Molecular basis for interactions of G protein bg subunits with effectors

Both the a and bg subunits of heterotrimeric guanine nucleotide–binding proteins (G proteins) communicate signals from receptors to effectors. Gbg subunits can regulate a diverse array of effectors, including ion channels and enzymes. Ga subunits bound to guanine diphosphate (Ga-GDP) inhibit signal transduction through Gbg subunits, sug-gesting a common interface on Gbg subunits for Ga binding and effector interaction. The molecular basis for interaction of Gbg with effectors was characterized by mutational analysis of Gb residues that make contact with Ga-GDP. Analysis of the ability of these mutants to regulate the activity of calcium and potassium channels, adenylyl cyclase 2, phospholipase C-b2, and b-adrenergic receptor kinase revealed the Gb residues re-quired for activation of each effector and provides evidence for partially overlapping domains on Gb for regulation of these effectors. This organization of interaction regions on Gb for different effectors and Ga explains why subunit dissociation is crucial for signal transmission through Gbg subunits. Upon receptor activation, G proteins dis-sociate into free Ga and Gbg subunits that can activate various effectors (1). Effector proteins of the Gbg complex include phos-pholipases (2), adenylyl cyclases (3), ion channels (4), G protein–coupled receptor kinases (5) and phosphoinositide 3-kinases (6). Other potential Gbg effectors include dynamin I and the nonreceptor protein ty-rosine kinases Btk and Tsk (7). GDP-bound Ga subunits (Ga-GDP) can compete with Gbg effectors and deactivate Gbg-depen-dent signaling, suggesting that Gbg may use a common binding surface for interaction with Ga and with its diverse effectors. Two regions on Gbg that interact with Ga have been defined by the crystal structures of heterotrimeric Gabg (8), the switch inter