The oncogene Ras gets acetylated

June 18, 2012 § Leave a comment

Orange highlights lysine 104 on Ras; dark blue is the domain which interacts with GEFs; red is the domain which interacts with GAPs; and purple is a GTP molecule. Image provided by Kevin Haigis.

Ubiquitination, phosphorylation and prenylation aren’t the only modifications to jockey for amino acids on Ras, the family of small GTPases that are central to signal transduction pathways. In a paper just out in the Proceedings of the National Academy of Sciences, researchers show that Ras is also acetylated.

Turning Ras on is like pushing on a trail of standing dominoes. When Ras gets switched on, it uses energy from GTP to set off other proteins. These proteins eventually affect genes involved in cell growth, differentiation and survival. Mutations in Ras have been found in various cancers, and drug companies are hotly pursuing drugs that target the protein.

A team led by Kevin Haigis at the Massachusetts General Hospital Harvard Medical School have now demonstrated that Ras gets an acetyl group added to its 104th amino acid, which affects its activity. Haigis says it wasn’t too far a stretch to think that Ras could be acetylated. “We knew that, in a general sense, acetylation plays a major role in regulating protein function,” he says. “We also knew from previous work that lysines on Ras proteins are modified because mono- and di-ubiquitination of Ras proteins had been reported.”

The investigators showed that acetylation alters the tertiary structure of the protein. The change in structure stops Ras from interacting with regulatory co-factors, such as guanine nucleotide exchange factors. These are known as GEFs and are responsible for reloading GDP-bound RAS with GTP.

Haigis explains that acetylation gives cells another way to control the activity of Ras, besides GEFs and GTPase-activating proteins (GAPs) that help Ras hydrolyze GTP effectively. “This makes sense, since having activated Ras is bad for a cell under most circumstances,” he notes.

Haigis says the discovery of Ras acetylation provides a new way to approach drug development. “Drugs that target Ras prenylation didn’t work out clinically, but maybe drugs that target other Ras modifications will.”

For now, Haigis and his colleagues have their work cut out for them. They need to now figure out when and how Ras gets acetylated.

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