scholarly journals Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin

Cell Reports ◽  
2016 ◽  
Vol 17 (11) ◽  
pp. 2857-2864 ◽  
Author(s):  
Arjun S. Adhikari ◽  
Kristina B. Kooiker ◽  
Saswata S. Sarkar ◽  
Chao Liu ◽  
Daniel Bernstein ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Atpase Activity ◽  
Early Onset ◽  
Cardiac Myosin ◽  
Cardiomyopathy Mutations

scholarly journals Mutations in the catalytic domain of human β-cardiac myosin that cause early onset hypertrophic cardiomyopathy significantly increase the fundamental parameters that determine ensemble force and velocity

2016 ◽  
Author(s):  
Arjun S. Adhikari ◽  
Kristina B. Kooiker ◽  
Chao Liu ◽  
Saswata S. Sarkar ◽  
Daniel Bernstein ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Single Molecule ◽  
Early Onset ◽  
Catalytic Domain ◽  
Cardiovascular Disorder ◽  
Cardiac Myosin ◽  
Binding Studies ◽  
Fundamental Parameters ◽  
Biomechanical Parameters ◽  
Myosin Motors

AbstractHypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. In infants it can be particularly severe and it is the leading cause of sudden cardiac death in pediatric populations. A high percentage of HCM is attributed to mutations in β-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two mutations that cause early-onset HCM, D239N and H251N, affect the mechanical output of human β-cardiac myosin at the molecular level. We observe extremely large increases (25% – 95%) in the actin gliding velocity, single molecule intrinsic force, and ATPase activity of the two mutant myosin motors compared to wild type myosin. In contrast to previous studies of HCM-causing mutations in human β-cardiac myosin, these mutations were striking in that they caused changes in biomechanical parameters that were both greater in magnitude and more uniformly consistent with a hyper-contractile phenotype. In addition, S1-S2 binding studies revealed a significant decrease in affinity of the H251N motor for S2, suggesting that this mutation may further increase hyper-contractility by releasing active motors from a sequestered state. This report shows, for the first time, a clear and significant gain in function for all tested molecular biomechanical parameters due to HCM mutations in human β-cardiac myosin.

scholarly journals Human hypertrophic cardiomyopathy mutation R712L suppresses the working stroke of cardiac myosin and can be rescued by omecamtiv mecarbil

2020 ◽  
Author(s):  
Aaron Snoberger ◽  
Bipasha Barua ◽  
Jennifer L. Atherton ◽  
Henry Shuman ◽  
Eva Forgacs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Atpase Activity ◽  
Single Molecule ◽  
Cardiac Failure ◽  
Flow Chamber ◽  
Severe Form ◽  
Gliding Motility ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

AbstractHypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

scholarly journals Hypertrophic cardiomyopathy mutations at the folded-back sequestered β-cardiac myosin S1-S2 and S1-S1 interfaces release sequestered heads and increase myosin enzymatic activity

2019 ◽  
Author(s):  
Arjun S. Adhikari ◽  
Darshan V. Trivedi ◽  
Saswata S. Sarkar ◽  
Dan Song ◽  
Kristina B. Kooiker ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Functional Data ◽  
Catalytic Domain ◽  
Myosin Head ◽  
Intramolecular Interactions ◽  
Cardiac Myosin ◽  
Myosin S1 ◽  
Force Velocity ◽  
Cardiomyopathy Mutations ◽  
Contractility Of The Heart

AbstractHypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart. Nearly 40 percent of HCM-causing mutations are found in human β-cardiac myosin. Previous studies looking at the effect of HCM mutations on the force, velocity and ATPase activity of the catalytic domain of human β-cardiac myosin have not shown clear trends leading to hypercontractility at the molecular scale. Here we present functional data showing that four separate HCM mutations located at the myosin head-tail (R249Q, H251N) and head-head (D382Y, R719W) interfaces of a folded-back sequestered state referred to as the interacting heads motif lead to a significant increase in the number of heads functionally accessible for interaction with actin. These results provide evidence that HCM mutations can modulate myosin activity by disrupting intramolecular interactions within the proposed sequestered state, thereby leading to hypercontractility at the molecular level.

scholarly journals The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin

2020 ◽  
Vol 6 (14) ◽  
pp. eaax0069 ◽  
Author(s):  
Saswata S. Sarkar ◽  
Darshan V. Trivedi ◽  
Makenna M. Morck ◽  
Arjun S. Adhikari ◽  
Shaik N. Pasha ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Myosin ◽  
Similar Reduction ◽  
Enzymatic Assays ◽  
Single Turnover ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Contractile Parameters ◽  
Myosin Binding ◽  
Cardiomyopathy Mutations

Hypertrophic cardiomyopathy (HCM) mutations in β-cardiac myosin and myosin binding protein-C (MyBP-C) lead to hypercontractility of the heart, an early hallmark of HCM. We show that hypercontractility caused by the HCM-causing mutation R663H cannot be explained by changes in fundamental myosin contractile parameters, much like the HCM-causing mutation R403Q. Using enzymatic assays with purified human β-cardiac myosin, we provide evidence that both mutations cause hypercontractility by increasing the number of functionally accessible myosin heads. We also demonstrate that the myosin mutation R403Q, but not R663H, ablates the binding of myosin with the C0-C7 fragment of MyBP-C. Furthermore, addition of C0-C7 decreases the wild-type myosin basal ATPase single turnover rate, while the mutants do not show a similar reduction. These data suggest that a primary mechanism of action for these mutations is to increase the number of myosin heads functionally available for interaction with actin, which could contribute to hypercontractility.

scholarly journals β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Arjun S. Adhikari ◽  
Darshan V. Trivedi ◽  
Saswata S. Sarkar ◽  
Dan Song ◽  
Kristina B. Kooiker ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Enzymatic Activity ◽  
Cardiac Myosin ◽  
Cardiomyopathy Mutations

scholarly journals Hypertrophic Cardiomyopathy Mutations Disrupt Human Beta Cardiac Myosin Intramolecular Interactions Leading to Increased Myosin Activity

2018 ◽  
Vol 114 (3) ◽  
pp. 139a
Author(s):  
Arjun S. Adhikari ◽  
Darshan V. Trivedi ◽  
Saswata S. Sarkar ◽  
Kathleen M. Ruppel ◽  
Spudich A. James
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Intramolecular Interactions ◽  
Cardiac Myosin ◽  
Cardiomyopathy Mutations

scholarly journals Impact of Hypertrophic Cardiomyopathy Mutations on the Cardiac Myosin Super-Relaxed State

2019 ◽  
Vol 116 (3) ◽  
pp. 118a-119a
Author(s):  
Sriya Byrapuneni ◽  
Sami Chu ◽  
Joseph M. Muretta ◽  
David D. Thomas
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Myosin ◽  
Cardiomyopathy Mutations
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