Evolutionary trace of G protein-coupled receptors reveals clusters of residues that determine global and class-specific functions.

@article{citeulike:375854, abstract = {G protein-coupled receptor (GPCR) activation mediated by ligand-induced structural reorganization of its helices is poorly understood. To determine the universal elements of this conformational switch, we used evolutionary tracing (ET) to identify residue positions commonly important in diverse GPCRs. When mapped onto the rhodopsin structure, these trace residues cluster into a network of contacts from the retinal binding site to the G protein-coupling loops. Their roles in a generic transduction mechanism were verified by 211 of 239 published mutations that caused functional defects. When grouped according to the nature of the defects, these residues sub-divided into three striking sub-clusters: a trigger region, where mutations mostly affect ligand binding, a coupling region near the cytoplasmic interface to the G protein, where mutations affect G protein activation, and a linking core in between where mutations cause constitutive activity and other defects. Differential ET analysis of the opsin family revealed an additional set of opsin-specific residues, several of which form part of the retinal binding pocket, and are known to cause functional defects upon mutation. To test the predictive power of ET, we introduced novel mutations in bovine rhodopsin at a globally important position, Leu-79, and at an opsin-specific position, Trp-175. Both were functionally critical, causing constitutive G protein activation of the mutants and rapid loss of regeneration after photobleaching. These results define in GPCRs a canonical signal transduction mechanism where ligand binding induces conformational changes propagated through adjacent trigger, linking core, and coupling regions.}, address = {Program in Structural and Computational Biology and Molecular Biophysics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.}, author = {Madabushi, S. and Gross, A. K. and Philippi, A. and Meng, E. C. and Wensel, T. G. and Lichtarge, O. }, citeulike-article-id = {375854}, doi = {http://dx.doi.org/10.1074/jbc.M312671200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {activation, binding, gpcr, sequence, switch}, month = {February}, number = {9}, pages = {8126--8132}, posted-at = {2005-11-01 20:03:29}, priority = {0}, title = {Evolutionary trace of G protein-coupled receptors reveals clusters of residues that determine global and class-specific functions.}, url = {http://dx.doi.org/10.1074/jbc.M312671200}, volume = {279}, year = {2004} }

TY - JOUR ID - citeulike:375854 L3 - citeulike-article-id:375854 N2 - G protein-coupled receptor (GPCR) activation mediated by ligand-induced structural reorganization of its helices is poorly understood. To determine the universal elements of this conformational switch, we used evolutionary tracing (ET) to identify residue positions commonly important in diverse GPCRs. When mapped onto the rhodopsin structure, these trace residues cluster into a network of contacts from the retinal binding site to the G protein-coupling loops. Their roles in a generic transduction mechanism were verified by 211 of 239 published mutations that caused functional defects. When grouped according to the nature of the defects, these residues sub-divided into three striking sub-clusters: a trigger region, where mutations mostly affect ligand binding, a coupling region near the cytoplasmic interface to the G protein, where mutations affect G protein activation, and a linking core in between where mutations cause constitutive activity and other defects. Differential ET analysis of the opsin family revealed an additional set of opsin-specific residues, several of which form part of the retinal binding pocket, and are known to cause functional defects upon mutation. To test the predictive power of ET, we introduced novel mutations in bovine rhodopsin at a globally important position, Leu-79, and at an opsin-specific position, Trp-175. Both were functionally critical, causing constitutive G protein activation of the mutants and rapid loss of regeneration after photobleaching. These results define in GPCRs a canonical signal transduction mechanism where ligand binding induces conformational changes propagated through adjacent trigger, linking core, and coupling regions. IS - 9 JF - J Biol Chem SN - 0021-9258 AD - Program in Structural and Computational Biology and Molecular Biophysics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. EP - 8132 TI - Evolutionary trace of G protein-coupled receptors reveals clusters of residues that determine global and class-specific functions. VL - 279 SP - 8126 KW - activation KW - binding KW - gpcr KW - sequence KW - switch AU - Madabushi, S AU - Gross, AK AU - Philippi, A AU - Meng, EC AU - Wensel, TG AU - Lichtarge, O PY - 2004/02/27/ UR - http://dx.doi.org/10.1074/jbc.M312671200 ER -