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Papers In Press, published online ahead of print September 28, 2001
Department of Pharmacology, Box 1215, Mount Sinai School of Medicine, New York, NY 10029
Corresponding Author: ravi.iyengar{at}mssm.edu
The crystal structure of soluble functional fragments of adenylyl cyclase complexed with Gas and forskolin, shows three regions of Gas in direct contact with adenylyl cyclase. The functions of these three regions are not known. We tested synthetic peptides encoding these regions of Gas on the activities of full length adenylyl cyclases 2 and 6. A peptide encoding the Switch II region (amino acids 222-247) stimulated both adenylyl cyclases two-three fold. Forskolin synergized the stimulation. Addition of peptides in the presence of activated Gas partially inhibited Gas stimulation. Corresponding Switch II region peptides from Gaq and Gai did not stimulate adenylyl cyclase. A peptide encoding the Switch I region (amino acids 199-216) also stimulated AC2 and AC6. The stimulatory effects of the two peptides at saturating concentrations were non-additive. A peptide encoding the third contact region (amino acids 268-286) located in the {a}3-{b}5 region, inhibits basal, forskolin and Gas stimulated enzymatic activities Since this region in Gas interacts with both the central cytoplasmic loop and C-terminal tail of adenylyl cyclases this peptide may be involved in blocking interactions between these two domains. These functional data in conjunction with the available structural information suggest that Gas activation of adenylyl cyclase is a complex event where the {a}3-{b}5 loop of G{a}s may bring together the central cytoplasmic loop and C-terminal tail of adenylyl cyclase thus allowing the Switch I and Switch II regions to function as signal transfer regions to activate adenylyl cyclase.
J. Biol. Chem, 10.1074/jbc.M107191200
Submitted on July 29, 2001
Revised on September 24, 2001
Accepted on September 28, 2001
The signal transfer regions of G
s
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