title: RAS/Effector Interactions from Structural and Biophysical Perspective.
abstract: 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.
authors.forename: Ariel
authors.initials: A
authors.lastname: Erijman
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. jshifman@mail.huji.ac.il.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Shifman
mesh_terms: D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013816:Thermodynamics; D010738:Type C Phospholipases / Q000737:chemistry / Q000378:metabolism; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D006160:Guanosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D019908:Proto-Oncogene Proteins c-raf; D010738:Type C Phospholipases; D018631:ras Proteins