G-Protein Signaling through Tubby Proteins

• Published in: Science (American Association for the Advancement of Science) 2001-06, Vol.292 (5524), p.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: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Amino acids; Animals; Biological and medical sciences; Cell Membrane - metabolism; Cell membranes; Cell nucleus; Cell Nucleus - metabolism; Cell physiology; Cells, Cultured; Crystallography, X-Ray; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetic aspects; Genetics; GTP-Binding Protein alpha Subunits, Gq-G11; Heterotrimeric GTP-Binding Proteins - metabolism; Human genetics; Humans; Inositols; Isoenzymes - metabolism; Lipids; Membrane Lipids - metabolism; Membranes; Mice; Models, Biological; Molecular and cellular biology; Molecular Sequence Data; Molecules; Neurons; Nuclear Localization Signals; Obesity; Obesity - genetics; Obesity - metabolism; Perceptual localization; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phosphatidylinositol Phosphates - metabolism; Phosphatidylinositols; Phospholipase C beta; phospholipase C-^b; Phosphorylation; Plasma; Protein Structure, Tertiary; Proteins; Proteins - chemistry; Proteins - genetics; Proteins - metabolism; Receptor, Serotonin, 5-HT2C; Receptors; Receptors, Muscarinic - metabolism; Receptors, Serotonin - metabolism; Recombinant Fusion Proteins - metabolism; Rodents; Signal Transduction; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; tubby protein; TULP3 protein; Type C Phospholipases - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1061233

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.