Regulation of G proteins by covalent modification

Abstract

Heterotrimeric G protein α,β, and γ subunits are subject to several kinds of co- and post-translational covalent modifications. Among those relevant to G protein-coupled receptor signaling in normal cell function are lipid modifications and phosphorylation. N-myristoylation is a co-translational modification occurring for members of the Gi family of Gα subunits, while palmitoylation is a post-translational modification that occurs for these and most other Gα subunits. One or both modifications are required for plasma membrane targeting and contribute to regulating strength of interaction with the Gβγ heterodimer, effectors, and regulators of G protein signaling (RGS proteins). Gα subunits, including those with transforming activity, are often inactive when unable to be modified with lipids. The reversible nature of palmitoylation is intriguing in this regard, as it lends itself to a regulation integrated with the activation state of the G protein. Several Gα subunits are substrates for phosphorylation by protein kinase C and at least one is a substrate for phosphorylation by the p21-activated protein kinase. Phosphorylation in both instances inhibits the interactions of these subunits with the Gβγ heterodimer and RGS proteins. Several Gα subunits are also substrates for tyrosine phosphorylation. A Gγ subunit is phosphorylated by protein kinase C, with the consequence that it interacts more tightly with a Gα subunit but less well with an effector.