title: Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method.
abstract: Recent studies employing differential epitope tagging, selective immunoprecipitation of receptor complexes and fluorescence or bioluminescence resonance energy transfer techniques provide direct evidence for heterodimerization between both closely and distantly related members of the G-protein coupled receptor (GPCR) family. Since heterodimerization appears to play a role in modulating agonist affinity, efficacy and/or trafficking properties, the molecular models of GPCRs required to understand receptor function must consider these oligomerization hypotheses. To advance knowledge in this field, we present here a computational approach based on correlated mutation analysis and the structural information contained in three-dimensional molecular models of the transmembrane regions of GPCRs built using the rhodopsin crystal structure as a template. The new subtractive correlated mutation method reveals likely heterodimerization interfaces amongst the different alternatives for the positioning of two tightly packed bundles of seven transmembrane domains next to each other in contact heterodimers of GPCRs. Predictions are applied to GPCRs in the class of opioid receptors. However, in the absence of a known structure of any GPCR dimer, the features of the method and predictions are also illustrated and analyzed for a dimeric complex of known structure.
authors.affiliation: Department of Physiology and Biophysics, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA. marta.filizola@physbio.mssm.edu
authors.forename: Marta
authors.initials: M
authors.lastname: Filizola
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Olmea
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D009154:Mutation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011957:Receptors, Opioid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011956:Receptors, Cell Surface; D011957:Receptors, Opioid