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Sci Rep. 2018 Feb 8;8(1):2604. doi: 10.1038/s41598-018-21053-1.

Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner.

Author information

1
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL, 60153, USA.
2
Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT, 05405, USA.
3
Bosch Institute, Discipline of Anatomy and Histology, University of Sydney, Sydney, 2006, Australia.
4
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
5
Department of Structure and Function of Neural Network, Korea Brain Research Institute, Dong-gu, Daegu, Korea.
6
Departments of Biomedical Engineering and Cellular and Molecular Physiology, Yale University, New Haven, CT, 06520, USA.
7
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL, 60153, USA. sadayasl@ucmail.uc.edu.

Abstract

Muscle contraction, which is initiated by Ca2+, results in precise sliding of myosin-based thick and actin-based thin filament contractile proteins. The interactions between myosin and actin are finely tuned by three isoforms of myosin binding protein-C (MyBP-C): slow-skeletal, fast-skeletal, and cardiac (ssMyBP-C, fsMyBP-C and cMyBP-C, respectively), each with distinct N-terminal regulatory regions. The skeletal MyBP-C isoforms are conditionally coexpressed in cardiac muscle, but little is known about their function. Therefore, to characterize the functional differences and regulatory mechanisms among these three isoforms, we expressed recombinant N-terminal fragments and examined their effect on contractile properties in biophysical assays. Addition of the fragments to in vitro motility assays demonstrated that ssMyBP-C and cMyBP-C activate thin filament sliding at low Ca2+. Corresponding 3D electron microscopy reconstructions of native thin filaments suggest that graded shifts of tropomyosin on actin are responsible for this activation (cardiac > slow-skeletal > fast-skeletal). Conversely, at higher Ca2+, addition of fsMyBP-C and cMyBP-C fragments reduced sliding velocities in the in vitro motility assays and increased force production in cardiac muscle fibers. We conclude that due to the high frequency of Ca2+ cycling in cardiac muscle, cardiac MyBP-C may play dual roles at both low and high Ca2+. However, skeletal MyBP-C isoforms may be tuned to meet the needs of specific skeletal muscles.

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