A gain-of-function missense mutation in codon 12 of KRAS substitutes glycine with valine (G12V). Which of the following correctly describes why this mutation renders the Ras protein constitutively active?
- A The G12V mutation impairs GAP-mediated GTP hydrolysis by creating steric hindrance at the catalytic glutamine-61 equivalent site, trapping Ras-GTP ✓
- B Valine substitution directly activates intrinsic GTPase activity, sustaining RAS in the GTP-bound state
- C Valine stabilizes the inactive GDP-bound form, preventing exchange by GEFs
- D The mutation enhances nucleotide exchange by increasing the rate of GDP-to-GTP substitution
Correct answer: A. The G12V mutation impairs GAP-mediated GTP hydrolysis by creating steric hindrance at the catalytic glutamine-61 equivalent site, trapping Ras-GTP
Explanation
RAS normally cycles between the inactive GDP-bound and active GTP-bound states; GTPase-activating proteins (GAPs) like NF1 accelerate intrinsic GTP hydrolysis. The G12V mutation at the P-loop creates steric clash with the arginine finger of RAS-GAP, preventing proper alignment of the catalytic water and glutamine-61, thus blocking GTP hydrolysis. The result is constitutive Ras-GTP, with persistent activation of RAF-MEK-ERK and PI3K-AKT cascades, driving proliferation and survival.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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