A surface on the G protein β-subunit involved in interactions with adenylyl cyclases

Receptor activation of heterotrimeric G proteins dissociates Gα from the Gβγ complex, allowing both to regulate effectors. Little is known about the effector-interaction regions of Gβγ. We had used molecular modeling to dock a peptide encoding the region of residues 956–982 of adenylyl cyclase (AC) 2 onto Gβ to identify residues on Gβ that may interact with effectors. Based on predictions from the model, we synthesized peptides encoding sequences of residues 86–105 (Gβ86–105) and 115–135 (Gβ115–135) from Gβ. The Gβ86–105 peptide inhibited Gβγ stimulation of AC2 and blocked Gβγ inhibition of AC1 and by itself inhibited calmodulin-stimulated AC1, thus displaying partial agonist activity. Substitution of Met-101 with Asn in this peptide resulted in the loss of both the inhibitory and partial agonist activities. Most activities of the Gβ115–135 peptide were similar to those of Gβ86–105 but Gβ115–135 was less efficacious in blocking Gβγ inhibition of AC1. Substitution of Tyr-124 with Val in the Gβ115–135 peptide diminished all of its activities. These results identify the region encoded by amino acids 84–143 of Gβ as a surface that is involved in transmitting signals to effectors.