[Covalent lipid modifications of heterotrimeric G proteins]

Guanine nucleotide-binding regulatory proteins (heterotrimeric G proteins) are composed of alpha-, beta- and gamma- subunits, and they mediate a variety of intracellular signal transductions by coupling activated membrane receptors with effector enzymes and channels. Activated receptors catalyze the exchange of GDP bound to the alpha-subunits for cytosolic GTP, and GTP-bound alpha-subunits in turn regulate activities or functions of the effectors. The beta gamma-complex is not dissociable under physiological conditions, and it is indispensable for the GDP/GTP exchange reaction on the alpha-subunit. Recently, three kinds of lipid modifications have been found in the alpha- and gamma-subunits. The first is the attachment of fatty acids, myristate (C14:0) or structurally related fatty acids to the N-terminal glycine residues of some members of the alpha-subunits. Another type of fatty acylation to be characterized is the linkage of palmitate (C16:0) to a number of alpha-subunits via a thioester bond at their cysteine residues. The third type of modification is polyisoprenylation (farnesylation or geranylgeranylation) and alpha-carboxyl methylation at the C-terminal cysteine residue of the gamma-subunit. These modifications on the two subunits have been shown to play a critical role in not only protein-membrane interaction but also proper protein-protein interaction, both of which are required for the G protein function.