Cardiac myosin-binding protein C: hypertrophic cardiomyopathy mutations and structure–function relationships

Sequeira, Vasco; Witjas-Paalberends, E. Rosalie; Kuster, Diederik W.D.; Velden, Jolanda van der

doi:10.1007/s00424-013-1400-3

Cited by 24 publications

(27 citation statements)

References 70 publications

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“…In vivo , phosphorylation occurs in r o to β-adrenergic stimulation, enhancing cardiac contractility 4; 8; 9; 10; 11; 12 . Mutations in cMyBP-C are one of the most common causes of inherited hypertrophic cardiomyopathy (HCM) 3; 13 , and alterations in cMyBP-C phosphorylation levels have been implicated in heart failure and HCM 14 .…”

Section: Introductionmentioning

confidence: 99%

Orientation of Myosin Binding Protein C in the Cardiac Muscle Sarcomere Determined by Domain-Specific Immuno-EM

Lee

Harris

Sadayappan

et al. 2015

Journal of Molecular Biology

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Myosin binding protein-C is a thick filament protein of vertebrate striated muscle. The cardiac isoform (cMyBP-C) is essential for normal cardiac function, and mutations in cMyBP-C cause cardiac muscle disease. The rod-shaped molecule is composed primarily of 11 immunoglobulin- or fibronectin-like domains, and is located at 9 sites, 43 nm apart, in each half of the A-band. To understand how cMyBP-C functions, it is important to know its structural organization in the sarcomere, as this will affect its ability to interact with other sarcomeric proteins. Several models have been proposed, in which cMyBP-C wraps around, extends radially from, or runs axially along the thick filament. Our goal was to define cMyBP-C orientation by determining the relative axial positions of different cMyBP-C domains. Immuno-electron microscopy was performed using mouse cardiac myofibrils labeled with antibodies specific to the N- and C-terminal domains and to the middle of cMyBP-C. Antibodies to all regions of the molecule, except the C-terminus, labeled at the same nine axial positions in each half A-band, consistent with a circumferential and/or radial rather than an axial orientation of the bulk of the molecule. The C-terminal antibody stripes were slightly displaced axially, demonstrating an axial orientation of the C-terminal 3 domains, with the C-terminus closer to the M-line. These results, combined with previous studies, suggest that the C-terminal domains of cMyBP-C run along the thick filament surface, while the N-terminus extends towards neighboring thin filaments. This organization provides a structural framework for understanding cMyBP-C’s modulation of cardiac muscle contraction.

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Section: Introductionmentioning

confidence: 99%

Orientation of Myosin Binding Protein C in the Cardiac Muscle Sarcomere Determined by Domain-Specific Immuno-EM

Lee

Harris

Sadayappan

et al. 2015

Journal of Molecular Biology

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“…These mechanochemical regulatory processes are fine-tuned by proteins within the thick filament, including cardiac myosin-binding protein C (cMyBP-C). Although cMyBP-C is not essential for cardiac contractility, its importance in contractile function is evidenced by mutations in the MYBPC3 gene being a leading cause of inherited hypertrophic cardiomyopathy (1,2). Because of the prevalence of this disease (affecting 1 in 500 people) and the potential for therapeutic intervention, much work during the last two decades has focused on defining cMyBP-C's structure and function within the sarcomere (3).…”

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confidence: 99%

Phosphorylation and calcium antagonistically tune myosin-binding protein C’s structure and function

Previs

Mun

Michalek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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During each heartbeat, cardiac contractility results from calcium-activated sliding of actin thin filaments toward the centers of myosin thick filaments to shorten cellular length. Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filament that appears to tune these mechanochemical interactions by its N-terminal domains transiently interacting with actin and/or the myosin S2 domain, sensitizing thin filaments to calcium and governing maximal sliding velocity. Both functional mechanisms are potentially further tunable by phosphorylation of an intrinsically disordered, extensible region of cMyBP-C’s N terminus, the M-domain. Using atomic force spectroscopy, electron microscopy, and mutant protein expression, we demonstrate that phosphorylation reduced the M-domain’s extensibility and shifted the conformation of the N-terminal domain from an extended structure to a compact configuration. In combination with motility assay data, these structural effects of M-domain phosphorylation suggest a mechanism for diminishing the functional potency of individual cMyBP-C molecules. Interestingly, we found that calcium levels necessary to maximally activate the thin filament mitigated the structural effects of phosphorylation by increasing M-domain extensibility and shifting the phosphorylated N-terminal fragments back to the extended state, as if unphosphorylated. Functionally, the addition of calcium to the motility assays ablated the impact of phosphorylation on maximal sliding velocities, fully restoring cMyBP-C’s inhibitory capacity. We conclude that M-domain phosphorylation may have its greatest effect on tuning cMyBP-C’s calcium-sensitization of thin filaments at the low calcium levels between contractions. Importantly, calcium levels at the peak of contraction would allow cMyBP-C to remain a potent contractile modulator, regardless of cMyBP-C’s phosphorylation state.

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“…Due to an ancient founder mutation, 4% of the population of India carries a truncating MYBPC3 mutation (14,15). The majority of cardiac MYBPC3 mutations are predicted to encode truncated proteins that lack portions of either the carboxyl myosin and/or titin binding domains (7,13). These truncating MYBPC3 mutations are thought to cause cardiac hypertrophy by inducing myocyte hypertrophy (increased cell size), rather than myocyte hyperplasia.…”

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confidence: 99%

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

Jiang

Burgon

Wakimoto

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Homozygous cardiac myosin binding protein C-deficient (Mybpc t/t ) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold. We have investigated the mechanism of cardiac enlargement in these hearts. Throughout embryogenesis myocytes undergo cell division while maintaining the capacity to pump blood by rapidly disassembling and reforming myofibrillar components of the sarcomere throughout cell cycle progression. Shortly after birth, myocyte cell division ceases. Cardiac MYBPC is a thick filament protein that regulates sarcomere organization and rigidity. We demonstrate that many Mybpc t/t myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes. Short-hairpin RNA knockdown of Mybpc3 mRNA in wild-type mice similarly extended the postnatal window of myocyte proliferation. However, adult Mybpc t/t myocytes are unable to fully regenerate the myocardium after injury. MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression. We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc t/t mice. Human patients, with heterozygous truncating MYBPC3 mutations, like mice with similar mutations, have hypertrophic cardiomyopathy. However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3 +/− individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3 −/− mice is primarily myocyte hyperplasia.myosin binding protein C | cardiac dilation | cardiac hypertrophy | cytokinesis | hyperplasia

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Cardiac myosin-binding protein C: hypertrophic cardiomyopathy mutations and structure–function relationships

Cited by 24 publications

References 70 publications

Orientation of Myosin Binding Protein C in the Cardiac Muscle Sarcomere Determined by Domain-Specific Immuno-EM

Orientation of Myosin Binding Protein C in the Cardiac Muscle Sarcomere Determined by Domain-Specific Immuno-EM

Phosphorylation and calcium antagonistically tune myosin-binding protein C’s structure and function

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

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