Familial hypertrophic cardiomyopathy (FHC) is an inherited autosomal dominant disease caused by mutations in sarcomeric proteins. Among these, that affect myosin binding protein-C (MyBP-C), abundant component of the thick filaments, account for 20% to 30% all linked FHC. However, mechanisms which MyBP-C cause and function are not well understood. Therefore, assess deficits due elimination MyBP-C, we used gene targeting produce a knockout mouse lacks heart. Knockout mice were produced...

Cardiac myosin-binding protein C (cMyBP-C) is a regulatory expressed in cardiac sarcomeres that known to interact with myosin, titin, and actin. cMyBP-C modulates actomyosin interactions phosphorylation-dependent way, but it unclear whether or actin are required for these effects. Here we show using cosedimentation binding assays, the 4 N-terminal domains of murine (i.e. C0-C1-m-C2) bind F-actin dissociation constant (Kd) ∼10 μm molar ratio (Bmax) near 1.0, indicating 1:1 (mol/mol) Electron...

The "super-relaxed state" (SRX) of myosin represents a 'reserve' motors in the heart. Myosin heads SRX are bound to thick filament and have very low ATPase rate. Changes likely modulate cardiac contractility. We previously demonstrated that is significantly reduced mouse cardiomyocytes lacking binding protein–C (cMyBP-C). Here, we report effect mutations cMyBP-C gene (MYBPC3) using samples from human patients with hypertrophic cardiomyopathy (HCM). Left ventricular (LV) 11 HCM were obtained...

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening left ventricle. Left ventricular outflow tract (LVOT) obstruction present in approximately two-thirds patients and substantially increases risk complications. Invasive treatment with septal myectomy or alcohol ablation can improve symptoms functional status, but currently available drugs for reducing have pleiotropic effects variable therapeutic responses. New...

Abstract Muscle contraction is produced via the interaction of myofilaments and regulated so that muscle performance matches demand. Myosin-binding protein C (MyBP-C) a long flexible tightly bound to thick filament at its C-terminal end (MyBP-C C8C10 ), but may be loosely middle- N-terminal C1C7 ) myosin heads and/or thin filament. MyBP-C thought control regulation motors, as mutations lead debilitating disease. We use combination mechanics small-angle X-ray diffraction study immediate...

Myosin binding protein-C (MyBP-C) is localized to the thick filaments of striated muscle where it appears have both structural and regulatory functions. Importantly, mutations in cardiac MyBP-C gene are associated with familial hypertrophic cardiomyopathy. The purpose this study was examine role that plays regulating force, power output, force development rates myocytes. Skinned myocytes from wild-type (WT) knockout (MyBP-C-/-) mice were attached between a transducer position motor. Force,...

Myosin binding protein-C (MyBP-C) is a thick-filament protein whose precise function within the sarcomere not known. However, recent evidence from cMyBP-C knock-out mice that lack MyBP-C in heart suggest normally slows cross-bridge cycling rates and reduces myocyte power output. To investigate possible mechanisms by which limits kinetics we assessed effects of recombinant N-terminal domains on ability heavy meromyosin (HMM) to support movement actin filaments using vitro motility assays....

Myosin binding protein C (MyBP-C) is a component of the thick filament striated muscle. The importance this revealed by recent evidence that mutations in cardiac gene are major cause familial hypertrophic cardiomyopathy. Here we investigate distribution MyBP-C A-bands and skeletal muscles compare to A-band structure muscle MyBP-C-deficient mice. We have used novel averaging technique obtain axial density electron micrographs well-preserved specimens. show very similar, with length 1.58 ±...

Cardiac myosin-binding protein C (cMyBP-C) is an accessory of striated muscle sarcomeres that vital for maintaining regular heart function. Its 4 N-terminal regulatory domains, C0-C1-m-C2 (C0C2), influence actin and myosin interactions, the basic contractile proteins muscle. Using neutron contrast variation data, we have determined C0C2 forms a repeating assembly with filamentous actin, where C0 C1 domains attach near DNase I-binding loop subdomain 1 adjacent monomers. Direct interactions...

Despite advances in the molecular biology of cardiac myosin binding protein-C (cMyBP-C), little is understood about its precise role muscle contraction, particularly intact heart. We tested hypothesis that cMyBP-C central to time course and magnitude left ventricular systolic elastance (chamber stiffening), assessed mechanisms for this influence hearts, trabeculae, skinned fibers from wild-type (+/+) homozygous truncated (t/t) male mice. protein was not detected by gel electrophoresis or...

Cardiac myosin binding protein-C (cMyBP-C) is a large multidomain accessory protein bound to thick filaments in striated muscle sarcomeres. It plays an important role the regulation of contraction, and mutations gene encoding cMyBP-C are common cause familial hypertrophic cardiomyopathy, leading sudden cardiac death young people. (1) The N-terminal domains including C0, C1, motif, C2 play crucial maintaining modulating actomyosin interactions (keeping normal function)...

Mutations in genes encoding myosin, the molecular motor that powers cardiac muscle contraction, and its accessory protein, myosin binding protein C (cMyBP-C), are two most common causes of hypertrophic cardiomyopathy (HCM). Recent studies established N-terminal domains (NTDs) cMyBP-C (e.g., C0, C1, M, C2) can bind to activate or inhibit thin filament (TF). However, mechanism(s) by which NTDs modulate interaction with TF remains unknown contribution each individual NTD activation/inhibition...

Abstract Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease in humans and cats lacks efficacious pharmacologic interventions preclinical phase of disease. LV outflow tract obstruction (LVOTO) commonly observed HCM-affected patients a primary driver heart failure symptoms reduced quality life. Novel small-molecule myosin inhibitors target actin-myosin interactions to alleviate overactive protein interactions. A prospective, randomized, controlled cross-over...

ABSTRACT Both Na+/H+ exchange and the electrogenic extrusion of H+via an H+-ATPase have been postulated to drive acid excretion across branchial epithelium fishes. While H+-ATPase/Na+ channel system appears be predominant mechanism in some freshwater species, it may play a reduced role seawater brackish-water animals, where high external Na+ concentrations thermodynamically favor driven by antiporter (NHE). In this study, we used molecular immunological methods assess NHE isoforms marine...

Mutations in the cardiac myosin binding protein-C gene (cMyBP-C) are among most prevalent causes of inherited hypertrophic cardiomyopathy. Although cMyBP-C mutations cause reading frameshifts that predicted to encode truncated peptides, it is not known if or how expression these peptides disease. One possibility because N-terminus contains a unique site for S2 subfragment myosin, shortened could directly affect contraction by S2. To test this hypothesis, we compared effects C1C2 protein...

cMyBP-C (cardiac myosin-binding protein-C) is a critical regulator of heart contraction, but the mechanisms by which affects actin and myosin are only partly understood. A primary obstacle that localization on thick filaments may be key factor defining its interactions, most in vitro studies cannot duplicate unique spatial arrangement within sarcomere.The goal this study was to validate novel hybrid genetic/protein engineering approach for rapid manipulation sarcomeres situ.We designed cut...

Myosin-binding protein C (MyBP-C) is a critical regulator of muscle performance that was first identified through its strong binding interactions with myosin, the force-generating muscle. Almost simultaneously discovery, MyBP-C soon found to bind actin, physiological catalyst for myosin's activity. However, two observations posed an apparent paradox, in part because myosin were on thick filament, whereas actin thin filament. Despite intervening decades since these initial discoveries, it...