Official websites use. Share sensitive information only on official, secure websites. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active.
The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. RAS proteins play a causal role in human cancer: this has been recognized for many years and has inspired multiple attempts to find RAS inhibitors. Abnormal RAS activity may also play a significant role in autism and other neurological disorders.
Here, we will review biochemical and biophysical properties of RAS proteins and how they affect human disease. RAS proteins are binary molecular switches that cycle between active guanosine triphosphate GTP -bound and inactive guanosine diphosphate GDP -bound states.
GEFs and GAPs are large, multi-domain proteins capable of an astonishing variety of interactions with other proteins, lipids, and regulatory molecules that control levels of active and inactive RAS Bos et al.
However, they are governed by one important principle: translocation. This proximal positioning in a 2D surface is equivalent to five orders of magnitude increase in binding constant relative to free solution and is at the heart of understanding how RAS proteins are regulated. RAS proteins activate effectors by recruitment to the plasma membrane. Indeed, for RAF kinase, translocation appears to be sufficient to initiate the complicated activation process Leevers et al.
