Protein prenylation and CAAX processing (FTase/GGTase-I/RabGGTase -> RCE1 -> ICMT)

Prenylation is a lipid post-translational modification that irreversibly attaches a farnesyl (C15) or geranylgeranyl (C20) isoprenoid — supplied as FPP/GGPP from the mevalonate pathway — to C-terminal cysteines of ~300 human proteins (Ras, Rho, Rac, Rab and other small GTPases, nuclear lamins, kinases), anchoring them to membranes and enabling signalling and vesicular trafficking. Three heterodimeric prenyltransferases do the attachment. Farnesyltransferase (FTase = the shared alpha subunit FNTA + the beta subunit FNTB) and geranylgeranyltransferase type I (GGTase-I = FNTA + PGGT1B) recognise a C-terminal CAAX motif directly and prenylate its cysteine — FTase when X is Met/Ser/Gln/Ala, GGTase-I when X is Leu/Phe. Rab geranylgeranyltransferase (GGTase-II / RabGGTase = RABGGTA + RABGGTB) instead double-geranylgeranylates the C-terminal CC/CXC cysteines of Rab GTPases, which must first be presented by the Rab escort protein REP1/REP2 (CHM/CHML). For the CAAX (FTase/GGTase-I) substrates, two further ER-membrane maturation steps follow: the glutamate-type intramembrane protease RCE1 removes the -AAX tripeptide, exposing the prenylcysteine as the new C-terminus, and the SAM-dependent methyltransferase ICMT carboxymethylates that prenylcysteine, maximising hydrophobicity and membrane affinity. The pathway is a major anticancer target (Ras farnesylation; FTIs) and underlies Hutchinson-Gilford progeria (lamin A prenylation). RabGGTase/REP defects cause choroideremia (via CHM), and RCE1/ICMT are Ras-pathway drug targets.