Catalytic domain-lipid interactions negatively regulate RhoA signaling by modulating conformational dynamics

A polybasic patch on the RhoA G-domain (R5, K6, K7) controls membrane lipid engagement, and mutating it increases RhoA-driven F-actin accumulation and effector activation in cells.

• Why it matters: RhoA’s prenylated membrane anchoring is known, but how its plasma-membrane organization and lipid interactions tune its conformational dynamics and signaling remained unclear.
• What they did: The authors combined extensive atomistic molecular dynamics with simulations-guided cell experiments, mapping how GDP- and GTP-bound RhoA binds bilayers and testing Ala substitutions at R5, K6, and K7.
• The result: Wild-type RhoA shows a stable membrane organization in both nucleotide states, while the triple Ala mutant preserves global binding but disrupts cooperative lipid contacts and reroutes internal dynamics that primes Switch I for effector recognition.

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