Protein geranylgeranyltransferase type I alpha subunit (FNTA) (FNTA)

The Protein geranylgeranyltransferase type I alpha subunit (FNTA) is the shared alpha subunit of the heterodimeric enzyme protein geranylgeranyltransferase type I (GGTase-I), which pairs with the beta subunit encoded by PGGT1B to catalyze the post-translational attachment of a 20-carbon geranylgeranyl lipid group from geranylgeranyl pyrophosphate to the cysteine residue in the C-terminal CaaX motif (where A is aliphatic and X is typically leucine) of substrate proteins. This prenylation process renders proteins hydrophobic, enabling their membrane association and activation, particularly for GTP-binding proteins in the Rho, Rac, and Rap families, as well as certain heterotrimeric G protein gamma subunits like RAC1, RAC2, RAP1A, and RAP1B. FNTA forms a crescent-shaped alpha-helical structure that wraps around the beta subunit's alpha-alpha barrel, creating a active site with a zinc ion essential for catalysis and a hydrophobic pocket selective for the longer geranylgeranyl diphosphate over farnesyl diphosphate, distinguishing GGTase-I from farnesyltransferase. Loss of GGTase-I function disrupts these modifications, halting the cell cycle at the G1/S transition and inducing apoptosis, which underscores its role in cellular proliferation and survival signaling. In disease contexts, particularly cancer, GGTase-I is implicated due to its prenylation of oncogenic signaling proteins, making it a prospective therapeutic target where selective inhibitors are under investigation to block tumor growth by preventing membrane localization of these proteins. The enzyme's reaction cycle couples product release to lipid substrate specificity, ensuring fidelity in prenylation. Structural insights from mammalian GGTase-I complexes reveal conserved mechanisms across prenyltransferases, aiding inhibitor design that exploits beta subunit differences for selectivity. FNTA's dual role in both GGTase-I and farnesyltransferase highlights its broad impact on protein lipidation pathways critical for signal transduction.

Other names

CAAX farnesyltransferase subunit alphaFTase-alphaProtein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha

Inhibition of geranylgeranyl group transfer to CaaX motif proteins