Bullock Alex N, Rodriguez Maria C, Debreczeni Judit E, Songyang Zhou, Knapp Stefan
University of Oxford, Structural Genomics Consortium, Botnar Research Centre, Oxford OX3 7LD, United Kingdom.
Structure. 2007 Nov;15(11):1493-504. doi: 10.1016/j.str.2007.09.016.
Tyrosine kinase signaling is tightly controlled by negative feedback inhibitors including suppressors of cytokine signaling (SOCS). SOCS assemble as SH2 domain substrate recognition modules in ElonginB/C-cullin ubiquitin ligases. In accordance, SOCS4 reduces STAT3 signaling from EGFR through increased receptor degradation. Variable C-termini in SOCS4-SOCS7 exclude these family members from a SOCS2-type domain arrangement in which a strictly conserved C terminus determines domain packing. The structure of the SOCS4-ElonginC-ElonginB complex reveals a distinct SOCS structural class. The N-terminal ESS helix functionally replaces the CIS/SOCS1-SOCS3 family C terminus in a distinct SH2-SOCS box interface that facilitates further interdomain packing between the extended N- and C-terminal regions characteristic for this subfamily. Using peptide arrays and calorimetry the STAT3 site in EGFR (pY(1092)) was identified as a high affinity SOCS4 substrate (K(D) = 0.5 microM) revealing a mechanism for EGFR degradation. SOCS4 also bound JAK2 and KIT with low micromolar affinity, whereas SOCS2 was specific for GH-receptor.
酪氨酸激酶信号传导受到包括细胞因子信号抑制因子(SOCS)在内的负反馈抑制剂的严格控制。SOCS作为延伸蛋白B/C-泛素连接酶中SH2结构域底物识别模块进行组装。相应地,SOCS4通过增加受体降解来降低EGFR的STAT3信号传导。SOCS4 - SOCS7中可变的C末端使这些家族成员无法形成SOCS2型结构域排列,在这种排列中,严格保守的C末端决定结构域堆积。SOCS4 - 延伸蛋白C - 延伸蛋白B复合物的结构揭示了一种独特的SOCS结构类别。N端ESS螺旋在一个独特的SH2 - SOCS盒界面中在功能上取代了CIS/SOCS1 - SOCS3家族的C末端,该界面促进了该亚家族特有的延伸N端和C端区域之间进一步的结构域间堆积。使用肽阵列和量热法,EGFR中的STAT3位点(pY(1092))被鉴定为高亲和力的SOCS4底物(K(D) = 0.5 microM),揭示了EGFR降解的机制。SOCS4还以低微摩尔亲和力结合JAK2和KIT,而SOCS2对生长激素受体具有特异性。