scholarly journals Modulation of Thin Filament Activation of Myosin ATP Hydrolysis by N-Terminal Domains of Cardiac Myosin Binding Protein-C

Biochemistry ◽  
2014 ◽  
Vol 53 (42) ◽  
pp. 6717-6724 ◽  
Author(s):  
Betty Belknap ◽  
Samantha P. Harris ◽  
Howard D. White
Keyword(s):  
Protein C ◽  
Thin Filament ◽  
Atp Hydrolysis ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Filament Activation ◽  
Myosin Binding ◽  
Terminal Domains

scholarly journals N-Terminal Domains of Cardiac Myosin Binding Protein C Cooperatively Activate the Thin Filament

Structure ◽  
2018 ◽  
Vol 26 (12) ◽  
pp. 1604-1611.e4 ◽  
Author(s):  
Cristina Risi ◽  
Betty Belknap ◽  
Eva Forgacs-Lonart ◽  
Samantha P. Harris ◽  
Gunnar F. Schröder ◽  
...  
Keyword(s):  
Protein C ◽  
Thin Filament ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Terminal Domains

scholarly journals Human Cardiac Myosin-Binding Protein C N-Terminal Domains Cooperatively Impact Actin Structural Dynamics

2019 ◽  
Vol 116 (3) ◽  
pp. 266a
Author(s):  
Rhye-Samuel Kanassatega ◽  
Thomas A. Bunch ◽  
Victoria C. Lepak ◽  
Brett A. Colson
Keyword(s):  
Structural Dynamics ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Terminal Domains

scholarly journals C0 and C1 N-terminal Ig domains of myosin binding protein C exert different effects on thin filament activation

2016 ◽  
Vol 113 (6) ◽  
pp. 1558-1563 ◽  
Author(s):  
Samantha P. Harris ◽  
Betty Belknap ◽  
Robert E. Van Sciver ◽  
Howard D. White ◽  
Vitold E. Galkin
Keyword(s):  
Protein C ◽  
Thin Filament ◽  
Molecular Motor ◽  
Binding Protein ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Genes Encoding ◽  
Myosin Subfragment 1 ◽  
Filament Activation ◽  
Myosin Binding

Mutations in genes encoding myosin, the molecular motor that powers cardiac muscle contraction, and its accessory protein, cardiac myosin binding protein C (cMyBP-C), are the two most common causes of hypertrophic cardiomyopathy (HCM). Recent studies established that the N-terminal domains (NTDs) of cMyBP-C (e.g., C0, C1, M, and C2) can bind to and activate or inhibit the thin filament (TF). However, the molecular mechanism(s) by which NTDs modulate interaction of myosin with the TF remains unknown and the contribution of each individual NTD to TF activation/inhibition is unclear. Here we used an integrated structure–function approach using cryoelectron microscopy, biochemical kinetics, and force measurements to reveal how the first two Ig-like domains of cMyPB-C (C0 and C1) interact with the TF. Results demonstrate that despite being structural homologs, C0 and C1 exhibit different patterns of binding on the surface of F-actin. Importantly, C1 but not C0 binds in a position to activate the TF by shifting tropomyosin (Tm) to the “open” structural state. We further show that C1 directly interacts with Tm and traps Tm in the open position on the surface of F-actin. Both C0 and C1 compete with myosin subfragment 1 for binding to F-actin and effectively inhibit actomyosin interactions when present at high ratios of NTDs to F-actin. Finally, we show that in contracting sarcomeres, the activating effect of C1 is apparent only once low levels of Ca2+ have been achieved. We suggest that Ca2+ modulates the interaction of cMyBP-C with the TF in the sarcomere.

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 Revealing the mechanism of how cardiac myosin-binding protein C N-terminal fragments sensitize thin filaments for myosin binding

2019 ◽  
Vol 116 (14) ◽  
pp. 6828-6835 ◽  
Author(s):  
Alessio V. Inchingolo ◽  
Samantha Beck Previs ◽  
Michael J. Previs ◽  
David M. Warshaw ◽  
Neil M. Kad
Keyword(s):  
Protein C ◽  
Thin Filament ◽  
Binding Protein ◽  
Binding Mode ◽  
Cardiac Myosin ◽  
Thin Filaments ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Low Calcium ◽  
Myosin Binding

Cardiac muscle contraction is triggered by calcium binding to troponin. The consequent movement of tropomyosin permits myosin binding to actin, generating force. Cardiac myosin-binding protein C (cMyBP-C) plays a modulatory role in this activation process. One potential mechanism for the N-terminal domains of cMyBP-C to achieve this is by binding directly to the actin-thin filament at low calcium levels to enhance the movement of tropomyosin. To determine the molecular mechanisms by which cMyBP-C enhances myosin recruitment to the actin-thin filament, we directly visualized fluorescently labeled cMyBP-C N-terminal fragments and GFP-labeled myosin molecules binding to suspended actin-thin filaments in a fluorescence-based single-molecule microscopy assay. Binding of the C0C3 N-terminal cMyBP-C fragment to the thin filament enhanced myosin association at low calcium levels. However, at high calcium levels, C0C3 bound in clusters, blocking myosin binding. Dynamic imaging of thin filament-bound Cy3-C0C3 molecules demonstrated that these fragments diffuse along the thin filament before statically binding, suggesting a mechanism that involves a weak-binding mode to search for access to the thin filament and a tight-binding mode to sensitize the thin filament to calcium, thus enhancing myosin binding. Although shorter N-terminal fragments (Cy3-C0C1 and Cy3-C0C1f) bound to the thin filaments and displayed modes of motion on the thin filament similar to that of the Cy3-C0C3 fragment, the shorter fragments were unable to sensitize the thin filament. Therefore, the longer N-terminal fragment (C0C3) must possess the requisite domains needed to bind specifically to the thin filament in order for the cMyBP-C N terminus to modulate cardiac contractility.

scholarly journals Structure, sarcomeric organization, and thin filament binding of cardiac myosin-binding protein-C

2014 ◽  
Vol 466 (3) ◽  
pp. 425-431 ◽  
Author(s):  
Roger Craig ◽  
Kyoung Hwan Lee ◽  
Ji Young Mun ◽  
Iratxe Torre ◽  
Pradeep K. Luther
Keyword(s):  
Protein C ◽  
Thin Filament ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding
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