Regulation of G proteins by covalent modification

Heterotrimeric G protein alpha,beta, and gamma 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 (G)i family of G alpha subunits, while palmitoylation is a post-translational modification that occurs for these and most other G alpha subunits, One or both modifications are required for plasma membrane targeting and contribute to regulating strength of interaction with the G beta gamma heterodimer, effecters, and regulators of G protein signaling (RGS proteins). G alpha 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 G alpha 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 G beta gamma heterodimer and RGS proteins. Several G alpha subunits are also substrates for tyrosine phosphorylation, A G gamma subunit is phosphorylated by protein kinase C, with the consequence that it interacts tightly with a G alpha subunit but less well with an effector.