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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase
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Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase

机译：SOCS2-延伸蛋白C-延伸蛋白B复合物的晶体结构定义了典型的SOCS盒泛素连接酶

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摘要

Growth hormone (GH) signaling is tightly controlled by ubiquitination of GH receptors, phosphorylation levels, and accessibility of binding sites for downstream signaling partners. Members of the suppressors of cytokine signaling (SOCS) family function as key regulators at all levels of this pathway, and mouse knockout studies implicate SOCS2 as the primary suppressor. To elucidate the structural basis for SOCS2 function, we determined the 1.9-angstrom crystal structure of the ternary complex of SOCS2 with elongin C and elongin B. The structure defines a prototypical SOCS box ubiquitin ligase with a Src homology 2 (SH2) domain as a substrate recognition motif. Overall, the SOCS box and SH2 domain show a conserved spatial domain arrangement with the BC box and substrate recognition domain of the von Hippel-Linclau (VHL) tumor suppressor protein, suggesting a common mechanism of ubiquitination in these cullin-dependent E3 ligases. The SOCS box binds elongin BC in a similar fashion to the VHL BC box and shows extended structural conservation with the F box of the Skp2 ubiquitin ligase. A previously unrecognized feature of the SOCS box is revealed with the burial of the C terminus, which packs together with the N-terminal extended SH2 subdomain to create a stable interface between the SOCS box and SH2 domain. This domain organization is conserved in SOCS1-3 and CIS1, which share a strictly conserved length of their C termini, but not in SOCS4, 5, and 7, which have extended C termini defining two distinct classes of inter- and intramolecular SOCS box interactions.
机译：生长激素（GH）信号传导受到GH受体的泛素化，磷酸化水平和下游信号传导伙伴结合位点的可及性的严格控制。细胞因子信号传导（SOCS）家族抑制因子的成员在该途径的所有水平上均起着关键调节剂的作用，而小鼠基因敲除研究表明SOCS2是其主要抑制因子。为了阐明SOCS2功能的结构基础，我们确定了带有延伸蛋白C和延伸蛋白B的SOCS2三元复合物的1.9埃晶体结构。该结构定义了具有Src同源性2（SH2）结构域的原型SOCS盒泛素连接酶。底物识别基序。总体而言，SOCS框和SH2结构域与von Hippel-Linclau（VHL）肿瘤抑制蛋白的BC框和底物识别结构域显示了一个保守的空间结构域排列，提示这些cullin依赖的E3连接酶中泛素化的常见机制。 SOCS盒以类似于VHL BC盒的方式结合elongin BC，并显示出Skp2泛素连接酶的F盒具有扩展的结构保守性。 C端的埋葬揭示了SOCS框以前无法识别的功能，它与N端扩展的SH2子域打包在一起，在SOCS框和SH2域之间创建了稳定的接口。该域组织在SOCS1-3和CIS1中是保守的，它们严格守恒其C末端的长度，但在SOCS4、5和7中却没有，后者扩展了C末端，从而定义了分子间和分子内SOCS盒相互作用的两个不同类别。

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