Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy
James A. Spudich, Neha Nandwani, Julien Robert‐Paganin, Anne Houdusse, Kathleen M. Ruppel
Abstract
Human β-cardiac myosin exists in an ON-state where both myosin heads are accessible for interaction with actin, and an OFF-state where the heads are folded back onto their own coiled-coil tail, interacting with each other via an interacting-heads motif (IHM). Hypertrophic cardiomyopathy (HCM) mutations in β-cardiac myosin cause hypercontractility of the heart. Nine years ago, a unifying hypothesis proposed that hypercontractility caused by myosin HCM-associated mutations is primarily due to an increase in the number of ON-state myosin molecules, rather than altered fundamental alterations of functional myosin parameters such as intrinsic motor force, its velocity of movement along actin, or its ATPase turnover rate, all of which impact power output. We here revisit this unifying hypothesis in light of accumulated data measuring all these parameters, and the recent availability of a 3.6 Å-resolution structure of the human β-cardiac myosin IHM. Biochemical measurements show that nearly all myosin HCM mutations examined exhibit more ON-state myosin regardless of where they occur in the myosin head domain, consistent with the unifying hypothesis. Significant advances in structural and biochemical research validate the 9-year-old hypothesis that cardiac hypercontractility seen in patients with hypertrophic cardiomyopathy is primarily caused by sarcomeric mutations that increase the number of myosin molecules available for actin interaction.