GEFs and GAPs turn RAS on and off when they are recruited to the plasma membrane and placed in direct proximity to RAS. However, they are governed by one important principle: translocation. 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., 2007).ĭependence of RAS and other GTPases on GEFs and GAPs to switch them on and off allows both processes to be highly regulated and responsive to multiple signal inputs. Conversion back to the inactive form is mediated by GTPase-activating proteins (GAPs) ( Cherfils and Zeghouf, 2013). The conversion from stable, inactive GDP-bound forms to the active GTP-bound form is stimulated by guanine nucleotide exchange-factors (GEFs). This switch mechanism has been highly conserved among GDP/GTP binding proteins as diverse as bacterial elongation factors, heterotrimeric G-proteins, and a myriad of small GTPases with diverse biological functions.
RAS proteins are binary molecular switches that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound states. Here, we will review biochemical and biophysical properties of RAS proteins and how they affect human disease. Abnormal RAS activity may also play a significant role in autism and other neurological disorders. “RASopathies,” a collection of developmental conditions caused by germline mutations that activate RAS/MAPK signaling, affect more than 400,000 individuals in the United States alone.
Mutations in RAS regulators, such as neurofibromin and SPRED1, also make significant contributions to cancer. 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.
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