Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP.
Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP.
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DOI：
10.1016/j.cell.2018.03.018
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发表时间：
2018-05-17
期刊：
影响因子：
64.5
通讯作者：
Shokat KM
中科院分区：
文献类型：
--
作者：
Hu Q;Shokat KM
The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gαs. The current model explaining the gain-of-function 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 binding by directly activating GDP-bound Gαs through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation 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-function mutation in Gαs that causes pseudohypoparathyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase-activating activity of Gαs bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Gαs can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mechanism of G proteins. Frequent pathogenic mutations in G proteins can cause signaling activation by converting GDP into an activator, rather than locking the proteins at a GTP-bound state.
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