Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase
Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase
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DOI：
10.1073/pnas.0601638103
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发表时间：
2006-05-16
影响因子：
11.1
通讯作者：
Knapp, Stefan
中科院分区：
文献类型：
--
作者：
Bullock, Alex N.;Debreczeni, Judit E.;Knapp, Stefan
生长激素（GH）信号受到生长激素受体泛素化、磷酸化水平和下游信号伙伴结合位点的可及性的严格控制。细胞因子信号传导抑制因子（SOCS）家族的成员在该通路的所有水平上都是关键的调节因子，小鼠敲除研究表明SOCS2是主要的抑制因子。为了阐明SOCS2功能的结构基础，我们确定了SOCS2与长链蛋白C和长链蛋白b的三元配合物的1.9埃晶体结构，该结构定义了一个具有Src同源2 （SH2）结构域的原型SOCS盒泛素连接酶作为底物识别基序。总的来说，SOCS盒子和SH2结构域与VHL肿瘤抑制蛋白的BC盒子和底物识别结构域呈现保守的空间排列，表明这些cullin依赖性E3连接酶的泛素化机制是共同的。SOCS盒子以类似于VHL BC盒子的方式结合长链BC，并与Skp2泛素连接酶的F盒子显示出扩展的结构保守性。随着C末端的埋藏，揭示了SOCS盒的一个以前未被认识到的特征，C末端与n端扩展SH2子域一起打包，在SOCS盒和SH2子域之间创建了一个稳定的接口。这种结构域组织在SOCS1-3和CIS1中是保守的，它们共享严格保守的C端长度，但在SOCS4、5和7中不是，它们具有扩展的C端，定义了分子间和分子内SOCS盒相互作用的两种不同类型。
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.