EzCatDB: M00326
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DB codeM00326
RLCP classification3.103.130000.1162 : Transfer
CATH domainDomain 12.60.-.-
Domain 22.60.40.60 : Immunoglobulin-like
Domain 32.60.-.-
Domain 42.60.-.-
Domain 5-.-.-.-
Domain 6-.-.-.-
Domain 7-.-.-.-
Domain 83.30.200.20 : Phosphorylase Kinase; domain 1
Domain 91.10.510.10 : Transferase(Phosphotransferase); domain 1Catalytic domain
Domain 10-.-.-.-
E.C.2.7.10.1

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,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344
3.30.200.20 : Phosphorylase Kinase; domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00325,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344,D00298

Enzyme Name
UniProtKBKEGG

P07949
Protein nameProto-oncogene tyrosine-protein kinase receptor RetReceptor protein-tyrosine kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
Protein-tyrosine kinase (ambiguous)
Protein tyrosine kinase (ambiguous)
Receptor protein tyrosine kinase
RET
SynonymsEC 2.7.10.1
Cadherin family member 12
Proto-oncogene c-Ret
ContainsSoluble RET kinase fragment
Extracellular cell-membrane anchored RET cadherin 120 kDa fragment
RefSeqNP_065681.1 (Protein)
NM_020630.4 (DNA/RNA sequence)
NP_066124.1 (Protein)
NM_020975.4 (DNA/RNA sequence)
PfamPF00028 (Cadherin)
PF07714 (Pkinase_Tyr)
[Graphical view]


UniProtKB:Accession NumberP07949
Entry nameRET_HUMAN
ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SubunitPhosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7 (By similarity). Interacts (not phosphorylated) with CC PTK2/FAK1 (via FERM domain). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas. Interacts with AIP in the pituitary gland, this interaction prevents the formation of the AIP-survivin complex. Binds to ARTN.
Subcellular locationCell membrane, Single-pass type I membrane protein. Endosome membrane, Single-pass type I membrane protein.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00002C00585C00008C01167
CompoundMgATP[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

             
2x2uA01UnboundUnboundUnboundUnboundUnbound
2x2uA02UnboundUnboundUnboundUnboundUnbound
2ivsA01UnboundUnboundUnboundAnalogue:ACKUnbound
2ivsB01UnboundUnboundUnboundAnalogue:ACKUnbound
2ivtA01UnboundUnboundUnboundAnalogue:AMPUnbound
2ivuA01UnboundUnboundUnboundUnboundUnbound
2ivvA01UnboundUnboundUnboundUnboundUnbound
2x2kA01UnboundUnboundUnboundUnboundUnbound
2x2lA01UnboundUnboundUnboundUnboundUnbound
2x2mA01UnboundUnboundUnboundUnboundUnbound
2x2mB01UnboundUnboundUnboundUnboundUnbound
2ivsA02UnboundUnboundUnboundUnboundUnbound
2ivsB02UnboundUnboundUnboundUnboundUnbound
2ivtA02UnboundUnboundUnboundUnboundUnbound
2ivuA02UnboundUnboundUnboundUnboundUnbound
2ivvA02UnboundUnboundUnboundUnboundUnbound
2x2kA02UnboundUnboundUnboundUnboundUnbound
2x2lA02UnboundUnboundUnboundUnboundUnbound
2x2mA02UnboundUnboundUnboundUnboundUnbound
2x2mB02UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P07949
pdbCatalytic residuesCofactor-binding residuesModified residuescomment
            
2x2uA01 
 
 
 
2x2uA02 
 
 
 
2ivsA01               
 
 
 
2ivsB01               
 
 
 
2ivtA01               
 
 
invisible 712-714
2ivuA01               
 
 
invisible 713
2ivvA01               
 
 
invisible 712-715
2x2kA01               
 
 
invisible 712-714
2x2lA01               
 
 
invisible 713-714
2x2mA01               
 
 
invisible 713
2x2mB01               
 
 
invisible 712-714
2ivsA02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
TYR 905 (auto-phosphorylation)
invisible 828-843
2ivsB02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
        (auto-phosphorylation)
invisible 822-843, 900-910
2ivtA02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
PTR 905 (auto-phosphorylation)
invisible 823-843
2ivuA02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
PTR 905 (auto-phosphorylation)
invisible 821-843
2ivvA02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
PTR 905 (auto-phosphorylation)
invisible 821-845
2x2kA02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
PTR 905 (auto-phosphorylation)
invisible 823-843
2x2lA02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
PTR 905 (auto-phosphorylation)
invisible 823-843
2x2mA02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
PTR 905 (auto-phosphorylation)
invisible 821-844
2x2mB02ASP 874;ARG 878
ASN 879;ASP 892 (Magnesium binding)
PTR 905 (auto-phosphorylation)
invisible 820-844

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[12]Figure 5

references
[1]
PubMed ID8674117
JournalCell
Year1996
Volume85
Pages1113-24
AuthorsJing S, Wen D, Yu Y, Holst PL, Luo Y, Fang M, Tamir R, Antonio L, Hu Z, Cupples R, Louis JC, Hu S, Altrock BW, Fox GM
TitleGDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.
[2]
PubMed ID8657309
JournalNature
Year1996
Volume382
Pages80-3
AuthorsTreanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD, Gray C, Armanini MP, Pollock RA, Hefti F, Phillips HS, Goddard A, Moore MW, Buj-Bello A, Davies AM, Asai N, Takahashi M, Vandlen R, Henderson CE, Rosenthal A
TitleCharacterization of a multicomponent receptor for GDNF.
[3]
PubMed ID9192898
JournalNature
Year1997
Volume387
Pages717-21
AuthorsKlein RD, Sherman D, Ho WH, Stone D, Bennett GL, Moffat B, Vandlen R, Simmons L, Gu Q, Hongo JA, Devaux B, Poulsen K, Armanini M, Nozaki C, Asai N, Goddard A, Phillips H, Henderson CE, Takahashi M, Rosenthal A
TitleA GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.
[4]
PubMed ID9467954
JournalOncogene
Year1998
Volume16
Pages293-9
AuthorsNozaki C, Asai N, Murakami H, Iwashita T, Iwata Y, Horibe K, Klein RD, Rosenthal A, Takahashi M
TitleCalcium-dependent Ret activation by GDNF and neurturin.
[5]
PubMed ID10545102
JournalEMBO J
Year1999
Volume18
Pages5901-10
AuthorsEketjall S, Fainzilber M, Murray-Rust J, Ibanez CF
TitleDistinct structural elements in GDNF mediate binding to GFRalpha1 and activation of the GFRalpha1-c-Ret receptor complex.
[6]
PubMed ID11445581
JournalJ Biol Chem
Year2001
Volume276
Pages35808-17
AuthorsAnders J, Kjar S, Ibanez CF
TitleMolecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site.
[7]
PubMed ID11988777
JournalNat Rev Neurosci
Year2002
Volume3
Pages383-94
AuthorsAiraksinen MS, Saarma M
TitleThe GDNF family: signalling, biological functions and therapeutic value.
[8]
PubMed ID14514671
JournalJ Biol Chem
Year2003
Volume278
Pages47898-904
AuthorsKjaer S, Ibanez CF
TitleIdentification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET.
[9]
PubMed ID15044950
JournalEMBO J
Year2004
Volume23
Pages1452-62
AuthorsLeppanen VM, Bespalov MM, Runeberg-Roos P, Puurand U, Merits A, Saarma M, Goldman A
TitleThe structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation.
[10]
PubMed ID15722196
JournalCell Signal
Year2005
Volume17
Pages717-27
AuthorsAmoresano A, Incoronato M, Monti G, Pucci P, de Franciscis V, Cerchia L
TitleDirect interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex.
[11]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 705-1013 ALONE AND IN COMPLEX WITH INHIBITORS, MASS SPECTROMETRY, PHOSPHORYLATION AT TYR-900 AND TYR-905.
PubMed ID16928683
JournalJ Biol Chem
Year2006
Volume281
Pages33577-87
AuthorsKnowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibanez CF, McDonald NQ
TitleStructure and chemical inhibition of the RET tyrosine kinase domain.
Related PDB2ivs,2ivt,2ivu,2ivv
Related UniProtKBP07949
[12]
PubMed ID17013378
JournalNat Chem Biol
Year2006
Volume2
Pages636-44
AuthorsSchlee S, Carmillo P, Whitty A
TitleQuantitative analysis of the activation mechanism of the multicomponent growth-factor receptor Ret.
[13]
PubMed ID16765900
JournalStructure
Year2006
Volume14
Pages1083-92
AuthorsWang X, Baloh RH, Milbrandt J, Garcia KC
TitleStructure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors.
[14]
PubMed ID17218019
JournalTrends Pharmacol Sci
Year2007
Volume28
Pages68-74
AuthorsBespalov MM, Saarma M
TitleGDNF family receptor complexes are emerging drug targets.
[15]
PubMed ID18845535
JournalJ Biol Chem
Year2008
Volume283
Pages35164-72
AuthorsParkash V, Leppanen VM, Virtanen H, Jurvansuu JM, Bespalov MM, Sidorova YA, Runeberg-Roos P, Saarma M, Goldman A
TitleThe structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding.
[16]
PubMed ID20117004
JournalBioorg Med Chem
Year2010
Volume18
Pages1482-96
AuthorsMologni L, Rostagno R, Brussolo S, Knowles PP, Kjaer S, Murray-Rust J, Rosso E, Zambon A, Scapozza L, McDonald NQ, Lucchini V, Gambacorti-Passerini C
TitleSynthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Related PDB2x2k,2x2l,2x2m
Related UniProtKBP07949
[17]
PubMed ID20473317
JournalNat Struct Mol Biol
Year2010
Volume17
Pages726-31
AuthorsKjaer S, Hanrahan S, Totty N, McDonald NQ
TitleMammal-restricted elements predispose human RET to folding impairment by HSCR mutations.
Related PDB2x2u
Related UniProtKBP07949

comments
This enzyme belongs to receptor tyrosine kinase family.
This enzyme consists of the N-terminal extracellular region, the transmembrane region, and the C-terminal intracellular region (see [7] and [11]). The extracellular region is composed of four N-terminal cadherin-like domains followed by a cysteine-rich domain (see [6], [7] and [11]). On the other hand, the intracellular region is composed of a juxtamembrane domain, a kinase domain, and a tail region (see [7] and [11]).
The catalytic domain of this enzyme is homologous to that of vascular endothelial growth factor receptor (M00131 in EzCatDB).
According to the literature [7], [8], [10] and [11], this enzyme is activated by binding to a complex of a glial cell line-derived neutrophic factor (GDNF) family ligand and its cognate receptor, the GDNF family receptor alpha (GFRalpha).
The GDNF family ligands, including GDNF, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), are homologous to the transforming growth factor-beta (TGF-beta) (see [7]). GFRalpha1 binds preferentially to GDNF, GFRalpha2 to NRTN, GFRalpha3 to ARTN, and GFRalpha4 to PSPN (see [7] and [13]). These receptor complexes with this enzyme can be drug targets (see [14]).
According to the literature[11], autophosphorylation of Tyr905 on A-loop is not required for RET catalytic activity.

createdupdated
2011-10-262012-12-21


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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