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Nat Struct Mol Biol. 2018 Jun;25(6):505-514. doi: 10.1038/s41594-018-0069-x. Epub 2018 Jun 4.

Controlling load-dependent kinetics of β-cardiac myosin at the single-molecule level.

Author information

1
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. liuchao@stanford.edu.
2
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
3
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
4
Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA, USA.
5
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. jspudich@stanford.edu.

Abstract

Concepts in molecular tension sensing in biology are growing and have their origins in studies of muscle contraction. In the heart muscle, a key parameter of contractility is the detachment rate of myosin from actin, which determines the time that myosin is bound to actin in a force-producing state and, importantly, depends on the load (force) against which myosin works. Here we measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds. Our results suggest that activating versus inhibitory perturbations of cardiac myosin are discriminated by the aggregate result on duty ratio, average force, and ultimately average power output and suggest that cardiac contractility can be controlled by tuning the load-dependent kinetics of single myosin molecules.

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