Structural Biochemistry, Proteins, Prenylation

Prenylation

Prenylation, isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is believed that prenyl groups (3-methyl-2-buten-1-yl) facilitate attachment to cell membranes membrane, similar to lipid anchor like the GPI anchor, though direct evidence is missing. Prenyl groups have been shown to be important for protein-protein binding through specialized prenyl-binding domains.

Protein prenylation involves the transfer of either a farnesyl or a geranyl-geranyl moiety to C-terminal cysteine(s) of the target protein. There are three enzymes that carry out prenylation in the cell.

Farnesyltransferase and geranylgeranyltransferase I

Farnesyltransferase and Geranylgeranyltransferase I are very similar proteins. They consist of two subunits, the α-subunit which is common to both enzymes, and the β-subunit whose sequence identity is just 25%. These enzymes recognise the CaaX box at the C-terminus of the target protein. C is the cysteine that is prenylated, a is any aliphatic amino acid, and the identity of X determines which enzyme acts on the protein. Work reported in the journal Genome Biology in 2005 reports refinement of computational detection methods for identification of protein prenylation motifs and establishment of an on-line analysis facility entitled "PrePS".

Proteins that undergo prenylation include Ras, which plays a central role in the development of cancer. This suggests that inhibitors of prenylation enzymes (e.g. farnesyltransferase) may influence tumor growth. Recent work has shown that farnesyltransferase inhibitors (FTIs) also inhibit Rab geranylgeranyltransferase and that the success of such inhibitors in clinical trials may be as much due to effects on Rab prenylation as on Ras prenylation.

Reference:

Sebastian Maurer-Stroh and Frank Eisenhaber (2005). "Refinement and prediction of protein prenylation motifs". Genome Biology.

Taylor J, Reid T, Terry K, Casey P, Beese L (2003). "Structure of mammalian protein geranylgeranyltransferase type-I".

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