Gβγ Activation Site in Adenylyl Cyclase Type II

Abstract

The Gβγ complex of heterotrimeric G proteins is the most outstanding example for the divergent regulation of mammalian adenylyl cyclases. The heterodimeric Gβγ complex inhibits some isoforms, e.g. ACI, and stimulates the isoforms ACII, -IV, and -VII. Although former studies identified the QEHA region located in the C2 domain of ACII as an important interaction site for Gβγ, the determinant of the stimulatory effect of Gβγ has not been detected. Here, we identified the C1b domain as the stimulatory region using full-length adenylyl cyclase. The relevant Gβγ signal transfer motif in IIC1b was determined as MTRYLESWGAAKPFAHL (amino acids 493-509). Amino acids of this PFAHL motif were absolutely necessary for ACII to be stimulated by Gβγ, whereas they were dispensable for Gαs or forskolin stimulation. The PFAHL motif is present in all three adenylyl cyclase isoforms that are activated by Gβγ but is absent in other adenylyl cyclase isoforms as well as other known effectors of Gβγ. The emerging concept of two contact sites on different molecule halves for effective regulation of adenylyl cyclase is discussed. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.