title: Universal allosteric mechanism for Gα activation by GPCRs.
abstract: G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are ∼800 human GPCRs and 16 different Gα genes, this raises the question of whether a universal allosteric mechanism governs Gα activation. Here we show that different GPCRs interact with and activate Gα proteins through a highly conserved mechanism. Comparison of Gα with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR-Gα system diversified rapidly, while conserving the allosteric activation mechanism.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Tilman
authors.initials: T
authors.lastname: Flock
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Charles N J
authors.initials: CNJ
authors.lastname: Ravarani
authors.affiliation: Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland.|Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Dawei
authors.initials: D
authors.lastname: Sun
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Venkatakrishnan
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Melis
authors.initials: M
authors.lastname: Kayikci
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Tate
authors.affiliation: Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland.|Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Dmitry B
authors.initials: DB
authors.lastname: Veprintsev
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: M Madan
authors.initials: MM
authors.lastname: Babu
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D017124:Conserved Sequence; D004789:Enzyme Activation; D019143:Evolution, Molecular; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005818:Genetic Engineering; D006153:Guanosine Diphosphate / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D043562:Receptors, G-Protein-Coupled; D006153:Guanosine Diphosphate; D018631:ras Proteins