GGTases

GGTases, or geranylgeranyltransferases, are a family of enzymes that catalyze the transfer of the 20-carbon isoprenoid geranylgeranyl group from geranylgeranyl pyrophosphate (GGPP) to specific substrate proteins. This post-translational modification, known as geranylgeranylation, promotes membrane association and proper localization and function of many signaling and trafficking proteins.

Two major members are GGTase I and GGTase II (Rab geranylgeranyltransferase). GGTase I recognizes substrates bearing a C-terminal CaaX motif, where the cysteine is the site of modification and the terminal residues influence enzyme specificity. GGTase II is a heterodimer that modifies Rab family small GTPases, typically with C-terminal CC or CXC motifs, and requires the Rab escort protein (REP) to present substrates to the enzyme. Both enzymes use GGPP as the donor of the geranylgeranyl group.

The reaction attaches the geranylgeranyl moiety to the cysteine of the target motif, forming a thioether linkage. In many CaaX substrates, subsequent proteolysis of the C-terminus and methylation by ICMT may follow to complete maturation, though processing after GGTase II modification differs among Rab proteins.

Biological significance lies in the role of geranylgeranylation in membrane targeting and functional regulation of a broad set of proteins, including members of the Ras, Rho, and Rab families. This modification influences signal transduction, vesicular trafficking, cytoskeletal organization, and cell growth.

Clinical and research relevance includes the study of GGTase inhibitors as potential anticancer or antipathogen agents. Inhibitors of GGTase I and II have been developed and studied, though therapeutic application remains an area of ongoing investigation.