EzCatDB: M00124
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DB codeM00124
RLCP classification3.103.130000.1162 : Transfer
CATH domainDomain 12.60.120.260 : Jelly Rolls
Domain 2-.-.-.-
Domain 32.60.40.30 : Immunoglobulin-like
Domain 42.60.40.30 : Immunoglobulin-like
Domain 53.30.200.20 : Phosphorylase Kinase; domain 1
Domain 61.10.510.10 : Transferase(Phosphotransferase); domain 1Catalytic domain
Domain 71.10.150.50 : DNA polymerase; domain 1
E.C.2.7.10.1

CATH domainRelated DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1M00125,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344
2.60.120.260 : Jelly RollsT00005,T00065,T00066
2.60.40.30 : Immunoglobulin-likeM00134,M00129,M00136,M00149,M00192
3.30.200.20 : Phosphorylase Kinase; domain 1M00125,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344,D00298

Enzyme Name
UniProtKBKEGG

P54763P28693
Protein nameEphrin type-B receptor 2Ephrin type-B receptor 2receptor protein-tyrosine kinase
AATK
AATYK
AATYK2
AATYK3
ACH
ALK
anaplastic lymphoma kinase
ARK
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
AXL
Bek
Bfgfr
BRT
Bsk
C-FMS
CAK
CCK4
CD115
CD135
CDw135
Cek1
Cek10
Cek11
Cek2
Cek3
Cek5
Cek6
Cek7
CFD1
CKIT
CSF1R
DAlk
DDR1
DDR2
Dek
DKFZp434C1418
Drosophila Eph kinase
DRT
DTK
Ebk
ECK
EDDR1
Eek
EGFR
Ehk2
Ehk3
Elk
EPH
EPHA1
EPHA2
EPHA6
EPHA7
EPHA8
EPHB1
EPHB2
EPHB3
EPHB4
EphB5
ephrin-B3 receptor tyrosine kinase
EPHT
EPHT2
EPHT3
EPHX
ERBB
ERBB1
ERBB2
ERBB3
ERBB4
ERK
Eyk
FGFR1
FGFR2
FGFR3
FGFR4
FLG
FLK1
FLK2
FLT1
FLT2
FLT3
FLT4
FMS
Fv2
HBGFR
HEK11
HEK2
HEK3
HEK5
HEK6
HEP
HER2
HER3
HER4
HGFR
HSCR1
HTK
IGF1R
INSR
INSRR
insulin receptor protein-tyrosine kinase
IR
IRR
JTK12
JTK13
JTK14
JWS
K-SAM
KDR
KGFR
KIA0641
KIAA1079
KIAA1459
Kil
Kin15
Kin16
KIT
KLG
LTK
MCF3
Mdk1
Mdk2
Mdk5
MEhk1
MEN2A/B
Mep
MER
MERTK
MET
Mlk1
Mlk2
Mrk
MST1R
MTC1
MUSK
Myk1
N-SAM
NEP
NET
Neu
neurite outgrowth regulating kinase
NGL
NOK
nork
novel oncogene with kinase-domain
Nsk2
NTRK1
NTRK2
NTRK3
NTRK4
NTRKR1
NTRKR2
NTRKR3
Nuk
NYK
PCL
PDGFR
PDGFRA
PDGFRB
PHB6
protein-tyrosine kinase (ambiguous)
protein tyrosine kinase (ambiguous)
PTK
PTK3
PTK7
receptor protein tyrosine kinase
RET
RON
ROR1
ROR2
ROS1
RSE
RTK
RYK
SEA
Sek2
Sek3
Sek4
Sfr
SKY
STK
STK1
TEK
TIE
TIE1
TIE2
TIF
TKT
TRK
TRKA
TRKB
TRKC
TRKE
TYK1
TYRO10
Tyro11
TYRO3
Tyro5
Tyro6
TYRO7
UFO
VEGFR1
VEGFR2
VEGFR3
Vik
YK1
Yrk
SynonymsEC 2.7.10.1
Tyrosine-protein kinase receptor EPH-3
Neural kinase
Nuk receptor tyrosine kinase
SEK-3
EC 2.7.10.1
Tyrosine-protein kinase receptor CEK5
RefSeq
NP_996834.1 (Protein)
NM_206951.3 (DNA/RNA sequence)
PfamPF01404 (Ephrin_lbd)
PF00041 (fn3)
PF07699 (GCC2_GCC3)
PF07714 (Pkinase_Tyr)
PF00536 (SAM_1)
[Graphical view]
PF01404 (Ephrin_lbd)
PF00041 (fn3)
PF07699 (GCC2_GCC3)
PF07714 (Pkinase_Tyr)
PF00536 (SAM_1)
[Graphical view]


UniProtKB:Accession NumberP54763P28693
Entry nameEPHB2_MOUSEEPHB2_CHICK
ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SubunitInteracts with PRKCABP. The ligand-activated form interacts with multiple proteins, including GTPase-activating protein (RASGAP) through its SH2 domain. Binds RASGAP through the juxtamembrane tyrosines residues (By similarity). Interacts with PRKCABP and GRIP1.
Subcellular locationMembrane, Single-pass type I membrane protein.Membrane, Single-pass type I membrane protein.
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

             
1nukAUnboundUnboundUnboundUnboundUnbound
1kgyAUnboundUnboundUnboundUnboundUnbound
1kgyBUnboundUnboundUnboundUnboundUnbound
1kgyCUnboundUnboundUnboundUnboundUnbound
1kgyDUnboundUnboundUnboundUnboundUnbound
1jpaA01UnboundUnboundUnboundAnalogue:ANPUnbound
1jpaB01UnboundUnboundUnboundAnalogue:ANPUnbound
1jpaA02UnboundUnboundUnboundUnboundUnbound
1jpaB02UnboundUnboundUnboundUnboundUnbound
1sggAUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot & Similarity with M00129
pdbCatalytic residuesCofactor-binding residuesModified residuescomment
            
1nukA 
 
 
 
1kgyA 
 
 
 
1kgyB 
 
 
 
1kgyC 
 
 
 
1kgyD 
 
 
 
1jpaA01 
 
 
mutant Y604F, Y610F
1jpaB01 
 
 
mutant Y604F, Y610F
1jpaA02ASP 754;ARG 758
ASN 759;ASP 772(Magnesium binding)
 
 
1jpaB02ASP 754;ARG 758
ASN 759;ASP 772(Magnesium binding)
 
 
1sggA 
 
TYR 25 (Phospholylated)
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[9]

[10]


references
[1]
PubMed ID9233798
JournalEMBO J
Year1997
Volume16
Pages3877-88
AuthorsHolland SJ, Gale NW, Gish GD, Roth RA, Songyang Z, Cantley LC, Henkemeyer M, Yancopoulos GD, Pawson T
TitleJuxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells.
[2]
CommentsX-ray crystallography
PubMed ID9853759
JournalNature
Year1998
Volume396
Pages486-91
AuthorsHimanen JP, Henkemeyer M, Nikolov DB
TitleCrystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2.
Related PDB1nuk
[3]
CommentsINTERACTION WITH PRKCABP
Medline ID99098206
PubMed ID9883737
JournalNeuron
Year1998
Volume21
Pages1453-63
AuthorsTorres R, Firestein BL, Dong H, Staudinger J, Olson EN, Huganir RL, Bredt DS, Gale NW, Yancopoulos GD
TitlePDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands.
Related UniProtKBP54763
[4]
PubMed ID9632142
JournalOncogene
Year1998
Volume16
Pages2657-70
AuthorsZisch AH, Kalo MS, Chong LD, Pasquale EB
TitleComplex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region.
[5]
PubMed ID10523848
JournalOncogene
Year1999
Volume18
Pages5680-90
AuthorsYoshii S, Tanaka M, Otsuki Y, Wang DY, Guo RJ, Zhu Y, Takeda R, Hanai H, Kaneko E, Sugimura H
TitlealphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase.
[6]
PubMed ID10555534
JournalCell Tissue Res
Year1999
Volume298
Pages1-9
AuthorsKalo MS, Pasquale EB
TitleSignal transfer by Eph receptors.
[7]
PubMed ID10356296
JournalMol Cell Neurosci
Year1999
Volume13
Pages337-47
AuthorsScully AL, McKeown M, Thomas JB
TitleIsolation and characterization of Dek, a Drosophila eph receptor protein tyrosine kinase.
[8]
PubMed ID10449409
JournalEMBO J
Year1999
Volume18
Pages4438-45
AuthorsChi SW, Ayed A, Arrowsmith CH
TitleSolution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain.
[9]
PubMed ID9886291
JournalNat Struct Biol
Year1999
Volume6
Pages44-9
AuthorsStapleton D, Balan I, Pawson T, Sicheri F
TitleThe crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization.
[10]
CommentsNMR Structures
PubMed ID10548040
JournalProtein Sci
Year1999
Volume8
Pages1954-61
AuthorsSmalla M, Schmieder P, Kelly M, Ter Laak A, Krause G, Ball L, Wahl M, Bork P, Oschkinat H
TitleSolution structure of the receptor tyrosine kinase EphB2 SAM domain and identification of two distinct homotypic interaction sites.
Related PDB1sgg
[11]
PubMed ID9933164
JournalScience
Year1999
Volume283
Pages833-6
AuthorsThanos CD, Goodwill KE, Bowie JU
TitleOligomeric structure of the human EphB2 receptor SAM domain.
[12]
PubMed ID10848605
JournalMol Cell Biol
Year2000
Volume20
Pages4791-805
AuthorsBinns KL, Taylor PP, Sicheri F, Pawson T, Holland SJ
TitlePhosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors.
[13]
CommentsFUNCTION
Medline ID20171264
PubMed ID10704386
JournalDevelopment
Year2000
Volume127
Pages1397-410
AuthorsImondi R, Wideman C, Kaprielian Z
TitleComplementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: a possible role in constraining the orientation of longitudinally projecting axons.
Related UniProtKBP54763
[14]
PubMed ID11572780
JournalCell
Year2001
Volume106
Pages745-57
AuthorsWybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F
TitleStructural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region.
Related PDB1jpa
[15]
PubMed ID11780069
JournalNature
Year2001
Volume414
Pages933-8
AuthorsHimanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB
TitleCrystal structure of an Eph receptor-ephrin complex.
Related PDB1kgy
[16]
PubMed ID11718293
JournalEur Biophys J
Year2001
Volume30
Pages411-5
AuthorsBehlke J, Labudde D, Ristau O
TitleSelf-association studies on the EphB2 receptor SAM domain using analytical ultracentrifugation.
[17]
PubMed ID12054873
JournalJ Mol Biol
Year2002
Volume319
Pages823-37
AuthorsBaldisseri DM, Margolis JW, Weber DJ, Koo JH, Margolis FL
TitleOlfactory marker protein (OMP) exhibits a beta-clam fold in solution: implications for target peptide interaction and olfactory signal transduction.
[18]
PubMed ID12054872
JournalJ Mol Biol
Year2002
Volume319
Pages807-21
AuthorsSmith PC, Firestein S, Hunt JF
TitleThe crystal structure of the olfactory marker protein at 2.3 A resolution.
[19]
PubMed ID12141423
JournalInt J Dev Biol
Year2002
Volume46
Pages375-84
AuthorsCoulthard MG, Duffy S, Down M, Evans B, Power M, Smith F, Stylianou C, Kleikamp S, Oates A, Lackmann M, Burns GF, Boyd AW
TitleThe role of the Eph-ephrin signalling system in the regulation of developmental patterning.
[20]
PubMed ID12528767
JournalEur J Cancer
Year2002
Volume38 Suppl 5
PagesS3-10
AuthorsPawson T
TitleRegulation and targets of receptor tyrosine kinases.
[21]
PubMed ID12100883
JournalCurr Opin Genet Dev
Year2002
Volume12
Pages397-402
AuthorsDrescher U
TitleEph family functions from an evolutionary perspective.

comments
The E.C. was transferred from 2.7.1.112 to 2.7.10.1.
The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and the kinase activation segment. This receptor enzyme has N-terminal extracellular region, which is composed of ligand-binding domain, Cys-rich domain, and two fibronectine type-III domain, transmembrane region, and cytoplasmic region, which is composed of juxtamembrane region, protein kinase domain, and SAM domain.
PDB structures, 1nuk & 1kgy, correspond to the first domain of this enzyme, ligand-binding domain, the other structure, 1jpa, comprises the fifth domain, juxtamembrane region, and the sixth domain, protein kinase domain. PDB structure, 1sgg, corresponds to the last domain, SAM. However, tertiary structures of the rest of domains, the second domain, Cys-rich domain, the third and fourth domains, two fibronectin type-III domains, have not been determined yet.
The last domain is sterile alpha motif (SAM) domain, which was found in various signaling proteins such as tyrosine and serine/threonine protein kinases, regulators of lipid metabolism, and GTPases, according to the literature [9]. The SAM domain is involved in protein-protein interaction, rather than catalysis, through the ability to oligomerize with other SAM domains [9].
This SAM domain has a conserved tyrosine (Tyr25, PDB;1sgg), which was reported to be essential for the interaction with SH2 domains after its phosphorylation (see paper [10]).
Although the tertiary structure of the catalytic domain has been determined, its catalytic mechanism is still unclear. However, since the structure is homologous to other kinase domains with complete conservation of active site residues, the mechanism can be similar to those ones (see M00129).

createdupdated
2003-07-222009-02-26


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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