Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3
Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3
复制标题
DOI：
10.1016/j.str.2006.06.011
复制
发表时间：
2006-08-01
期刊：
影响因子：
5.7
通讯作者：
Hubbard, Stevan R.
中科院分区：
文献类型：
--
作者：
Bergamin, Elisa;Wu, Jinhua;Hubbard, Stevan R.
细胞因子信号转导抑制因子（SOCS）蛋白是精氨酸刺激的Janus激酶（JAK）-信号转导和转录激活因子（STAT）信号转导通路中不可或缺的负调控因子。SOCS蛋白（SOCS 1 -7和CIS）由可变的N-末端区域、中心Src同源性-2（SH 2）结构域和C-末端SOCS盒组成。SOCS 1和SOCS 3中的N-末端区域包括所谓的激酶抑制区域，其已显示抑制JAK 2的催化活性。在这里，我们提出了一个晶体结构在2.0埃分辨率的N-末端延伸的SH 2结构域的SOCS 3在复杂的磷酸肽靶细胞因子受体gp 130。该结构揭示了SOCS 3 SH 2结构域的EF和BG环中的主要插入负责以高亲和力和特异性结合gp 130。此外，该结构提供了对SOCS 3和SOCS 1抑制JAK 2激酶活性的可能机制的见解。
Suppressor of cytokine signaling (SOCS) proteins are indispensable negative regulators of cytokine-stimulated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathways. SOCS proteins (SOCS1-7 and CIS) consist of a variable N-terminal region, a central Src homology-2 (SH2) domain, and a C-terminal SOCS box. The N-terminal region in SOCS1 and SOCS3 includes the so-called kinase inhibitory region that has been shown to inhibit the catalytic activity of JAK2. Here, we present a crystal structure at 2.0 angstrom resolution of the N-terminally extended SH2 domain of SOCS3 in complex with its phosphopeptide target on the cytokine receptor gp130. The structure reveals that major insertions in the EF and BG loops of the SOCS3 SH2 domain are responsible for binding to gp130 with high affinity and specificity. In addition, the structure provides insights into the possible mechanisms by which SOCS3 and SOCS1 inhibit JAK2 kinase activity.