Farnesyltransferase has two subunits: a 48kDa alpha subunit and a 46kDa beta subunit. Both subunits are primarily composed of alpha helices. The α subunit is made of a double layer of paired alpha helices stacked in parallel, which wraps partly around the beta subunit like a blanket. The alpha helices of the β subunit form a barrel. The active site is formed by the center of the β subunit flanked by part of the α subunit. Farnesyltransferase coordinates a zinccation on its β subunit at the lip of the active site. Farnesyltransferase has a hydrophobic binding pocket for farnesyl diphosphate, the lipid donor molecule. All farnesyltransferase substrates have a cysteine as their fourth-to-last residue. This cysteine engages in an SN2 type attack, coordinated by the zinc and a transient stabilizing magnesium ion on the farnesyl diphosphate, displacing the diphosphate. The product remains bound to farnesyltransferase until displaced by new substrates. The last three amino acids of the CaaX motif are removed later.
There are four binding pockets in FTase, which accommodate the last four amino acids on the carboxyl-terminus of a protein. Only those with a suitable CaaX motif can bind ('C' is Cysteine, 'a' is an aliphatic amino acid, and 'X' is variable). The carboxyl-terminal amino acid (X) discriminates FTase’s targets from those of the other prenyltransferases, allowing only six different amino acids to bind with any affinity. It has been shown that geranylgeranyltransferase can prenylate some of the substrates of Farnesyltransferase and vice versa.
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