Fig. 1
Myosin mesa and sequestered state. a Schematic representation of the motor cycle and the regulation of the β-cardiac myosin activity. On the left, when the motor detaches from the track upon ATP binding, the motor adopts the post-rigor (PR) state in which the lever arm is down and the motor has poor affinity for F-actin. During the recovery stroke, repriming of the lever arm leads to the pre-powerstroke (PPS) state in which hydrolysis can occur. The swing of the lever arm (powerstroke) upon reattachment of the motor to F-actin is coupled with the release of hydrolysis products. The nucletotide-free or rigor state has the highest affinity for F-actin. On the right, scheme of the sequestered state that is formed during relaxation. According to the mesa hypothesis, HCM mutations disrupt the sequestered state, increasing the number of myosin heads available to produce force. According to the Hypercontractile hypothesis, HCM mutations alter the myosin motor activity. b The mesa (purple dashed lines) is a long and flat surface of the myosin head composed of several myosin subdomains conserved in myosin IIs. c Electron density map of the human cardiac filament obtained from negative staining23 (EMDB code EMD-2240). In the relaxed state, interactions between the blocked head (BH) and the free head (FH) of the myosin 2 dimer stabilize an asymmetric configuration. Extra densities of the filament correspond to other components of the thick filament, the cardiac myosin MyBP-C, and titin. Location of the mesa for each head indicates that the FH mesa (*) interacts with the BH while the BH mesa (#) is buried and interacts with components of the thick filament
