Ras protein 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 behaviors. Ras proteins are highly conserved small GTP-binding proteins (G-proteins) that regulate critical cellular functions such as proliferation, survival, migration.
Ras proteins are binary molecular switches that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound states. Specifically, Ras is a guanosine-nucleotide-binding protein and is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases). In the "off" state, it is bound to the nucleotide guanosine diphosphate (GDP), while in the "on" state, it is bound to guanosine triphosphate (GTP). Active Ras drives the growth, proliferation, and migration of 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. 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.
Mutant Ras proteins have been difficult to target, in part, because they are defective in an intrinsic enzyme activity, freezing them in the “on” (GTP-bound) state. Despite repeated attempts, researchers failed to develop a drug that could inhibit the activity of Ras proteins in cancers. However, advances in technology and improved understanding of Ras signaling and regulation have created opportunities to address this situation.
