Ras GTPase

Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction). Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours.

When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation, and survival. Mutations in Ras genes can lead to the production of permanently activated Ras proteins, which can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals.

Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer. The three Ras genes in humans (HRAS, KRAS, and NRAS) are the most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20 to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer). For this reason, Ras inhibitors are being studied as a treatment for cancer and other diseases with Ras overexpression.

The first two Ras genes, HRAS and KRAS, were identified from studies of two cancer-causing viruses, the Harvey sarcoma virus and Kirsten sarcoma virus, by Edward M. Scolnick and colleagues at the National Institutes of Health (NIH). These viruses were discovered originally in rats during the 1960s by Jennifer Harvey and Werner H. Kirsten, respectively, hence the name Rat sarcoma. In 1982, activated and transforming human ras genes were discovered in human cancer cells by Geoffrey M. Cooper at Harvard, Mariano Barbacid and Stuart A. Aaronson at the NIH, Robert Weinberg at MIT, and Michael Wigler at Cold Spring Harbor Laboratory. A third ras gene was subsequently discovered by researchers in the group of Robin Weiss at the Institute of Cancer Research, and Michael Wigler at Cold Spring Harbor Laboratory, named NRAS, for its initial identification in human neuroblastoma cells.

The three human ras genes encode extremely similar proteins made up of chains of 188 to 189 amino acids. Their gene symbols are HRAS, NRAS and KRAS, the latter of which produces the K-Ras4A and K-Ras4B isoforms from alternative splicing.^{[citation needed]}

Ras contains six beta strands and five alpha helices. It consists of two domains: a G domain of 166 amino acids (about 20 kDa) that binds guanosine nucleotides, and a C-terminal membrane targeting region (CAAX-COOH, also known as CAAX box), which is lipid-modified by farnesyl transferase, RCE1, and ICMT.^{[citation needed]}

The G domain contains five G motifs that bind GDP/GTP directly. The G1 motif, or the P-loop, binds the beta phosphate of GDP and GTP. The G2 motif, also called Switch I or SW1, contains threonine35, which binds the terminal phosphate (γ-phosphate) of GTP and the divalent magnesium ion bound in the active site. The G3 motif, also called Switch II or SW2, has a DXXGQ motif. The D is aspartate57, which is specific for guanine versus adenine binding, and Q is glutamine61, the crucial residue that activates a catalytic water molecule for hydrolysis of GTP to GDP. The G4 motif contains a LVGNKxDL motif, and provides specific interaction to guanine. The G5 motif contains a SAK consensus sequence. The A is alanine146, which provides specificity for guanine rather than adenine.

The two switch motifs, G2 (SW1) and G3 (SW2), are the main parts of the protein that move when GTP is hydrolyzed into GDP. This conformational change by the two switch motifs is what mediates the basic functionality as a molecular switch protein. This GTP-bound state of Ras is the "on" state, and the GDP-bound state is the "off" state. The two switch motifs have a number of conformations when binding GTP or GDP or no nucleotide (when bound to SOS1, which releases the nucleotide).