威廉希尔学术报告
题目：Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP
演讲人：胡奇
Postdoctoral Scholar, 
University of California, San Francisco
时间：2018年4月26日（星期四）13:00-14:00
地点：金光生命科学大楼411
摘要：
The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gas. The current model explaining the gain-of-func- tion activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP bind- ing by directly activating GDP-bound Gas through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function muta- tion can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP. Indeed, we found R228C, a loss-of-func- tion mutation in Gas that causes pseudohypopara- thyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase-activating activity of Gas bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Gas can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mecha- nism of G proteins.
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