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The Molecular Perspective: Protein Farnesyltransferase

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell

In cell signaling, a lot of the action occurs at the cell membrane. Messages arrive at the cell surface and are picked up by receptors. Then, they are processed by a collection of proteins on the inner surface of the membrane and, finally, they are dispatched to their different recipients in the cytoplasm or nucleus. Most of these proteins need ways of staying close to the membrane, where the action is, and not wandering off to other areas. Receptors are often built with large segments that cross the membrane, anchoring them permanently in place. The various signal-processing proteins on the inner surface, however, take a leaner approach.

Proteins like Ras and the trimeric G proteins use small lipid molecules to anchor themselves to the inner surface of the cell membrane. These lipids are attached directly to the protein chain. Some are snaky saturated lipids, like 14-carbon myristoyl chains or 16-carbon palmitoyl chains, and some are rigidified unsaturated lipids built from isoprene units, such as 15-carbon farnesyl groups and 20-carbon geranylgeranyl groups. All of them strongly prefer the lipid environment of the membrane rather than the watery environment of the cytoplasm, so they insert into the membrane, tethering the protein in place.

The enzyme protein farnesyltransferase attaches farnesyl groups to cysteine amino acids at the ends of certain protein chains, such as that of the Ras protein (Fig. 1). The enzyme acts on proteins with a specific signal sequence at the end: a cysteine followed by three additional amino acids. The last amino acid determines which lipid will be added. If it is serine, methionine, or glutamine, protein farnesyltransferase will add a farnesyl group. If the last amino acid is leucine, however, a different enzyme is recruited and a longer lipid is added. The farnesyl chain itself is sufficient to tether Ras loosely to the membrane. To improve the attachment, the protein chain is trimmed after the farnesyl lipid is added, removing the last three amino acids. Finally, the end of the chain is methylated, neutralizing a negative charge that would interact unfavorably with the surface of the membrane.

View larger version (73K): [in this window] [in a new window]   Figure 1. Protein farnesyltransferase in action. The tail end of the Ras protein, shown at the top in pink, inserts into the active site of the enzyme, shown at the bottom in blue. The enzyme uses a zinc ion, shown in green, to attach the lipid, shown in the active site to the right of the Ras tail. An activated form of the lipid, with two phosphate groups attached (colored bright red), is used in the reaction. Coordinates were taken from entries 121p and 1jcs [PDB] at the Protein Data Bank (http://www.pdb.org).

ADDITIONAL READING

Casey PJ. Protein lipidation in cell signaling. Science 1995;268:221–225.[Abstract/Free Full Text]

Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 1996;65:241–269.[CrossRef][Medline]

Long SB, Casey PJ, Beese LS. Reaction path of protein farnesyltransferase at atomic resolution. Nature 2002;419:645–650.[CrossRef][Medline]

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