Abstract
Cardiac ventricular myosin (βmys) translates actin by transducing ATP free energy into mechanical work during muscle contraction. Unitary βmys translation of actin is the step-size. In vitro and in vivo βmys regulates contractile force and velocity autonomously by remixing three different step-sizes with adaptive stepping frequencies. Cardiac and skeletal actin isoforms have a specific 1 : 4 stoichiometry in normal adult human ventriculum. Human adults with inheritable hypertrophic cardiomyopathy (HCM) upregulate skeletal actin in ventriculum probably compensating the diseased muscle's inability to meet demand by adjusting βmys force–velocity characteristics. βmys force–velocity characteristics were compared for skeletal versus cardiac actin substrates using ensemble in vitro motility and single myosin assays. Two competing myosin strain-sensitive mechanisms regulate step-size choices dividing single βmys mechanics into low- and high-force regimes. The actin isoforms alter myosin strain-sensitive regulation such that onset of the high-force regime, where a short step-size is a large or major contributor, is offset to higher loads probably by the unique cardiac essential light chain (ELC) N-terminus/cardiac actin contact at Glu6/Ser358. It modifies βmys force–velocity by stabilizing the ELC N-terminus/cardiac actin association. Uneven onset of the high-force regime for skeletal versus cardiac actin modulates force–velocity characteristics as skeletal/cardiac actin fractional content increases in diseased muscle.
Highlights
Cardiac myosin has a 140 kDa N-terminal globular head called subfragment 1 (S1) and an extended a-helical tail domain
We find substantial differences in bmys ensemble force–velocity characteristics due to the different actin substrates that are linked to a molecular mechanism involving the S358/E6 interaction specific to cardiac muscle by using single myosin mechanical characteristics measured with the Qdot assay
We propose that the cardiac actin impact on cardiac myosin load sensitivity is from the unique and specific actin/essential light chain (ELC) N-terminus contact at S358/E6
Summary
Cardiac myosin has a 140 kDa N-terminal globular head called subfragment 1 (S1) and an extended a-helical tail domain. S1 has the ATP and actin-binding sites (the motor) and a lever arm whose rotary movement cyclically applies tension to move a load when myosin is strongly actin bound [3]. The approximately 20 kDa RLC stabilizes the lever arm [10,11,12] and disease implicated RLC mutants lower velocity, force and strain sensitivity [13] suggesting they alter lever arm processing of shear stress [14,15]. The approximately 25 kDa skeletal myosin ELC (A1) has an N-terminus extension containing sites for ELC/actin binding localized in the N-terminal fragment
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