Dimeric Quaternary Structure of the Prototypical Dual Specificity Phosphatase VH1
Dimeric Quaternary Structure of the Prototypical Dual Specificity Phosphatase VH1
复制标题
DOI：
10.1074/jbc.m808362200
复制
发表时间：
2009-04-10
影响因子：
4.8
通讯作者：
Cingolani, Gino
中科院分区：
文献类型：
--
作者：
Koksal, Adem C.;Nardozzi, Jonathan D.;Cingolani, Gino
痘苗病毒H1基因产物VH1是一种双特异性磷酸酶，通过去磷酸化STAT1下调细胞抗病毒反应。在1.32埃分辨率下测定的VH1的晶体结构揭示了一种新的二聚体四元结构，该结构揭示了两个相距约39埃的活性中心。VH1通过N-末端螺旋(残基1-20)的广泛结构域交换形成稳定的二聚体。在体外，VH1可以去磷酸化激活的STAT1，这个反应与核转运蛋白Importinα5竞争。有趣的是，VH1对于与DNA结合的STAT1是无效的，这表明病毒磷酸酶主要作用于激活的STAT1的细胞质池。我们认为，VH1的二聚体四元结构对于激活的STAT1的特异性识别是必不可少的，它阻止了它的核转位，从而阻止了干扰素-伽马信号转导和抗病毒反应。
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 angstrom resolution, reveals a novel dimeric quaternary structure, which exposes two active sites spaced similar to 39 angstrom away from each other. VH1forms 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 alpha 5. 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.