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164 a.a.
 Protein tyrosine phosphate |
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H(2)O |
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 protein tyrosine |
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 phosphate |
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Key reference
DOI no: 10.1074/jbc.M808362200 J Biol Chem 284:10129-10137 (2009) PubMed id: 19211553
Dimeric quaternary structure of the prototypical dual specificity phosphatase VH1. A.C.Koksal, J.D.Nardozzi, G.Cingolani. ABSTRACT
The Vaccinia virus H1 gene product, VH1, is a dual specificity phosphatase that down-regulates the cellular antiviral response by dephosphorylating STAT1. The crystal structure of VH1, determined at 1.32 A resolution, reveals a novel dimeric quaternary structure, which exposes two active sites spaced approximately 39 A away from each other. VH1 forms a stable dimer via an extensive domain swap of the N-terminal helix (residues 1-20). In vitro, VH1 can dephosphorylate activated STAT1, in a reaction that is competed by the nuclear transport adapter importin alpha5. Interestingly, VH1 is inactive with respect to STAT1 bound to DNA, suggesting that the viral phosphatase acts predominantly on the cytoplasmic pool of activated STAT1. We propose that the dimeric quaternary structure of VH1 is essential for specific recognition of activated STAT1, which prevents its nuclear translocation, thus blocking interferon-gamma signal transduction and antiviral response.
Selected figure(s)
Figure 3.
Structural view of the two binding determinants stabilizing the VH1 dimerization interface. A, six residues on the surface of helix α1, Lys^8/Ser^14/Thr^15 and Tyr^9/Leu^13/Leu^14 engage in extensive electrostatic and hydrophobic contacts, respectively, with the other VH1 protomer. Only the electrostatic contacts made by Lys^8/Ser^14/Thr^15 are shown in a as dashed black lines. B, the interface involving α5 helices of both protomers consists of three hydrophobic contacts that spans beneath the two N-terminal α1 helices of the VH1 dimer.Figure 6.
Model for VH1-mediated dephosphorylation of activated STAT1. A, activated STAT1 adopts a parallel conformation stabilized by interactions of the Tyr(P)^701 with the SH2 domains (33). L, linker; DBD, DNA-binding domain; CC, coiled-coil domain; N, N-terminal domain; P, phosphate on Tyr^701. B, dimeric VH1 is active with respect to this conformation of activated STAT1, which we hypothesize exists in the cytoplasm. C, upon dephosphorylation, STAT1 adopts a dimeric antiparallel conformation stabilized by reciprocal interactions of the N-terminal domains (33). D, as an alternative route, activated STAT1 can be imported into the cell nucleus by a heterodimer of importin α5 and importin β, where it binds to specific promoter sequences. As demonstrated in this paper, the structure of STAT1 bound to DNA is not accessible by VH1, probably due to the poor accessibility of the Tyr(P)s buried against the SH2 domains (29).The above figures are reprinted by permission from the ASBMB: J Biol Chem (2009, 284, 10129-10137) copyright 2009. Figures were selected by an automated process.
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