致病突变使 G 蛋白 Gαs 颠覆 GDP 和 GTP 的作用。
Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP.
机构信息
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, CA 94158, USA.
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, CA 94158, USA; Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA.
出版信息
Cell. 2018 May 17;173(5):1254-1264.e11. doi: 10.1016/j.cell.2018.03.018. Epub 2018 Apr 5.
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.
所有异三聚体 G 蛋白中最常见的致癌突变是 Gαs 中的 R201C。目前解释 R201 突变获得功能活性的模型是通过丧失 GTPase 活性和无法切换到 GDP 状态。在这里，我们发现 R201C 突变可以通过稳定分子内氢键网络，直接激活 GDP 结合的 Gαs，从而绕过 GTP 结合的需求。既然发现功能获得性突变可以将 GDP 转化为激活剂，我们推测相应的突变可能会破坏 GTP 的正常作用。事实上，我们发现 Gαs 中的 R228C 是一种功能丧失性突变，可导致假性甲状旁腺功能减退症 1a 型 (PHP-Ia)，该突变破坏了与非水解 GTP 类似物结合的 Gαs 的腺苷酸环化酶激活活性。这些发现表明，Gαs 中的致病突变可以颠覆 GDP 和 GTP 的典型作用，为 G 蛋白的调节机制提供了新的见解。
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