Department of Cell and Developmental Biology; Department of Radiology; Craig Lab
Biochemistry | Cell Biology | Cellular and Molecular Physiology
Muscle contraction, which is initiated by Ca(2+), 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 Ca(2+). 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 Ca(2+), 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 Ca(2+) cycling in cardiac muscle, cardiac MyBP-C may play dual roles at both low and high Ca(2+). However, skeletal MyBP-C isoforms may be tuned to meet the needs of specific skeletal muscles.
Atomic force microscopy, Muscle contraction
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DOI of Published Version
Sci Rep. 2018 Feb 8;8(1):2604. doi: 10.1038/s41598-018-21053-1. Link to article on publisher's site
Lin, Brian Leei; Li, Amy; Mun, Ji Young; Previs, Michael J.; Previs, Samantha Beck.; Campbell, Stuart G.; Dos Remedios, Cristobal G.; P. Tombe, Pieter de; Craig, Roger; Warshaw, David M.; and Sadayappan, Sakthivel, "Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca(2+)-dependent manner" (2018). Radiology Publications and Presentations. 381.
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This work is licensed under a Creative Commons Attribution 4.0 License.