Farnesylation

Farnesylation is a type of post-translational modification of proteins, which involves the addition of a 15-carbon isoprenoid lipid known as a farnesyl group to a cysteine residue at or near the C-terminus of a protein. This modification is crucial for the proper localization and function of a variety of proteins, including members of the Ras superfamily of small GTPases.

Mechanism of Farnesylation

Farnesylation is catalyzed by the enzyme farnesyltransferase, which transfers the farnesyl group from farnesyl pyrophosphate (FPP) to the target protein. The target protein typically contains a C-terminal CAAX motif, where 'C' is cysteine, 'A' is an aliphatic amino acid, and 'X' is any amino acid that determines the specificity of the prenylation.

Steps of Farnesylation

1. Recognition: The farnesyltransferase enzyme recognizes the CAAX motif at the C-terminus of the target protein.
2. Transfer: The farnesyl group is transferred from farnesyl pyrophosphate to the thiol group of the cysteine residue in the CAAX motif.
3. Proteolysis: The AAX amino acids are cleaved off by a specific protease.
4. Methylation: The newly exposed carboxyl group of the cysteine is methylated by an enzyme called isoprenylcysteine carboxyl methyltransferase.

Biological Significance

Farnesylation is essential for the membrane localization and function of many proteins. It facilitates the attachment of proteins to cell membranes, which is critical for their biological activity. Proteins that undergo farnesylation include members of the Ras family, Rho family, and Rab family of GTPases, which are involved in signal transduction pathways that regulate cell growth, differentiation, and survival.

Role in Cancer

Mutations in the Ras protein that lead to its constitutive activation are implicated in many types of cancer. Farnesylation is required for the proper localization and function of Ras proteins, making farnesyltransferase a target for anticancer drug development. Farnesyltransferase inhibitors (FTIs) are being investigated as potential therapeutic agents for the treatment of cancers driven by aberrant Ras signaling.

Clinical Implications

Farnesylation has been implicated in several diseases beyond cancer. For example, defects in protein farnesylation are associated with Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder characterized by accelerated aging. In HGPS, the mutant form of the protein lamin A, known as progerin, remains farnesylated, leading to its abnormal accumulation at the nuclear envelope and contributing to the disease phenotype.

Research and Therapeutic Approaches

Research into farnesylation has led to the development of farnesyltransferase inhibitors (FTIs) as potential therapeutic agents. These inhibitors aim to block the farnesylation of proteins like Ras, thereby preventing their proper localization and function. FTIs have shown promise in preclinical models and are undergoing clinical trials for various cancers.

Farnesylation Resources
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