scholarly journals The myosin mesa and a possible unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy

2015 ◽  
Vol 43 (1) ◽  
pp. 64-72 ◽  
Author(s):  
James A. Spudich
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Structural Feature ◽  
Power Output ◽  
Molecular Basis ◽  
Protein C ◽  
Binding Protein ◽  
Myosin Molecule ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

No matter how many times one explores the structure of the myosin molecule, there is always something new to discover. Here, I describe the myosin mesa, a structural feature of the motor domain that has the characteristics of a binding domain for another protein, possibly myosin-binding protein C (MyBP-C). Interestingly, many well-known hypertrophic cardiomyopathy (HCM) mutations lie along this surface and may affect the putative interactions proposed here. A potential unifying hypothesis for the molecular basis of human hypertrophic cardiomyopathy is discussed here. It involves increased power output of the cardiac muscle as a result of HCM mutations causing the release of inhibition by myosin binding protein C.

scholarly journals Beyond the myosin mesa: a potential unifying hypothesis on the underlying molecular basis of hyper-contractility caused by a majority of hypertrophic cardiomyopathy mutations

2016 ◽  
Author(s):  
Suman Nag ◽  
Darshan V. Trivedi ◽  
Saswata S. Sarkar ◽  
Shirley Sutton ◽  
Kathleen M. Ruppel ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Molecular Basis ◽  
Protein C ◽  
Structural Model ◽  
Binding Protein ◽  
Coiled Coil ◽  
Major Effect ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Abstract:Hypertrophic cardiomyopathy (HCM), the most commonly occurring inherited cardiovascular disease, is primarily caused by mutations in human β-cardiac myosin and myosin binding protein-C. It has been thought that such mutations in myosin increase the intrinsic force of the motor, its velocity of contraction, or its ATPase activity, giving rise to hyper-contractility. We hypothesize that while these parameters are mildly affected by most myosin HCM-causing mutations, a major effect of a majority of myosin HCM mutations is likely to involve an increase in the number of myosin heads that are functionally accessible (Na) for interaction with actin in the sarcomere. We consider a model involving three types of interactions involving the myosin mesa and the converter domain of the myosin motor that hold myosin heads in a sequestered state, likely to be released in a graded manner as the demands on the heart increase: 1) the two myosin heads binding to one another, 2) one head binding to its own coiled-coil tail, and 3) the other head binding to myosin binding protein-C. In addition there is clear evidence of interaction between the coiled-coil tail of myosin and myosin binding protein-C. Experimentally, here we focus on myosin head binding to its own coiled-coil tail and to myosin binding protein-C. We show that phosphorylation of the myosin regulatory light chain and myosin binding protein-C weaken these respective associations, consistent with known enhancements of sarcomere function by these phosphorylations. We show that these interactions are weakened as a result of myosin HCM mutations, in a manner consistent with our structural model. Our data suggests a potential unifying hypothesis for the molecular basis of hyper-contractility caused by human hypertrophic cardiomyopathy myosin mutations, whereby the mutations give rise to an increase in the number of myosin heads that are functionally accessible for interaction with actin in the sarcomere, causing the hyper-contractility observed clinically.

scholarly journals Clinical Expression in Patients With Hypertrophic Cardiomyopathy Caused by Cardiac Myosin-Binding Protein C Gene Mutation

Circulation ◽  
1999 ◽  
Vol 100 (4) ◽  
pp. 446-449 ◽  
Author(s):  
Yoshinori L. Doi ◽  
Hiroaki Kitaoka ◽  
Nobuhiko Hitomi ◽  
Manatsu Satoh ◽  
Akinori Kimura
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Gene Mutation ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Clinical Expression ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals A novel cardiac myosin-binding protein C S297X mutation in hypertrophic cardiomyopathy

2010 ◽  
Vol 56 (1) ◽  
pp. 59-65 ◽  
Author(s):  
Takayoshi Hirota ◽  
Toru Kubo ◽  
Hiroaki Kitaoka ◽  
Tomoyuki Hamada ◽  
Yuichi Baba ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Myosin binding protein-C and hypertrophic cardiomyopathy: role of altered C10 domain

2019 ◽  
Vol 115 (14) ◽  
pp. 1943-1945 ◽  
Author(s):  
Mohammad Bakhtiar Hossain ◽  
Zaher Elbeck ◽  
Humam Siga ◽  
Ralph Knöll
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein C ◽  
Binding Protein ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers

Open Heart ◽  
2020 ◽  
Vol 7 (1) ◽  
pp. e001220
Author(s):  
Berglind Adalsteinsdottir ◽  
Michael Burke ◽  
Barry J Maron ◽  
Ragnar Danielsen ◽  
Begoña Lopez ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Clinical Evaluation ◽  
Protein C ◽  
Founder Mutation ◽  
Binding Protein ◽  
Phenotypic Expression ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Ecg Abnormalities

ObjectiveThe myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation.MethodsWe studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped.ResultsGenetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH−) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH− subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives.ConclusionsPhenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH− individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.

Mutations in the Gene for Cardiac Myosin-Binding Protein C and Late-Onset Familial Hypertrophic Cardiomyopathy

1998 ◽  
Vol 338 (18) ◽  
pp. 1248-1257 ◽  
Author(s):  
Hideshi Niimura ◽  
Linda L. Bachinski ◽  
Somkiat Sangwatanaroj ◽  
Hugh Watkins ◽  
Albert E. Chudley ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein C ◽  
Late Onset ◽  
Binding Protein ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding
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