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Effects of cardiomyopathy-related mutations in alpha-cardiac actin on the actin-myosin complex

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Title: Effects of cardiomyopathy-related mutations in alpha-cardiac actin on the actin-myosin complex
Author: Dahari
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Abstract: Cardiomyopathies are a distinct class of heart disease and are the third most common cause of heart failure. These conditions are generally characterized by remodeling of the left ventricle; however, the molecular mechanisms leading to the pathological states are still not fully understood. Mutated genes encoding for sarcomeric proteins have been shown to influence the development of cardiomyopathies. Missense mutations in alpha-cardiac actin (ACTC) have been associated with both hypertrophic and dilated cardiomyopathies (HCM and DCM respectively). Twelve of these mutations contribute to the onset of HCM: E99K, P164A, A331P, Y166C, A230V, A295S, M305L, S271F, H88Y, R95C, F90del and R312C while two contribute to the onset of DCM: E361G and R312H. These mutations are proposed to have detrimental effects on the structure and function of alpha-cardiac actin, thus leading to the diseased state. A295S ACTC did not exhibit intrinsic defects in protein folding and polymerization as seen with other ACTC variants with subdomain 3 mutations. Actin-activated ATPase rates measured showed the E99K ACTC variant increased the ATPase rate of skeletal myosin by approximately 30% compared to WT ACTC. E99K ACTC also exhibited decreased filament motility approximately 40-50% slower that WT ACTC at all ionic and ATP conditions examined demonstrating a reduction in force generation. These results demonstrate deficiencies in myosin binding of the E99K ACTC variant, providing insight into the primary molecular disruptions leading to the development of cardiomyopathies.
Date: 2012-09
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