Geranylgeranylated

Geranylgeranylation is a post-translational lipid modification in which a geranylgeranyl group, a 20-carbon isoprenoid, is covalently attached to a cysteine residue near the C-terminus of a target protein. The addition increases the protein’s hydrophobicity and promotes stable association with cellular membranes, enabling proper localization and function of a subset of signaling and trafficking proteins.

The modification is carried out by two related enzymes: geranylgeranyltransferase I (GGTase-I) and geranylgeranyltransferase II (GGTase-II, also known as Rab geranylgeranyltransferase). GGTase-I typically modifies proteins bearing a CaaX motif at their C-terminus, where X is leucine. GGTase-II recognizes Rab and related small GTPases that have C-terminal CC or CXC motifs and often catalyzes double geranylgeranylation. After prenylation, further processing by proteases such as Rce1 and by the methyltransferase Icmt commonly occurs, removing the terminal AAX residues and methylating the carboxyl group to yield a mature, membrane-associated protein.

Substrates include Rab family GTPases and various other signaling proteins that rely on membrane targeting for activity. Geranylgeranylated proteins frequently participate in vesicular trafficking, cytoskeletal organization, and signal transduction. Regulation occurs at multiple levels, including the mevalonate pathway (which supplies geranylgeranyl diphosphate), enzyme activity of GGTases, and post-prenylation processing steps. Inhibitors of geranylgeranyltransferases (GGTIs) have been used as research tools and have been explored for therapeutic potential, particularly in cancer, by disrupting membrane localization and function of essential Rab and related proteins.