STRUCTURAL INTERPRETATION OF THE MUTATIONS IN THE BETA-CARDIAC MYOSINTHAT HAVE BEEN IMPLICATED IN FAMILIAL HYPERTROPHIC CARDIOMYOPATHY

In 10-30% of hypertrophic cardiomyopathy kindreds, the disease is caus ed by >29 missense mutations in the cardiac beta-myosin heavy chain (M YH7) gene. The amino acid sequence similarity between chicken skeletal muscle and human beta-cardiac myosin and the three-dimensional struct ure of the chicken skeletal muscle myosin head have provided the oppor tunity to examine the structural consequences of these naturally occur ring mutations in human beta-cardiac myosin. This study demonstrates t hat the mutations are related to distinct structural and functional do mains. Twenty-four are clustered around four specific locations in the myosin head that are (i) associated with the actin binding interface, (ii) around the nucleotide binding site, (iii) adjacent to the region that connects the two reactive cysteine residues, and (iv) in close p roximity to the interface of the heavy chain with the essential light chain. The remaining five mutations are in the myosin rod. The locatio ns of these mutations provide insight into the way they impair the fun ctioning of this molecular motor and also into the mechanism of energy transduction.