Structural evidence for feedback activation by Ras-GTP of the Ras-specific nucleotide exchange factor SOS
Structural evidence for feedback activation by Ras-GTP of the Ras-specific nucleotide exchange factor SOS
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DOI：
10.1016/s0092-8674(03)00149-1
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发表时间：
2003-03-07
期刊：
影响因子：
64.5
通讯作者：
Kuriyan, J
中科院分区：
文献类型：
--
作者：
Margarit, SM;Sondermann, H;Kuriyan, J
生长因子受体通过将SOS的核苷酸交换因子SON募集到细胞膜上来激活RAS，从而触发GTP负载的RAS的产生。结合在SOS催化模块上的RAS的结晶学分析意外地发现了SOS上一个高度保守的RAS结合部位，该结合部位位于活性部位的远端，是RAS-GTP所特有的。晶体结构表明，RAS-GTP以变构的方式稳定了SOS的活性中心，并与SOScat在溶液中形成三元络合物，显著增加了SOScat刺激的核苷酸从RAS释放的速率。这些结果证明了RAS的时空调控存在正反馈机制。
Growth factor receptors activate Ras by recruiting the nucleotide exchange factor son of sevenless (SOS) to the cell membrane, thereby triggering the production of GTP-loaded Ras. Crystallographic analyses of Ras bound to the catalytic module of SOS have led to the unexpected discovery of a highly conserved Ras binding site on SOS that is located distal to the active site and is specific for Ras-GTP. The crystal structures suggest that Ras-GTP stabilizes the active site of SOS allosterically, and we show that Ras-GTP forms ternary complexes with SOScat in solution and increases significantly the rate of SOScat-stimulated nucleotide release from Ras. These results demonstrate the existence of a positive feedback mechanism for the spatial and temporal regulation of Ras.