Cardiac myosin contraction and mechanotransduction in health and disease

Figures

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  Figure 1. Cardiac myosin structure.A, schematic structure of cardiac myosin showing the regions named for proteolytic fragments heavy meromyosin (HMM), light meromyosin (LMM), subfragment-1 (S1), and subfragment-2 (S2). Full-length myosin consists of two heavy chains (yellow and green), each bound to an essential light chain (ELC, dark pink) and a regulatory light chain (RLC, light pink). The myosin heads (S1 region) contain the sites of ATP and actin binding. The tails (LMM) are coiled coils that assemble into the thick filament. B, structure of the human cardiac myosin motor domain based on PDB ID 4PA0, where the loops not resolved in the crystal structure were modeled using homology modeling. Structural domains related to the mechanical power stroke, actin binding, and nucleotide binding to the active site are highlighted. For additional details on the structural mechanism of myosin force generation, the reader is referred to (7).

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  Figure 2. Cardiac myosin integration into the sarcomere.A, diagram of the sarcomere, drawn roughly to scale. Bands and discs observed by electron microscopy are labeled. B, cartoon showing a zoomed-in view of the sarcomere within the C-zone. Elements are drawn roughly to scale. Myosin heads in the super relaxed state (SRX) are bound to the thick filament backbone, whereas myosin heads in the disordered relaxed state (DRX) are freed from the backbone. C, schematic structure of myosin in the autoinhibited, interacting heads motif (IHM) associated with the SRX (left and center) and the DRX (right). In the IHM, the blocked head (yellow) interacts with the free head (green). It has been proposed that the IHM is stabilized by cMyBP-C (blue), where phosphorylation of cMyBP-C reduces its interaction with myosin (center). Phosphorylation of the RLC (pink) and mechanical forces each promote the formation of the DRX; however, it is important to note that they are not required for the formation of the DRX. Note that RLC phosphorylation can occur on either one or both of the heads.

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  Figure 3. The myosin mechanochemical cycle and its regulation. For simplicity, only one myosin head is shown. In the super relaxed state (SRX, blue shaded box), myosin is autoinhibited. Force and RLC phosphorylation each promote the adoption of the disordered relaxed state (DRX). The thin filament can lie in the blocked, closed, or open states, where switching between states depends on calcium and myosin binding. In the open state, myosin can bind to and detach from the thin filament in a nucleotide-dependent manner. Bound and detached states are indicated by yellow and red shading, respectively. Force-dependent steps are indicated by red arrows. Mechanical substeps of the working stroke and structural states (pre-power stroke and post-power stroke) are labeled.

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  Figure 4. Pharmacological agents targeting cardiac myosin. Chemical structures, mechanisms, and current clinical trial status of myosin-targeting drugs that treat systolic (blue shading) or diastolic (red shading) dysfunction.