G-protein signaling through tubby proteins

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 t hat tubby functions in signal transduction from heterotrimeric GTP-binding protein (G protein)-coupled receptors. Tubby Localizes to the plasma membra ne by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl te rminal "tubby domain." X-ray crystallography reveals the atomic-level basis of this interaction and implicates tubby domains as phosphorylated-phospha tidylinositol binding factors. Receptor-mediated activation of G protein al pha (q) (G alpha (q)) releases tubby from the plasma membrane through the a ction of phospholipase C-beta, triggering translocation of tubby to the cel l nucleus. The localization of tubby-like protein 3 (TULP3) is similarly re gulated. These data suggest that tubby proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to pho sphoinositide hydrolysis, providing a direct link between G-protein signali ng and the regulation of gene expression.