Publication Date:
2001-05-26
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Santagata, S -- Boggon, T J -- Baird, C L -- Gomez, C A -- Zhao, J -- Shan, W S -- Myszka, D G -- Shapiro, L -- New York, N.Y. -- Science. 2001 Jun 15;292(5524):2041-50. Epub 2001 May 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11375483" target="_blank"〉PubMed〈/a〉
Keywords:
Active Transport, Cell Nucleus
;
Adaptor Proteins, Signal Transducing
;
Amino Acid Sequence
;
Animals
;
Cell Membrane/metabolism
;
Cell Nucleus/*metabolism
;
Cells, Cultured
;
Crystallography, X-Ray
;
GTP-Binding Protein alpha Subunits, Gq-G11
;
Gene Expression Regulation
;
Heterotrimeric GTP-Binding Proteins/*metabolism
;
Humans
;
Isoenzymes/*metabolism
;
Membrane Lipids/metabolism
;
Mice
;
Models, Biological
;
Molecular Sequence Data
;
Nuclear Localization Signals
;
Obesity/genetics/metabolism
;
Phosphatidylinositol 4,5-Diphosphate/*metabolism
;
Phosphatidylinositol Phosphates/metabolism
;
Phospholipase C beta
;
Phosphorylation
;
Protein Structure, Tertiary
;
Proteins/chemistry/genetics/*metabolism
;
Receptor, Serotonin, 5-HT2C
;
Receptors, Muscarinic/metabolism
;
Receptors, Serotonin/metabolism
;
Recombinant Fusion Proteins/metabolism
;
*Signal Transduction
;
Transcription Factors/chemistry/genetics/*metabolism
;
Type C Phospholipases/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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