scholarly journals Myosin filament-based regulation of the dynamics of contraction in heart muscle

2020 ◽  
Vol 117 (14) ◽  
pp. 8177-8186 ◽  
Author(s):  
Elisabetta Brunello ◽  
Luca Fusi ◽  
Andrea Ghisleni ◽  
So-Jin Park-Holohan ◽  
Jesus G. Ovejero ◽  
...  
Keyword(s):  
Heart Muscle ◽  
Time Course ◽  
Myosin Filament ◽  
X Ray Diffraction ◽  
X Ray ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Stress Sensing ◽  
Myosin Motors

Myosin-based mechanisms are increasingly recognized as supplementing their better-known actin-based counterparts to control the strength and time course of contraction in both skeletal and heart muscle. Here we use synchrotron small-angle X-ray diffraction to determine the structural dynamics of local domains of the myosin filament during contraction of heart muscle. We show that, although myosin motors throughout the filament contribute to force development, only about 10% of the motors in each filament bear the peak force, and these are confined to the filament domain containing myosin binding protein-C, the “C-zone.” Myosin motors in domains further from the filament midpoint are likely to be activated and inactivated first in each contraction. Inactivated myosin motors are folded against the filament core, and a subset of folded motors lie on the helical tracks described previously. These helically ordered motors are also likely to be confined to the C-zone, and the associated motor conformation reforms only slowly during relaxation. Myosin filament stress-sensing determines the strength and time course of contraction in conjunction with actin-based regulation. These results establish the fundamental roles of myosin filament domains and the associated motor conformations in controlling the strength and dynamics of contraction in heart muscle, enabling those structures to be targeted to develop new therapies for heart disease.

scholarly journals Four and a Half LIM Protein 1 Binds Myosin-binding Protein C and Regulates Myosin Filament Formation and Sarcomere Assembly

2006 ◽  
Vol 281 (11) ◽  
pp. 7666-7683 ◽  
Author(s):  
Meagan J. McGrath ◽  
Denny L. Cottle ◽  
Mai-Anh Nguyen ◽  
Jennifer M. Dyson ◽  
Imogen D. Coghill ◽  
...  
Keyword(s):  
Protein C ◽  
Binding Protein ◽  
Myosin Filament ◽  
Filament Formation ◽  
Lim Protein ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Sarcomere Assembly

Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle

2010 ◽  
Vol 49 (6) ◽  
pp. 1003-1011 ◽  
Author(s):  
O'Neal Copeland ◽  
Sakthivel Sadayappan ◽  
Andrew E. Messer ◽  
Ger J.M. Steinen ◽  
Jolanda van der Velden ◽  
...  
Keyword(s):  
Heart Muscle ◽  
Protein C ◽  
Human Heart ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals Structural and functional effects of myosin-binding protein-C phosphorylation in heart muscle are not mimicked by serine-to-aspartate substitutions

2018 ◽  
Vol 293 (37) ◽  
pp. 14270-14275 ◽  
Author(s):  
Thomas Kampourakis ◽  
Saraswathi Ponnam ◽  
Yin-Biao Sun ◽  
Ivanka Sevrieva ◽  
Malcolm Irving
Keyword(s):  
Heart Muscle ◽  
Protein C ◽  
Binding Protein ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals New X-ray Data about Myosin-binding Protein C in Frog Muscle

2009 ◽  
Vol 96 (3) ◽  
pp. 616a ◽  
Author(s):  
Hugh Huxley ◽  
Massimo Reconditi ◽  
Tom Irving
Keyword(s):  
Protein C ◽  
Binding Protein ◽  
Frog Muscle ◽  
X Ray ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals Myosin Binding Protein-C Forms Amyloid-Like Aggregates In Vitro

2021 ◽  
Vol 22 (2) ◽  
pp. 731
Author(s):  
Liya G. Bobyleva ◽  
Sergey A. Shumeyko ◽  
Elmira I. Yakupova ◽  
Alexey K. Surin ◽  
Oxana V. Galzitskaya ◽  
...  
Keyword(s):  
Protein C ◽  
Quaternary Structure ◽  
Binding Protein ◽  
Structural Features ◽  
X Ray ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

This work investigated in vitro aggregation and amyloid properties of skeletal myosin binding protein-C (sMyBP-C) interacting in vivo with proteins of thick and thin filaments in the sarcomeric A-disc. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) found a rapid (5–10 min) formation of large (>2 μm) aggregates. sMyBP-C oligomers formed both at the initial 5–10 min and after 16 h of aggregation. Small angle X-ray scattering (SAXS) and DLS revealed sMyBP-C oligomers to consist of 7–10 monomers. TEM and atomic force microscopy (AFM) showed sMyBP-C to form amorphous aggregates (and, to a lesser degree, fibrillar structures) exhibiting no toxicity on cell culture. X-ray diffraction of sMyBP-C aggregates registered reflections attributed to a cross-β quaternary structure. Circular dichroism (CD) showed the formation of the amyloid-like structure to occur without changes in the sMyBP-C secondary structure. The obtained results indicating a high in vitro aggregability of sMyBP-C are, apparently, a consequence of structural features of the domain organization of proteins of this family. Formation of pathological amyloid or amyloid-like sMyBP-C aggregates in vivo is little probable due to amino-acid sequence low identity (<26%), alternating ordered/disordered regions in the protein molecule, and S–S bonds providing for general stability.

scholarly journals In the eye of the STORM: Tracking the myosin-binding protein C N terminus in heart muscle

2021 ◽  
Vol 153 (3) ◽  
Author(s):  
Brett A. Colson
Keyword(s):  
Cardiac Muscle ◽  
Heart Muscle ◽  
Protein C ◽  
Binding Protein ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Storm Tracking ◽  
N Terminus ◽  
Myosin Binding

Colson discusses a recent investigation of the localization of N-terminal myosin-binding protein C in cardiac muscle.

scholarly journals Inotropic interventions do not change the resting state of myosin motors during cardiac diastole

2018 ◽  
Vol 151 (1) ◽  
pp. 53-65 ◽  
Author(s):  
Marco Caremani ◽  
Francesca Pinzauti ◽  
Joseph D. Powers ◽  
Serena Governali ◽  
Theyencheri Narayanan ◽  
...  
Keyword(s):  
Protein C ◽  
Thin Filament ◽  
Sarcomere Length ◽  
Binding Protein ◽  
Thick Filament ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Filament Activation ◽  
Myosin Binding ◽  
Myosin Motors

When striated (skeletal and cardiac) muscle is in its relaxed state, myosin motors are packed in helical tracks on the surface of the thick filament, folded toward the center of the sarcomere, and unable to bind actin or hydrolyze ATP (OFF state). This raises the question of whatthe mechanism is that integrates the Ca2+-dependent thin filament activation, making myosin heads available for interaction with actin. Here we test the interdependency of the thin and thick filament regulatory mechanisms in intact trabeculae from the rat heart. We record the x-ray diffraction signals that mark the state of the thick filament during inotropic interventions (increase in sarcomere length from 1.95 to 2.25 µm and addition of 10−7 M isoprenaline), which potentiate the twitch force developed by an electrically paced trabecula by up to twofold. During diastole, none of the signals related to the OFF state of the thick filament are significantly affected by these interventions, except the intensity of both myosin-binding protein C– and troponin-related meridional reflections, which reduce by 20% in the presence of isoprenaline. These results indicate that recruitment of myosin motors from their OFF state occurs independently and downstream from thin filament activation. This is in agreement with the recently discovered mechanism based on thick filament mechanosensing in which the number of motors available for interaction with actin rapidly adapts to the stress on the thick filament and thus to the loading conditions of the contraction. The gain of this positive feedback may be modulated by both sarcomere length and the degree of phosphorylation of myosin-binding protein C.

scholarly journals Knockdown of fast skeletal myosin-binding protein C in zebrafish results in a severe skeletal myopathy

2016 ◽  
Vol 147 (4) ◽  
pp. 309-322 ◽  
Author(s):  
Mei Li ◽  
Monika Andersson-Lendahl ◽  
Thomas Sejersen ◽  
Anders Arner
Keyword(s):  
Small Angle ◽  
Intensity Ratio ◽  
Protein C ◽  
X Ray ◽  
Cross Bridge ◽  
Skeletal Myopathy ◽  
X Ray Scattering ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Myosin-binding protein C (MyBPC) in the muscle sarcomere interacts with several contractile and structural proteins. Mutations in the cardiac isoform (MyBPC-3) in humans, or animal knockout, are associated with cardiomyopathy. Function of the fast skeletal isoform (MyBPC-2) in living muscles is less understood. This question was addressed using zebrafish models, combining gene expression data with functional analysis of contractility and small-angle x-ray diffraction measurements of filament structure. Fast skeletal MyBPC-2B, the major isoform, was knocked down by &gt;50% using morpholino antisense nucleotides. These morphants exhibited a skeletal myopathy with elevated apoptosis and up-regulation of factors associated with muscle protein degradation. Morphant muscles had shorter sarcomeres with a broader length distribution, shorter actin filaments, and a wider interfilament spacing compared with controls, suggesting that fast skeletal MyBPC has a role in sarcomere assembly. Active force was reduced more than expected from the decrease in muscle size, suggesting that MyBPC-2 is required for optimal force generation at the cross-bridge level. The maximal shortening velocity was significantly increased in the MyBPC-2 morphants, but when related to the sarcomere length, the difference was smaller, reflecting that the decrease in MyBPC-2B content and the resulting myopathy were accompanied by only a minor influence on filament shortening kinetics. In the controls, equatorial patterns from small-angle x-ray scattering revealed that comparatively few cross-bridges are attached (as evaluated by the intensity ratio of the 11 and 10 equatorial reflections) during active contraction. X-ray scattering data from relaxed and contracting morphants were not significantly different from those in controls. However, the increase in the 11:10 intensity ratio in rigor was lower compared with that in controls, possibly reflecting effects of MyBPC on the cross-bridge interactions. In conclusion, lack of MyBPC-2 results in a severe skeletal myopathy with structural changes and muscle weakness.

scholarly journals The N terminus of myosin-binding protein C extends toward actin filaments in intact cardiac muscle

2021 ◽  
Vol 153 (3) ◽  
Author(s):  
Sheema Rahmanseresht ◽  
Kyoung H. Lee ◽  
Thomas S. O’Leary ◽  
James W. McNamara ◽  
Sakthivel Sadayappan ◽  
...  
Keyword(s):  
Actin Filaments ◽  
Protein C ◽  
Myosin Head ◽  
Binding Protein ◽  
Myosin Filament ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
N Terminus ◽  
Myosin Binding ◽  
Terminal Domains

Myosin and actin filaments are highly organized within muscle sarcomeres. Myosin-binding protein C (MyBP-C) is a flexible, rod-like protein located within the C-zone of the sarcomere. The C-terminal domain of MyBP-C is tethered to the myosin filament backbone, and the N-terminal domains are postulated to interact with actin and/or the myosin head to modulate filament sliding. To define where the N-terminal domains of MyBP-C are localized in the sarcomere of active and relaxed mouse myocardium, the relative positions of the N terminus of MyBP-C and actin were imaged in fixed muscle samples using super-resolution fluorescence microscopy. The resolution of the imaging was enhanced by particle averaging. The images demonstrate that the position of the N terminus of MyBP-C is biased toward the actin filaments in both active and relaxed muscle preparations. Comparison of the experimental images with images generated in silico, accounting for known binding partner interactions, suggests that the N-terminal domains of MyBP-C may bind to actin and possibly the myosin head but only when the myosin head is in the proximity of an actin filament. These physiologically relevant images help define the molecular mechanism by which the N-terminal domains of MyBP-C may search for, and capture, molecular binding partners to tune cardiac contractility.

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