A Molecular Mechanism for the Phosphorylation-Dependent Regulation of Heterotrimeric G Proteins by Phosducin

Visual signal transduction is a nearly noise-free process that is exquisitely well regulated over a wide dynamic range of light intensity. A key component in dark/light adaptation is phosducin, a phosphorylatable protein that modulates the amount of transducin heterotrimer (G tαβγ) available through sequestration of the βγ subunits (G tβγ). The structure of the phospho-phosducin/G tβγ complex combined with mutational and biophysical analysis provides a stereochemical mechanism for the regulation of the phosducin-G tβγ interaction. Phosphorylation of serine 73 causes an order-to-disorder transition of a 20-residue stretch, including the phosphorylation site, by disrupting a helix-capping motif. This transition disrupts phosducin’s interface with G tβγ, leading to the release of unencumbered G tβγ, which reassociates with the membrane and G tα to form a signaling-competent G tαβγ heterotrimer.