Bullock Alex N, Debreczeni Judit E, Edwards Aled M, Sundström Michael, Knapp Stefan
Structural Genomics Consortium, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, United Kingdom.
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7637-42. doi: 10.1073/pnas.0601638103. Epub 2006 May 4.
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-A 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-Lindau (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.
生长激素（GH）信号传导受到GH受体泛素化、磷酸化水平以及下游信号伴侣结合位点可及性的严格控制。细胞因子信号传导抑制因子（SOCS）家族成员在该信号通路的各个层面发挥关键调节作用，小鼠基因敲除研究表明SOCS2是主要抑制因子。为阐明SOCS2功能的结构基础，我们确定了SOCS2与延伸蛋白C和延伸蛋白B三元复合物的1.9埃晶体结构。该结构定义了一种典型的SOCS框泛素连接酶，其具有作为底物识别基序的Src同源2（SH2）结构域。总体而言，SOCS框和SH2结构域与冯·希佩尔-林道（VHL）肿瘤抑制蛋白的BC框和底物识别结构域呈现保守的空间结构域排列，提示这些依赖cullin的E3连接酶中存在泛素化的共同机制。SOCS框与延伸蛋白BC的结合方式类似于VHL的BC框，并且与Skp2泛素连接酶的F框具有延伸的结构保守性。通过C末端的埋藏揭示了SOCS框一个以前未被认识的特征，它与N末端延伸的SH2亚结构域聚集在一起，在SOCS框和SH2结构域之间形成稳定的界面。这种结构域组织在SOCS1 - 3和CIS1中保守，它们的C末端长度严格保守，但在SOCS4、5和7中不保守，它们具有延伸的C末端，定义了分子间和分子内SOCS框相互作用的两种不同类型。
