
Related UniProtKBP41240
[12]
PubMed ID10918051
JournalJ Biol Chem
Year2000
Volume275
Pages29183-6
AuthorsTakeuchi S, Takayama Y, Ogawa A, Tamura K, Okada M
TitleTransmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase, Csk.
[13]
CommentsINTERACTION WITH PAG1.
PubMed ID10790433
JournalJ Exp Med
Year2000
Volume191
Pages1591-604
AuthorsBrdicka T, Pavlistova D, Leo A, Bruyns E, Korinek V, Angelisova P, Scherer J, Shevchenko A, Hilgert I, Cerny J, Drbal K, Kuramitsu Y, Kornacker B, Horejsi V, Schraven B
TitlePhosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation.
[14]
CommentsINTERACTION WITH PAG1.
PubMed ID10801129
JournalNature
Year2000
Volume404
Pages999-1003
AuthorsKawabuchi M, Satomi Y, Takao T, Shimonishi Y, Nada S, Nagai K, Tarakhovsky A, Okada M
TitleTransmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases.
[15]
PubMed ID11551213
JournalBiochemistry
Year2001
Volume40
Pages11149-55
AuthorsShaffer J, Sun G, Adams JA
TitleNucleotide release and associated conformational changes regulate function in the COOH-terminal Src kinase, Csk.
[16]
CommentsPHOSPHORYLATION AT SER-364 BY PKA, MUTAGENESIS OF SER-364.
PubMed ID11181701
JournalJ Exp Med
Year2001
Volume193
Pages497-507
AuthorsVang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skalhegg BS, Hansson V, Mustelin T, Tasken K
TitleActivation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor.
[17]
PubMed ID11724538
JournalJ Mol Biol
Year2001
Volume314
Pages129-38
AuthorsShekhtman A, Ghose R, Wang D, Cole PA, Cowburn D
TitleNovel mechanism of regulation of the non-receptor protein tyrosine kinase Csk: insights from NMR mapping studies and site-directed mutagenesis.
[18]
CommentsSTRUCTURE BY NMR OF 1-83.
PubMed ID11685249
JournalNat Struct Biol
Year2001
Volume8
Pages998-1004
AuthorsGhose R, Shekhtman A, Goger MJ, Ji H, Cowburn D
TitleA novel, specific interaction involving the Csk SH3 domain and its natural ligand.
Related PDB1jeg
Related UniProtKBP41241
[19]
PubMed ID11884384
JournalJ Biol Chem
Year2002
Volume277
Pages14351-4
AuthorsOgawa A, Takayama Y, Sakai H, Chong KT, Takeuchi S, Nakagawa A, Nada S, Okada M, Tsukihara T
TitleStructure of the carboxyl-terminal Src kinase, Csk.
Related PDB1k9a
Related UniProtKBP32577
[20]
PubMed ID12417200
JournalJ Mol Biol
Year2002
Volume323
Pages871-81
AuthorsHamuro Y, Wong L, Shaffer J, Kim JS, Stranz DD, Jennings PA, Woods VL Jr, Adams JA
TitlePhosphorylation driven motions in the COOH-terminal Src kinase, CSK, revealed through enhanced hydrogen-deuterium exchange and mass spectrometry (DXMS).
[21]
PubMed ID12600271
JournalBiochem J
Year2003
Volume372
Pages271-8
AuthorsYaqub S, Abrahamsen H, Zimmerman B, Kholod N, Torgersen KM, Mustelin T, Herberg FW, Tasken K, Vang T
TitleActivation of C-terminal Src kinase (Csk) by phosphorylation at serine-364 depends on the Csk-Src homology 3 domain.
[22]
PubMed ID12686554
JournalJ Biol Chem
Year2003
Volume278
Pages24072-7
AuthorsLin X, Lee S, Sun G
TitleFunctions of the activation loop in Csk protein-tyrosine kinase.
[23]
PubMed ID15504335
JournalBiochem Biophys Res Commun
Year2004
Volume324
Pages1155-64
AuthorsRoskoski R Jr
TitleSrc protein-tyrosine kinase structure and regulation.
[24]
PubMed ID15312765
JournalJ Mol Biol
Year2004
Volume341
Pages93-106
AuthorsWong L, Lieser S, Chie-Leon B, Miyashita O, Aubol B, Shaffer J, Onuchic JN, Jennings PA, Woods VL Jr, Adams JA
TitleDynamic coupling between the SH2 domain and active site of the COOH terminal Src kinase, Csk.
[25]
PubMed ID15683240
JournalBiochemistry
Year2005
Volume44
Pages1561-7
AuthorsLin X, Ayrapetov MK, Lee S, Parang K, Sun G
TitleProbing the communication between the regulatory and catalytic domains of a protein tyrosine kinase, Csk.
[26]
CommentsREVIEW.
PubMed ID16243715
JournalGrowth Factors
Year2005
Volume23
Pages233-44
AuthorsChong YP, Mulhern TD, Cheng HC
TitleC-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)--endogenous negative regulators of Src-family protein kinases.
[27]
PubMed ID15623523
JournalJ Biol Chem
Year2005
Volume280
Pages7769-76
AuthorsLieser SA, Shindler C, Aubol BE, Lee S, Sun G, Adams JA
TitlePhosphoryl transfer step in the C-terminal Src kinase controls Src recognition.
[28]
PubMed ID16002086
JournalJ Mol Biol
Year2005
Volume351
Pages131-43
AuthorsWong L, Lieser SA, Miyashita O, Miller M, Tasken K, Onuchic JN, Adams JA, Woods VL Jr, Jennings PA
TitleCoupled motions in the SH2 and kinase domains of Csk control Src phosphorylation.
[29]
PubMed ID17018524
JournalJ Biol Chem
Year2006
Volume281
Pages38004-12
AuthorsLieser SA, Shaffer J, Adams JA
TitleSRC tail phosphorylation is limited by structural changes in the regulatory tyrosine kinase Csk.
[30]
PubMed ID16483606
JournalJ Mol Biol
Year2006
Volume357
Pages1263-73
AuthorsLin X, Wang Y, Ahmadibeni Y, Parang K, Sun G
TitleStructural basis for domain-domain communication in a protein tyrosine kinase, the C-terminal Src kinase.
[31]
PubMed ID17137590
JournalJ Mol Biol
Year2007
Volume365
Pages1460-8
AuthorsMills JE, Whitford PC, Shaffer J, Onuchic JN, Adams JA, Jennings PA
TitleA novel disulfide bond in the SH2 Domain of the C-terminal Src kinase controls catalytic activity.
[32]
PubMed ID18614016
JournalCell
Year2008
Volume134
Pages124-34
AuthorsLevinson NM, Seeliger MA, Cole PA, Kuriyan J
TitleStructural basis for the recognition of c-Src by its inactivator Csk.
Related PDB3d7t,3d7u
Related UniProtKBP41240
[33]
PubMed ID19244618
JournalJ Mol Biol
Year2009
Volume386
Pages1066-77
AuthorsHuang K, Wang YH, Brown A, Sun G
TitleIdentification of N-terminal lobe motifs that determine the kinase activity of the catalytic domains and regulatory strategies of Src and Csk protein tyrosine kinases.
[34]
PubMed ID20476842
JournalGrowth Factors
Year2010
Volume28
Pages329-50
AuthorsIa KK, Mills RD, Hossain MI, Chan KC, Jarasrassamee B, Jorissen RN, Cheng HC
TitleStructural elements and allosteric mechanisms governing regulation and catalysis of CSK-family kinases and their inhibition of Src-family kinases.

comments
This enzyme is a nonreceptor tyrosine kinase, whose catalytic domain is homologous to that of proto-oncogene tyrosine-protein kinase ABL1 (M00130 in EzCatDB). This enzyme is composed of SH2 domain, SH3 domain and catalytic domain.
Unlike other homologous enzymes, this enzyme is not regulated by autophosphorylation of its activation loop and does not have a phosphorylation site in the C-terminus.
According to the literature, this enzyme is involved in the regulation of the Src family tyrosine kinases (SFKs), which are also homologous to this enzyme. This enzyme phosphorylate the C-terminal tail of SFKs, which could repress the activity of those enzymes. Src is one of SFKs.

createdupdated
2012-05-222013-01-28
Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
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)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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