The hypertrophic cardiomyopathy myosin variant G256E decreased the ADP release rate by ~40% compared to wild-type myosin, leading to delayed crossbridge detachment and prolonged contractile relaxation.
The HCM-associated G256E mutation prolongs cardiac muscle relaxation by increasing ADP affinity and slowing ADP release from myosin, providing a structural basis for hypercontractility.
Absolute Event Rate: 71% vs 115%
p-value: p=0.0002
Abstract: Mutations in myosin alter its motor functions in diverse ways by affecting different structural and chemo-mechanical events. Multidisciplinary strategies can be used to understand how varying alterations in motor function converge to common phenotypes like hypercontractility and hypertrophic cardiomyopathy (HCM). We combined molecular dynamics (MD) simulations with protein biochemical and myofibril mechanical analyses to study the HCM-causing myosin variant G256E. MD simulations demonstrated that G256E induces structural changes that increase the work required to displace ADP.Mg 2+ from actomyosin. Stopped-flow biochemical analysis demonstrated increased ADP affinity and decreased ADP release rate, and single myofibril mechanics analysis demonstrated increased force generation and reduced ADP sensitivity of the early, slow phase of relaxation. Together, these results demonstrate that slower ADP release from myosin during contraction is a significant contributor to pathological contractile nature of the G256E mutation. This study highlights the importance of detailed chemo-mechanical analysis of mutations associated with hereditary cardiac diseases.
أجرى كاو وآخرون (الثلاثاء) دراسة أخرى في اعتلال عضلة القلب الضخامي. تم تقييم طفرة G256E في MYH7 مقابل المويسين البري (WT) على معدل إطلاق ADP (s-1) (p=0.0002). قلل المتغير G256E من مويسين اعتلال عضلة القلب الضخامي معدل إطلاق ADP بحوالي 40% مقارنة بالمويسين البري، مما أدى إلى تأخير انفصال الجسور العرضية وإطالة استرخاء الانقباض.