Cryo-EM structure of the folded-back state of human β-cardiac myosin.

Abstract

A large proportion of cardiac myosin heads are sequestered in an off-state during cardiac relaxation. Increasing exertion converts these heads to an on-state that are turned off during relaxation, a process essential for proper heart function. Point mutations that shift the equilibrium towards the on-state can lead to hypercontractility and the development of hypertrophic cardiomyopathy (HCM). The off-state is equated with an inactive, folded-back structural state called the interacted-head motif (IHM). The IHM is a regulatory feature of all muscle and non-muscle class-2 myosins. The off-state is equated with an inactive, folded-back structural state called the interacted-head motif (IHM). The IHM is a regulatory feature of all muscle and non-muscle myosins from class-2. In this work we report the cryo-EM structure of the human β-cardiac myosin IHM to 3.6 Å resolution. The structure reveals that the interface stabilizing the IHM are hot spots of HCM mutations. Importantly, the cardiac myosin IHM structure is significantly different from the previously described smooth muscle myosin IHM, revealing that the IHM structure is tailored to the distinct need of a given muscle type. This work now provides the missing puzzle piece needed to fully understand the molecular basis of inherited cardiomyopathy. It also paves the way for a personalized medicine approach to the design of new molecules that influence the stability of the IHM, to properly regulate cardiac contraction.