G-protein signaling through tubby proteins
G-protein signaling through tubby proteins
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DOI：
10.1126/science.1061233
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发表时间：
2001-06-15
期刊：
影响因子：
56.9
通讯作者：
Shapiro, L
中科院分区：
文献类型：
--
作者：
Santagata, S;Boggon, TJ;Shapiro, L
tubby蛋白的功能障碍导致小鼠的成熟型肥胖。Tubby被认为是一种转录调节因子，但其功能背后的分子机制的细节仍不清楚。在这里，我们表明，tubby功能的信号转导从异源三聚体GTP结合蛋白（G蛋白）偶联受体。通过羧基末端的“tubby结构域”结合磷脂酰肌醇4，5-二磷酸，定位于质膜。“X射线晶体学揭示了这种相互作用的原子水平基础，并暗示tubby结构域是磷酸化磷脂酰肌醇结合因子。受体介导的G蛋白α（q）（G α（q））活化通过磷脂酶C-β的作用从质膜释放tubby，触发tubby易位到细胞核。Tubby样蛋白3（TULP 3）的定位也受到类似的调节。这些数据表明，tubby蛋白作为膜结合的转录调节，易位到细胞核中的磷酸肌醇水解反应，提供了G蛋白信号和基因表达的调控之间的直接联系。
Dysfunction of the tubby protein results in maturity-onset obesity in mice. Tubby has been implicated as a transcription regulator, but details of the molecular mechanism underlying its function remain unclear. Here we show that tubby functions in signal transduction from heterotrimeric GTP-binding protein (G protein)-coupled receptors. Tubby Localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl terminal "tubby domain." X-ray crystallography reveals the atomic-level basis of this interaction and implicates tubby domains as phosphorylated-phosphatidylinositol binding factors. Receptor-mediated activation of G protein alpha (q) (G alpha (q)) releases tubby from the plasma membrane through the action of phospholipase C-beta, triggering translocation of tubby to the cell nucleus. The localization of tubby-like protein 3 (TULP3) is similarly regulated. These data suggest that tubby proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to phosphoinositide hydrolysis, providing a direct link between G-protein signaling and the regulation of gene expression.