These findings reveal the molecular basis for the final committed step of G protein activation. Replacement of network residues prevents subunit dissociation, regardless of agonist or GTP binding. This “G-R-E motif” secures GTP and, through an allosteric link, discharges the Gβγ dimer.
In the presence of the terminal phosphate of GTP, a glycine forms a polar network with an arginine and glutamate, putting torsional strain on the subunit binding interface. We use cell signaling assays, MD simulations, biochemistry and structural analysis to identify a conserved network of amino acids that dictates subunit release. In contrast, the mechanism of subunit dissociation is poorly understood. Structural studies have revealed the molecular basis for subunit association with receptors, RGS proteins and downstream effectors. Signaling is initiated by cell-surface receptors, which promote GTP binding and the dissociation of Gα from the Gβγ subunits.
G proteins play a central role in signal transduction and pharmacology.
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