title: Differences in intradomain and interdomain motion confer distinct activation properties to structurally similar Gα proteins.
abstract: Proteins with similar crystal structures can have dissimilar rates of substrate binding and catalysis. Here we used molecular dynamics simulations and biochemical analysis to determine the role of intradomain and interdomain motions in conferring distinct activation rates to two Gα proteins, Gα(i1) and GPA1. Despite high structural similarity, GPA1 can activate itself without a receptor, whereas Gα(i1) cannot. We found that motions in these proteins vary greatly in type and frequency. Whereas motion is greatest in the Ras domain of Gα(i1), it is greatest in helices αA and αB from the helical domain of GPA1. Using protein chimeras, we show that helix αA from GPA1 is sufficient to confer rapid activation to Gα(i1). Gα(i1) has less intradomain motion than GPA1 and instead displays interdomain displacement resembling that observed in a receptor-heterotrimer crystal complex. Thus, structurally similar proteins can have distinct atomic motions that confer distinct activation mechanisms.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Janice C
authors.initials: JC
authors.lastname: Jones
authors.forename: Alan M
authors.initials: AM
authors.lastname: Jones
authors.forename: Brenda R S
authors.initials: BR
authors.lastname: Temple
authors.forename: Henrik G
authors.initials: HG
authors.lastname: Dohlman
mesh_terms: D000595:Amino Acid Sequence; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry* / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11