10/10/2023
By Joanne Gagnon-Ketchen
Prof. Jeffrey R. Moore, Biology Dept., UMass Lowell will be giving a talk on "Altered contractile protein mechanochemistry in heart disease"
Abstract
Heart muscle contraction is driven by the molecular motor myosin, which generates a step for every ATP molecule consumed. The myosin motor consists of the head domain, which is responsible for ATP hydrolysis and an alpha-helical domain, which acts as a lever arm to amplify small conformational changes in the myosin head to generate force and motion. The regulatory light chain (RLC) serves an important structural role, supporting the myosin neck region and a modulatory role, tuning the kinetics of the actin myosin interaction. Given the importance of the RLC, it is not surprising that mutations of the RLC can lead to hypertrophic cardiomyopathy, the leading cause of sudden cardiac death in people under 30. Population studies identified two cardiomyopathy mutations located near the cationic binding site of the RLC, R58Q and N47K. Although these mutations are close in sequence, they differ in clinical presentation and prognosis, with R58Q showing a more severe phenotype. Here I will present molecular based changes in myosin that correlate with the disease phenotype by using a microscopic in vitro muscle model contractile system. We found that both R58Q and N47K mutations show reductions in force compared to the wild type that could result in compensatory hypertrophy. Furthermore, we observed a mutation-induced loss of load dependent biochemistry that could lead to decreased contractile efficiency, potentially explaining the more severe phenotype for the R58Q mutation.