Science · 1995 · 295 citations · 44 references
Life SciencesBiochemistryMolecular BiologyCell SignalingSignal TransductionStructural BiologyEnzyme FunctionG Protein-coupled Receptor SignalingLigand BindingMacromolecular AssemblyProtein StructureSmall Gtpase SignalingG Protein Subunit ActivationHeterotrimeric G Protein SignalingHydrolysisProtein Conformational ChangesQuaternary Structural RearrangementRas Conformational StatesRas Gtpase SignalingSmall G-protein Signaling
GTP hydrolysis induces conformational changes in the Giα1 subunit, as revealed by 2.2‑Å crystallography. GTP hydrolysis causes disorder of switch II/III and linker II, weakens contacts between the alpha‑helical and Ras domains, disorganizes the termini, and promotes quaternary contacts of the amino terminus with neighboring subunits, implying a role for multimeric signaling.
Crystallographic analysis of 2.2 angstrom resolution shows that guanosine triphosphate (GTP) hydrolysis triggers conformational changes in the heterotrimeric G-protein alpha subunit, Gi alpha 1. The switch II and switch III segments become disordered, and linker II connecting the Ras and alpha helical domains moves, thus altering the structures of potential effector and beta gamma binding regions. Contacts between the alpha-helical and Ras domains are weakened, possibly facilitating the release of guanosine diphosphate (GDP). The amino and carboxyl termini, which contain receptor and beta gamma binding determinants, are disordered in the complex with GTP, but are organized into a compact microdomain on GDP hydrolysis. The amino terminus also forms extensive quaternary contacts with neighboring alpha subunits in the lattice, suggesting that multimers of alpha subunits or heterotrimers may play a role in signal transduction.
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