Geranylgeranylation

Geranylgeranylation is a post-translational lipid modification in which a 20-carbon geranylgeranyl group is covalently attached to specific cysteine residues near the C-terminus of target proteins. This hydrophobic moiety promotes association with cellular membranes and influences protein localization and interactions, playing a key role in signaling and vesicle trafficking.

The modification is carried out by two major classes of enzymes. Geranylgeranyltransferase type I (GGTase I) transfers a single geranylgeranyl group to cysteine residues within CaaX motifs at the C-terminus of many cytosolic and peripheral membrane proteins, including members of the Rho family. Geranylgeranyltransferase type II (GGTase II), also known as Rab geranylgeranyltransferase, works in conjunction with Rab escort proteins (REPs) to attach geranylgeranyl groups to Rab family GTPases that possess CC or CXC C-termini, often adding two geranylgeranyl groups per Rab protein.

The donor substrate for both enzymes is geranylgeranyl pyrophosphate (GGPP), generated in the mevalonate pathway. After GGTase I action on CaaX substrates, proteolytic cleavage of the terminal AAX residues by Rce1 and methylation of the exposed carboxyl group by isoprenylcysteine carboxyl methyltransferase (ICMT) commonly follow. Rab substrates modified by GGTase II typically undergo continued maturation that supports stable membrane association.

Biological significance includes proper subcellular localization of signaling molecules and trafficking proteins. Dysregulation of geranylgeranylation has been linked to diseases and is a target of pharmacological research, with inhibitors of prenyltransferases or of the mevalonate pathway used to study or modulate related pathways.