title: Dimerization and domain swapping in G-protein-coupled receptors: a computational study.
abstract: In recent years there has been an increasing number of reports describing G protein-coupled receptor (GPCR) dimerization and heterodimerization. However, the evidence on the nature of the dimers and their role in GPCR activation is inconclusive. Consequently, we present here a review of our computational studies on G protein-coupled receptor dimerization and domain swapping. The studies described include molecular dynamics simulations on receptor monomers and dimers in the absence of ligand, in the presence of an agonist, and in the presence of an antagonist (or more precisely an inverse agonist). Two distinct sequence-based approaches to studying protein interfaces are also described, namely correlated mutation analysis and evolutionary trace analysis. All three approaches concur in supporting the proposal that the dimerization interface includes transmembrane helices 5 and 6. These studies cannot distinguish between domain swapped dimers and contact dimers as the models used were restricted to the helical part of the receptor. However, it is proposed that for the purpose of signalling, the domain swapped dimer and the corresponding contact dimer are equivalent. The evolutionary trace analysis suggests that every GPCR family and subfamily (for which sufficient sequence data is available) has the potential to dimerize through this common functional site on helices 5 and 6. The evolutionary trace results on the G protein are briefly described and these are consistent with GPCR dimerization. In addition to the functional site on helices 5 and 6, the evolutionary trace analysis identified a second functional site on helices 2 and 3. Possible roles for this site are suggested, including oligomerization.
authors.affiliation: Department of Biological Sciences, Central Campus, Wivenhoe Park, Colchester, Essex, United Kingdom.
authors.forename: P R
authors.initials: PR
authors.lastname: Gouldson
authors.forename: C
authors.initials: C
authors.lastname: Higgs
authors.forename: R E
authors.initials: RE
authors.lastname: Smith
authors.forename: M K
authors.initials: MK
authors.lastname: Dean
authors.forename: G V
authors.initials: GV
authors.lastname: Gkoutos
authors.forename: C A
authors.initials: CA
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D004252:DNA Mutational Analysis / Q000379:methods; D019281:Dimerization; D019143:Evolution, Molecular; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D018257:Helix-Loop-Helix Motifs / Q000502:physiology; D006801:Humans; D017434:Protein Structure, Tertiary / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000737:chemistry / Q000378:metabolism
chemical_list: D011956:Receptors, Cell Surface; D018080:Receptors, GABA-B; D019204:GTP-Binding Proteins