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Science 292 (5524): 2041-2050

Copyright © 2001 by the American Association for the Advancement of Science

G-Protein Signaling Through Tubby Proteins

Sandro Santagata,1 Titus J. Boggon,2 Cheryl L. Baird,4 Carlos A. Gomez,1 Jin Zhao,2 Wei Song Shan,3 David G. Myszka,4 Lawrence Shapiro12*

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-phosphatidyl- inositol binding factors. Receptor-mediated activation of G protein alpha q (Galpha 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.

1 Ruttenberg Cancer Center,
2 Structural Biology Program, Department of Physiology and Biophysics,
3 Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine of New York University, 1425 Madison Avenue New York, NY 10029, USA.
4 Center for Biomolecular Interaction Analysis, University of Utah, Salt Lake City, UT 84132, USA.
*   To whom correspondence should be addressed at the Structural Biology Program, Mount Sinai School of Medicine, Room 16-20, 1425 Madison Avenue, New York, NY 10029, USA. E-mail: shapiro{at}inka.mssm.edu



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