title: Dimerization in aminergic G-protein-coupled receptors: application of a hidden-site class model of evolution.
abstract: G-Protein-coupled receptors (GPCRs) are an important superfamily of transmembrane proteins involved in cellular communication. Recently, it has been shown that dimerization is a widely occurring phenomenon in the GPCR superfamily, with likely important physiological roles. Here we use a novel hidden-site class model of evolution as a sequence analysis tool to predict possible dimerization interfaces in GPCRs. This model aims to simulate the evolution of proteins at the amino acid level, allowing the analysis of their sequences in an explicitly evolutionary context. Applying this model to aminergic GPCR sequences, we first validate the general reasoning behind the model. We then use the model to perform a family specific analysis of GPCRs. Accounting for the family structure of these proteins, this approach detects different evolutionarily conserved and accessible patches on transmembrane (TM) helices 4-6 in different families. On the basis of these findings, we propose an experimentally testable dimerization mechanism, involving interactions among different combinations of these helices in different families of aminergic GPCRs.
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Orkun S
authors.initials: OS
authors.lastname: Soyer
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Dimmic
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.forename: Richard A
authors.initials: RA
authors.lastname: Goldstein
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019295:Computational Biology / Q000379:methods / Q000706:statistics & numerical data; D019281:Dimerization; D019143:Evolution, Molecular; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D005810:Multigene Family; D011336:Probability; D017982:Receptors, Biogenic Amine / Q000737:chemistry* / Q000145:classification* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000145:classification* / Q000235:genetics; D020539:Sequence Analysis, Protein / Q000379:methods / Q000706:statistics & numerical data
chemical_list: D017982:Receptors, Biogenic Amine; D043562:Receptors, G-Protein-Coupled