DB code: S00458

RLCP classification 1.15.36030.52 : Hydrolysis
CATH domain 3.90.190.10 : Protein-Tyrosine Phosphatase; Chain A Catalytic domain
E.C. 3.1.3.16 3.1.3.48
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
3.90.190.10 : Protein-Tyrosine Phosphatase; Chain A M00169 D00154 M00149 T00221

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P51452 Dual specificity protein phosphatase 3
EC 3.1.3.48
EC 3.1.3.16
Dual specificity protein phosphatase VHR
NP_004081.1 (Protein)
NM_004090.3 (DNA/RNA sequence)
PF00782 (DSPc)
[Graphical View]

KEGG enzyme name
phosphoprotein 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 )

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P51452 DUS3_HUMAN Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate. A phosphoprotein + H(2)O = a protein + phosphate.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00076 C00391 C00562 C01167 C00001 C00017 C00585 C00009
E.C. 3.1.3.16
3.1.3.16
3.1.3.16
3.1.3.48
3.1.3.16
3.1.3.48
3.1.3.16
3.1.3.48
3.1.3.16
3.1.3.48
Compound Calcium Calmodulin Phosphoprotein Protein tyrosine phosphate H2O Protein Protein tyrosine Orthophosphate
Type divalent metal (Ca2+, Mg2+) peptide/protein peptide/protein,phosphate group/phosphate ion aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion H2O peptide/protein aromatic ring (only carbon atom),peptide/protein phosphate group/phosphate ion
ChEBI 29108
15377
26078
PubChem 271
22247451
962
1004
22486802
1vhrA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Analogue:EPE Unbound Unbound Unbound Unbound
1vhrB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Analogue:SO4
1f5dA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Bound:PTR (chain D) Bound:PTR (chain D) Unbound Unbound Unbound
1j4xA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Bound:PTR (chain D) Bound:PTR (chain D) Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1vhrA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 92;CYS 124;ARG 130;SER 131 ARG 125;GLU 126;TYR 128;SER 129;ARG 130
1vhrB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 92;CYS 124;ARG 130;SER 131 ARG 125;GLU 126;TYR 128;SER 129;ARG 130
1f5dA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 92; ;ARG 130;SER 131 ARG 125;GLU 126;TYR 128;SER 129;ARG 130 mutant C124S
1j4xA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 92; ;ARG 130;SER 131 ARG 125;GLU 126;TYR 128;SER 129;ARG 130 mutant C124S

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
Fig.4, p.5913-5914 2
[2]
Fig.2, Fig.3, p.7088-7091
[3]
p.1330
[5]
Scheme.1, p.27574 4
[6]
p.3011

References
[1]
Resource
Comments
Medline ID
PubMed ID 7597052
Journal Proc Natl Acad Sci U S A
Year 1995
Volume 92
Pages 5910-4
Authors Denu JM, Dixon JE
Title A catalytic mechanism for the dual-specific phosphatases.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 8679534
Journal Biochemistry
Year 1996
Volume 35
Pages 7084-92
Authors Hengge AC, Denu JM, Dixon JE
Title Transition-state structures for the native dual-specific phosphatase VHR and D92N and S131A mutants. Contributions to the driving force for catalysis.
Related PDB
Related UniProtKB
[3]
Resource
Comments X-ray crystallography (2.1 Angstroms)
Medline ID 96243129
PubMed ID 8650541
Journal Science
Year 1996
Volume 272
Pages 1328-1331
Authors Yuvaniyama J, Denu JM, Dixon JE, Saper MA
Title Crystal structure of the dual specificity protein phosphatase VHR.
Related PDB 1vhr
Related UniProtKB P51452
[4]
Resource
Comments
Medline ID
PubMed ID 8969212
Journal J Biol Chem
Year 1996
Volume 271
Pages 33486-92
Authors Wiland AM, Denu JM, Mourey RJ, Dixon JE
Title Purification and kinetic characterization of the mitogen-activated protein kinase phosphatase rVH6.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 11346639
Journal J Biol Chem
Year 2001
Volume 276
Pages 27568-74
Authors Kim JH, Shin DY, Han MH, Choi MU
Title Mutational 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.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 11863439
Journal Biochemistry
Year 2002
Volume 41
Pages 3009-17
Authors Schumacher MA, Todd JL, Rice AE, Tanner KG, Denu JM
Title Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase.
Related PDB 1f5d 1j4x
Related UniProtKB

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.

Created Updated
2002-07-09 2009-02-26