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. 2021 Jul 8;8:707439. doi: 10.3389/fmolb.2021.707439

FIGURE 2.

FIGURE 2

Wild type and oncogenic RAS regulation by GEFs and GAPs. (A) The RAS nucleotide cycling regulated by GEF and GAP. GEFs bind to RAS, inducing conformation changes that reduce the RAS affinity for guanine nucleotide ligands. This leads to the dissociation of GDP and the formation of the nucleotide-free apo-form of RAS from the GDP-bound “OFF” state. Stochastic GTP loading to the apo-form of RAS facilitating the GTP-bound “ON” state, due to the higher GTP/GDP ratios in the cell. GAPs bind to the GTP-bound RAS and increases its intrinsic GTPase activity for GTP hydrolysis. (B) Activation mechanism of oncogenic RAS mutant. Upper: The RAS G12V oncogenic mutant impairs both intrinsic GTPase activity and GAP-dependent GTP hydrolysis. Lower: the RAS K117R mutant maintains intrinsic GTPase activity and GAP-dependent GTP-hydrolysis, but decreases the nucleotide affinity, leading to an increased GTP/GDP exchange.