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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.

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


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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