GGTaseII

GGTase II, also known as Rab geranylgeranyltransferase, is a cytosolic enzyme that catalyzes the post-translational addition of geranylgeranyl groups to Rab GTPases, enabling their association with membranes and participation in vesicular trafficking. It is a heterodimer composed of a catalytic alpha subunit (RabGGTase alpha, encoded by RabGGTA) and a beta subunit (RabGGTase beta, encoded by RabGGTB). The geranylgeranyl donor is geranylgeranyl pyrophosphate (GGPP). Rab proteins are delivered to the enzyme by Rab escort proteins (REP-1 and REP-2; CHM and CHML genes); REP-bound Rab is recognized by RabGGTase II and targeted for prenylation.

The enzyme specifically modifies Rab GTPases that bear C-terminal cysteine-containing motifs, typically CC or CXC sequences, by attaching two geranylgeranyl groups. This lipid modification promotes Rab association with membranes and is required for proper Rab cycling between compartments such as the endoplasmic reticulum, Golgi apparatus, endosomes, and the plasma membrane.

Physiological relevance and disease: Rab GGTase II activity is essential for efficient vesicular trafficking; disruption of Rab prenylation leads to mislocalization of Rab proteins and trafficking defects. REP-1 and REP-2 provide functional redundancy for Rab apo-proteins, and deficiencies in REP proteins are linked to human disease (for example CHM-related choroideremia). GGTase II function can be studied with selective inhibitors, which are used to dissect Rab-dependent pathways and may have therapeutic potential in diseases involving Rab misregulation.