Allosteric regulation of GRB2 modulates RAS activation

ABSTRACT RAS activation is a multiple‐step process in which linkage of the extracellular stimuli to the RAS activator SOS1 is the main step in RAS activation. GRB2 adaptor protein is the main modulator in SOS1 recruitment to the plasma membrane and its activation. This interaction is well studied but the exact mechanism of GRB2-SOS1 complex formation and SOS1 activation has yet remained obscure. Here, a new allosteric mechanism for the GRB2 regulation is described as a prerequisite for the modulation of SOS1 activation. This regulatory mechanism comprises a series of intramolecular interactions which are potentiated by GRB2 interaction with upstream ligands. Abbreviations: GRB2, growth factor receptor-bound protein 2; SOS1, son of sevenless 1; RAS, Rat Sarcoma; GEF, guanine nucleotide exchange factor; GAP, GTPase‐activating protein; HER2, human epidermal growth factor receptor; SH3, SRC Homology 3; SH2, SRC Homology 2; PRD, proline-rich domain; PRM, proline-rich motif; PRP, proline-rich peptide; RTK, receptor tyrosine kinases.