RAS is a molecular switch that regulates a large number of pathways through interactions
with many effector proteins. Most RAS/effector complexes are short-lived, demonstrating fast
association and fast dissociation rate and Kds ranging from 10-8–10-5 M, compatible with the signaling
function of these interactions in the cell. RAS effectors share little sequence homology but all contain
an RAS binding domain that exhibits ubiquitin fold. All effectors bind to the same epitope on RAS by
forming an intermolecular beta sheet and creating a number of favorable hydrogen bonds and salt
bridges across the binding interface. Several hot-spots on both RAS and effector molecules constitute
a general recognition mode. RAS/effector interactions occur only when RAS is found in the active, GTP-bound state, and
are disrupted upon GTP hydrolysis, most probably due to increased flexibility of the RAS molecule. Recent NMR studies
demonstrate how in the presence of multiple binding partners, RAS prefers certain effectors to others. The hierarchy of
these interactions could be altered for RAS oncogenic mutants, thus perturbing the network of the downstream signaling.
Insights obtained through biophysical and structural studies of effectors interacting with RAS and its mutants establish the
basic principles that could be used for designing drugs in RAS-associated diseases.
Keywords: Binding affinity, complex structure, intermolecular interactions, protein-protein interactions.
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