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 that tubby functions in signal transduction from heterotrimeric GTP-binding...

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Published inScience (American Association for the Advancement of Science) Vol. 292; no. 5524; pp. 2041 - 2050
Main Authors Santagata, Sandro, Boggon, Titus J., Baird, Cheryl L., Gomez, Carlos A., Zhao, Jin, Shan, Wei Song, Myszka, David G., Shapiro, Lawrence
Format Journal Article
LanguageEnglish
Published Washington, DC American Society for the Advancement of Science 15.06.2001
American Association for the Advancement of Science
The American Association for the Advancement of Science
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Summary: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-β, 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.
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ISSN:0036-8075
1095-9203
DOI:10.1126/science.1061233