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 (Gt alpha beta gamma) available through sequestration of the beta gamma subunits (Gt beta gamma). The structure of the phosphophosducin/Gt beta gamma complex combined with mutational and biophysical analysis provides a stereochemical mechanism for the regulation of the phosducin-Gt beta gamma 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 Gt beta gamma, leading to the release of unencumbered Gt beta gamma, which reassociates with the membrane and Gt alpha to form a signaling-competent Gt alpha beta gamma heterotrimer.
Gaudet
R
R
Department of Molecular Biophysics, Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06511, USA.
Savage
J R
JR
McLaughlin
J N
JN
Willardson
B M
BM
Sigler
P B
PB
D000818:Animals; D002942:Circular Dichroism; D004252:DNA Mutational Analysis; D010450:Endopeptidases / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020555:GTP-Binding Protein Regulators; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D012243:Rhodopsin / Q000378:metabolism; D012694:Serine; D014785:Vision, Ocular / Q000502:physiology*
D005136:Eye Proteins; D020555:GTP-Binding Protein Regulators; D010750:Phosphoproteins; C065631:phosducin; D012694:Serine; D012243:Rhodopsin; D011494:Protein Kinases; D010450:Endopeptidases; D019204:GTP-Binding Proteins