Structural basis for the interaction of the adaptor protein grb14 with activated ras.
Structural basis for the interaction of the adaptor protein grb14 with activated ras.
复制标题
DOI：
10.1371/journal.pone.0072473
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hubbard SR
中科院分区：
文献类型：
--
作者：
Qamra R;Hubbard SR
Grb 14是Grb 7 -10-14胞质衔接蛋白家族的成员，是胰岛素信号传导的组织特异性负调节因子。Grb 7 -10-14包含几个信号传导模块，包括Ras相关（RA）结构域、普列克底物蛋白同源（PH）结构域、家族特异性BPS（PH和SH 2之间）区域和C末端Src同源-2（SH 2）结构域。我们以前发现RA和PH结构域，沿着BPS区域和SH 2结构域，是下调胰岛素信号传导所必需的。在这里，我们报告的晶体结构在2.4-nm分辨率的Grb 14 RA和PH结构域与GTP负载的H-Ras（G12 V）的复合物。该结构揭示了Grb 14 RA和PH结构域形成能够同时结合小GTP酶和磷酸肌醇脂质的整合结构单元。Grb 14 RA结构域与活化的H-Ras结合的总体模式与RalGDS和Raf 1的RA结构域的结合模式相似，但具有重要的区别。Grb 7 -10-14中整合的RA-PH结构单元也在第二个衔接子家族中发现，该家族包括Rap 1相互作用衔接子分子（RIAM）和lamellipodin，参与肌动蛋白细胞骨架重排的蛋白质。Grb 14 RA-PH与H-Ras复合的结构代表了与小GT结合的串联RA-PH结构域的第一个详细的分子表征，并提供了特异性分子基础的见解。
Grb14, a member of the Grb7-10-14 family of cytoplasmic adaptor proteins, is a tissue-specific negative regulator of insulin signaling. Grb7-10-14 contain several signaling modules, including a Ras-associating (RA) domain, a pleckstrin-homology (PH) domain, a family-specific BPS (between PH and SH2) region, and a C-terminal Src-homology-2 (SH2) domain. We showed previously that the RA and PH domains, along with the BPS region and SH2 domain, are necessary for downregulation of insulin signaling. Here, we report the crystal structure at 2.4-Å resolution of the Grb14 RA and PH domains in complex with GTP-loaded H-Ras (G12V). The structure reveals that the Grb14 RA and PH domains form an integrated structural unit capable of binding simultaneously to small GTPases and phosphoinositide lipids. The overall mode of binding of the Grb14 RA domain to activated H-Ras is similar to that of the RA domains of RalGDS and Raf1 but with important distinctions. The integrated RA-PH structural unit in Grb7-10-14 is also found in a second adaptor family that includes Rap1-interacting adaptor molecule (RIAM) and lamellipodin, proteins involved in actin-cytoskeleton rearrangement. The structure of Grb14 RA-PH in complex with H-Ras represents the first detailed molecular characterization of tandem RA-PH domains bound to a small GTPase and provides insights into the molecular basis for specificity.
登录
查看更多内容
影响因子：
4.8
作者：
Rudolph, MG;Linnemann, T;Herrmann, C
通讯作者：
Herrmann, C
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.1532175100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Charalambous, M;Smith, FM;Ward, A
通讯作者：
Ward, A
影响因子：
4.8
作者：
Cariou, B;Capitaine, N;Burnol, AF
通讯作者：
Burnol, AF
DOI：
10.1016/j.bbrc.2005.02.047
发表时间：
2005-04-15
影响因子：
3.1
作者：
Shiura, H;Miyoshi, N;Kaneko-Ishino, T
通讯作者：
Kaneko-Ishino, T