G-protein signaling through tubby proteins

被引:289
作者
Santagata, S
Boggon, TJ
Baird, CL
Gomez, CA
Zhao, J
Shan, WS
Myszka, DG
Shapiro, L
机构
[1] NYU, Mt Sinai Sch Med, Struct Biol Program, New York, NY 10029 USA
[2] NYU, Mt Sinai Sch Med, Ruttenberg Canc Ctr, New York, NY 10029 USA
[3] NYU, Mt Sinai Sch Med, Dept Biochem & Mol Biol, New York, NY 10029 USA
[4] Univ Utah, Ctr Biomol Interact Anal, Salt Lake City, UT 84132 USA
关键词
D O I
10.1126/science.1061233
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-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.
引用
收藏
页码:2041 / 2050
页数:10
相关论文
共 58 条
[1]   Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions [J].
Aronheim, A ;
Zandi, E ;
Hennemann, H ;
Elledge, SJ ;
Karin, M .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (06) :3094-3102
[2]   NF-kappa B: Ten years after [J].
Baeuerle, PA ;
Baltimore, D .
CELL, 1996, 87 (01) :13-20
[3]   TULP1 mutation in two extended Dominican kindreds with autosomal recessive Retinitis pigmentosa [J].
Banerjee, P ;
Kleyn, PW ;
Knowles, JA ;
Lewis, CA ;
Ross, BM ;
Parano, E ;
Kovats, SG ;
Lee, JJ ;
Penchaszadeh, GK ;
Ott, J ;
Jacobson, SG ;
Gilliam, TC .
NATURE GENETICS, 1998, 18 (02) :177-179
[4]   Implication of tubby proteins as transcription factors by structure-based functional analysis [J].
Boggon, TJ ;
Shan, WS ;
Santagata, S ;
Myers, SC ;
Shapiro, L .
SCIENCE, 1999, 286 (5447) :2119-2125
[5]   Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans [J].
Brown, MS ;
Ye, J ;
Rawson, RB ;
Goldstein, JL .
CELL, 2000, 100 (04) :391-398
[6]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[7]  
BRUNGER AT, 1992, XPLOR VRSION 3 1 SYS
[8]   Body-mass index and mortality in a prospective cohort of US adults [J].
Calle, EE ;
Thun, MJ ;
Petrelli, JM ;
Rodriguez, C ;
Heath, CW .
NEW ENGLAND JOURNAL OF MEDICINE, 1999, 341 (15) :1097-1105
[9]   Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass [J].
Chen, AS ;
Marsh, DJ ;
Trumbauer, ME ;
Frazier, EG ;
Guan, XM ;
Yu, H ;
Rosenblum, CI ;
Vongs, A ;
Feng, Y ;
Cao, LH ;
Metzger, JM ;
Strack, AM ;
Camacho, RE ;
Mellin, TN ;
Nunes, CN ;
Min, W ;
Fisher, J ;
Gopal-Truter, S ;
MacIntyre, DE ;
Chen, HY ;
Van der Ploeg, LHT .
NATURE GENETICS, 2000, 26 (01) :97-102
[10]   FAT (FAT) AND TUBBY (TUB) - 2 AUTOSOMAL RECESSIVE MUTATIONS CAUSING OBESITY SYNDROMES IN THE MOUSE [J].
COLEMAN, DL ;
EICHER, EM .
JOURNAL OF HEREDITY, 1990, 81 (06) :424-427