Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes
AuthorMcNamara, James W.
Smith, Nicola J.
Graham, Robert M.
Kooiker, Kristina Bezold
van Dijk, Sabine J.
Remedios, Cristobal G. dos
Harris, Samantha P.
AffiliationUniv Arizona, Dept Cellular & Mol Med
Myosin binding protein-C (MyBP-C)
Myosin II ATPase
Thick filament structure
MetadataShow full item record
PublisherELSEVIER SCI LTD
CitationAblation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes 2016, 94:65 Journal of Molecular and Cellular Cardiology
RightsCrown Copyright © 2016 Published by Elsevier Ltd. All rights reserved.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractCardiac myosin binding protein-C (cMyBP-C) is a structural and regulatory component of cardiac thick filaments. It is observed in electron micrographs as seven to nine transverse stripes in the central portion of each half of the A band. Its C-terminus binds tightly to the myosin rod and contributes to thick filament structure, while the N-terminus can bind both myosin S2 and actin, influencing their structure and function. Mutations in the MYBPC3 gene (encoding cMyBP-C) are commonly associated with hypertrophic cardiomyopathy (HCM). In cardiac cells there exists a population of myosin heads in the super-relaxed (SRX) state, which are bound to the thick filament core with a highly inhibited ATPase activity. This report examines the role cMyBP-C plays in regulating the population of the SRX state of cardiac myosin by using an assay that measures single ATP turnover of myosin. We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type. A smaller, non-significant decrease is observed when thoracic aortic constriction is used to induce cardiac hypertrophy in mutation negative mice. These results support the proposal that cMyBP-C stabilises the thick filament and that the loss of cMyBP-C results in an untethering of myosin heads. This results in an increased myosin ATP turnover, further consolidating the relationship between thick filament structure and the myosin ATPase. Crown Copyright (C) 2016 Published by Elsevier Ltd. All rights reserved.
NoteAvailable online 26 March 2016. 12 month embargo.
VersionFinal accepted manuscript
SponsorsNG Macintosh Memorial Fund; National Heart Foundation [GNT1093852, PB 12S 6939]; NIH [R01 HL080367]; American Heart Association [13POST14780089]
- MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy.
- Authors: McNamara JW, Li A, Lal S, Bos JM, Harris SP, van der Velden J, Ackerman MJ, Cooke R, Dos Remedios CG
- Issue date: 2017
- Cardiac myosin binding protein-C phosphorylation regulates the super-relaxed state of myosin.
- Authors: McNamara JW, Singh RR, Sadayappan S
- Issue date: 2019 Jun 11
- E258K HCM-causing mutation in cardiac MyBP-C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP-C and myosin S2 interaction.
- Authors: De Lange WJ, Grimes AC, Hegge LF, Spring AM, Brost TM, Ralphe JC
- Issue date: 2013 Sep
- Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments.
- Authors: Kensler RW, Craig R, Moss RL
- Issue date: 2017 Feb 21
- Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy.
- Authors: Kuster DWD, Lynch TL, Barefield DY, Sivaguru M, Kuffel G, Zilliox MJ, Lee KH, Craig R, Namakkal-Soorappan R, Sadayappan S
- Issue date: 2019 Dec 1