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...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1061233