Faculty Collaboration Database

Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca²⁺-dependent manner. Sci Rep 2018 Feb 08;8(1):2604

Date

02/10/2018

Pubmed ID

29422607

Pubmed Central ID

PMC5805719

DOI

10.1038/s41598-018-21053-1

Scopus ID

2-s2.0-85041809111 (requires institutional sign-in at Scopus site)   30 Citations

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.

Author List

Lin BL, Li A, Mun JY, Previs MJ, Previs SB, Campbell SG, Dos Remedios CG, Tombe PP, Craig R, Warshaw DM, Sadayappan S

Author

Brian L. Lin PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Actins
Animals
Calcium
Carrier Proteins
Male
Muscle Contraction
Muscle, Skeletal
Myocardial Contraction
Myocardium
Protein Isoforms
Rats, Sprague-Dawley
Recombinant Proteins
Tropomyosin