EzCatDB: S00458
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DB codeS00458
RLCP classification1.15.36030.52 : Hydrolysis
CATH domainDomain 13.90.190.10 : Protein-Tyrosine Phosphatase; Chain ACatalytic domain
E.C.3.1.3.16,3.1.3.48

CATH domainRelated DB codes (homologues)
3.90.190.10 : Protein-Tyrosine Phosphatase; Chain AM00169,D00154,M00149,T00221

Enzyme Name
UniProtKBKEGG

P51452
Protein nameDual specificity protein phosphatase 3phosphoprotein phosphatase
   (EC 3.1.3.16)

protein phosphatase-1
   (EC 3.1.3.16)

protein phosphatase-2A
   (EC 3.1.3.16)

protein phosphatase-2B
   (EC 3.1.3.16)

protein phosphatase-2C
   (EC 3.1.3.16)

protein D phosphatase
   (EC 3.1.3.16)

phosphospectrin phosphatase
   (EC 3.1.3.16)

casein phosphatase
   (EC 3.1.3.16)

Aspergillus awamori acid protein phosphatase
   (EC 3.1.3.16)

calcineurin
   (EC 3.1.3.16)

phosphatase 2A
   (EC 3.1.3.16)

phosphatase 2B
   (EC 3.1.3.16)

phosphatase II
   (EC 3.1.3.16)

phosphatase IB
   (EC 3.1.3.16)

phosphatase C-II
   (EC 3.1.3.16)

polycation modulated (PCM-) phosphatase
   (EC 3.1.3.16)

phosphopyruvate dehydrogenase phosphatase
   (EC 3.1.3.16)

phosphatase SP
   (EC 3.1.3.16)

branched-chain alpha-keto acid dehydrogenase phosphatase
   (EC 3.1.3.16)

BCKDH phosphatase
   (EC 3.1.3.16)

3-hydroxy 3-methylglutaryl coenzymeA reductase phosphatase
   (EC 3.1.3.16)

HMG-CoA reductase phosphatase
   (EC 3.1.3.16)

phosphatase H-II
   (EC 3.1.3.16)

phosphatase III
   (EC 3.1.3.16)

phosphatase I
   (EC 3.1.3.16)

protein phosphatase
   (EC 3.1.3.16)

phosphatase IV
   (EC 3.1.3.16)

protein-tyrosine-phosphatase
   (EC 3.1.3.48)

phosphotyrosine phosphatase
   (EC 3.1.3.48)

phosphoprotein phosphatase (phosphotyrosine)
   (EC 3.1.3.48)

phosphotyrosine histone phosphatase
   (EC 3.1.3.48)

protein phosphotyrosine phosphatase
   (EC 3.1.3.48)

tyrosylprotein phosphatase
   (EC 3.1.3.48)

phosphotyrosine protein phosphatase
   (EC 3.1.3.48)

phosphotyrosylprotein phosphatase
   (EC 3.1.3.48)

tyrosine O-phosphate phosphatase
   (EC 3.1.3.48)

PPT-phosphatase
   (EC 3.1.3.48)

PTPase
   (EC 3.1.3.48)

[phosphotyrosine]protein phosphatase
   (EC 3.1.3.48)

PTP-phosphatase
   (EC 3.1.3.48)

SynonymsEC 3.1.3.48
EC 3.1.3.16
Dual specificity protein phosphatase VHR
RefSeqNP_004081.1 (Protein)
NM_004090.3 (DNA/RNA sequence)
PfamPF00782 (DSPc)
[Graphical view]


UniProtKB:Accession NumberP51452
Entry nameDUS3_HUMAN
ActivityProtein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.,A phosphoprotein + H(2)O = a protein + phosphate.
Subunit
Subcellular location
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00076C00391C00562C01167C00001C00017C00585C00009
E.C.3.1.3.163.1.3.163.1.3.163.1.3.483.1.3.16,3.1.3.483.1.3.163.1.3.483.1.3.16,3.1.3.48
CompoundCalciumCalmodulinPhosphoproteinProtein tyrosine phosphateH2OProteinProtein tyrosineOrthophosphate
Typedivalent metal (Ca2+, Mg2+)peptide/proteinpeptide/protein,phosphate group/phosphate ionaromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ionH2Opeptide/proteinaromatic ring (only carbon atom),peptide/proteinphosphate group/phosphate ion
ChEBI29108



15377


26078
PubChem271



962
22247451


22486802
1004
                
1vhrAUnboundUnboundAnalogue:EPEUnbound UnboundUnboundUnbound
1vhrBUnboundUnboundUnboundUnbound UnboundUnboundAnalogue:SO4
1f5dAUnboundUnboundBound:PTR(chain D)Bound:PTR(chain D) UnboundUnboundUnbound
1j4xAUnboundUnboundBound:PTR(chain D)Bound:PTR(chain D) UnboundUnboundUnbound

Active-site residues
pdbCatalytic residuesMain-chain involved in catalysiscomment
           
1vhrAASP 92;CYS 124;ARG 130;SER 131
ARG 125;GLU 126;TYR 128;SER 129;ARG 130
 
1vhrBASP 92;CYS 124;ARG 130;SER 131
ARG 125;GLU 126;TYR 128;SER 129;ARG 130
 
1f5dAASP 92;       ;ARG 130;SER 131
ARG 125;GLU 126;TYR 128;SER 129;ARG 130
mutant C124S
1j4xAASP 92;       ;ARG 130;SER 131
ARG 125;GLU 126;TYR 128;SER 129;ARG 130
mutant C124S

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]Fig.4, p.5913-59142
[2]Fig.2, Fig.3, p.7088-7091
[3]p.1330
[5]Scheme.1, p.275744
[6]p.3011

references
[1]
PubMed ID7597052
JournalProc Natl Acad Sci U S A
Year1995
Volume92
Pages5910-4
AuthorsDenu JM, Dixon JE
TitleA catalytic mechanism for the dual-specific phosphatases.
[2]
PubMed ID8679534
JournalBiochemistry
Year1996
Volume35
Pages7084-92
AuthorsHengge AC, Denu JM, Dixon JE
TitleTransition-state structures for the native dual-specific phosphatase VHR and D92N and S131A mutants. Contributions to the driving force for catalysis.
[3]
CommentsX-ray crystallography (2.1 Angstroms)
Medline ID96243129
PubMed ID8650541
JournalScience
Year1996
Volume272
Pages1328-1331
AuthorsYuvaniyama J, Denu JM, Dixon JE, Saper MA
TitleCrystal structure of the dual specificity protein phosphatase VHR.
Related PDB1vhr
Related UniProtKBP51452
[4]
PubMed ID8969212
JournalJ Biol Chem
Year1996
Volume271
Pages33486-92
AuthorsWiland AM, Denu JM, Mourey RJ, Dixon JE
TitlePurification and kinetic characterization of the mitogen-activated protein kinase phosphatase rVH6.
[5]
PubMed ID11346639
JournalJ Biol Chem
Year2001
Volume276
Pages27568-74
AuthorsKim JH, Shin DY, Han MH, Choi MU
TitleMutational and kinetic evaluation of conserved His-123 in dual specificity protein-tyrosine phosphatase vaccinia H1-related phosphatase: participation of Tyr-78 and Thr-73 residues in tuning the orientation of His-123.
[6]
PubMed ID11863439
JournalBiochemistry
Year2002
Volume41
Pages3009-17
AuthorsSchumacher MA, Todd JL, Rice AE, Tanner KG, Denu JM
TitleStructural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase.
Related PDB1f5d,1j4x

comments
According to the papers [1] & [2], Cys124 functions as nucleophile, which attacks the phosphate on a phosphotyrosine to form a thiol-phosphate intermediate, whilst Asp92 serves a role as general acid, protonating the phenolate leaving group in the first step. This intermediate formation is rate-limiting in the reaction mechanism [1].
In the second step, the same acidic residue, Asp92, might acts as the general base, which would activate a water molecule by proton abstraction, and the activated water would hydrolyze the thiol-phosphate [1]. In this breakdown of the phosphoenzyme, Ser131 facilitates the hydrolysis, by its hydroxyl group interacting with the catalytic thiol of Cys124 [1].
Moreover, the residue corresponding to Arg130 seems to be critical for transition-state stabilization [1]. Along with the sidechain of Arg130, mainchain amide groups of loop 125-130 seems to stabilize the phosphate group.
The paper [2] indicated that the catalytic mechanism of this enzyme involved a highly dissociative transition state (SN1-like reaction), in which bond cleavage and protonation of the leaving group by the acid seem well advanced.

createdupdated
2002-07-092009-02-26


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