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 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 alphaq (Galphaq) 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.
Santagata
S
S
Ruttenberg Cancer Center, Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine of New York University, 1425 Madison Avenue New York, NY 10029, USA.
Boggon
T J
TJ
Baird
C L
CL
Gomez
C A
CA
Zhao
J
J
Shan
W S
WS
Myszka
D G
DG
Shapiro
L
L
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005786:Gene Expression Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D054799:Phospholipase C beta; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008563:Membrane Lipids; D019913:Nuclear Localization Signals; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D011506:Proteins; D044405:Receptor, Serotonin, 5-HT2C; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D011993:Recombinant Fusion Proteins; C116465:TULP3 protein, human; D014157:Transcription Factors; C098988:Tub protein, mouse; C485499:Tulp3 protein, mouse; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins