scholarly journals Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation MYBPC3Δ25bp/D389V

2021 ◽  
Vol 22 (21) ◽  
pp. 11949
Author(s):  
Frederic V. Schwäbe ◽  
Emanuel K. Peter ◽  
Manuel H. Taft ◽  
Dietmar J. Manstein
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein Interactions ◽  
Protein C ◽  
Binding Protein ◽  
Thick Filament ◽  
C2 Domain ◽  
Double Mutation ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Mutations in the gene encoding cardiac myosin-binding protein-C (MyBPC), a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function, are a common cause for the development of hypertrophic cardiomyopathy. About 10% of carriers of the Δ25bp variant of MYBPC3, which is common in individuals from South Asia, are also carriers of the D389V variant on the same allele. Compared with noncarriers and those with MYBPC3Δ25bp alone, indicators for the development of hypertrophic cardiomyopathy occur with increased frequency in MYBPC3Δ25bp/D389V carriers. Residue D389 lies in the IgI-like C2 domain that is part of the N-terminal region of MyBPC. To probe the effects of mutation D389V on structure, thermostability, and protein–protein interactions, we produced and characterized wild-type and mutant constructs corresponding to the isolated 10 kDa C2 domain and a 52 kDa N-terminal fragment that includes subdomains C0 to C2. Our results show marked reductions in the melting temperatures of D389V mutant constructs. Interactions of construct C0–C2 D389V with the cardiac isoforms of myosin-2 and actin remain unchanged. Molecular dynamics simulations reveal changes in the stiffness and conformer dynamics of domain C2 caused by mutation D389V. Our results suggest a pathomechanism for the development of HCM based on the toxic buildup of misfolded protein in young MYBPC3Δ25bp/D389V carriers that is supplanted and enhanced by C-zone haploinsufficiency at older ages.

scholarly journals Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin–Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy–causing Double Mutation MYBPC3Δ25bp/D389V

2021 ◽  
Author(s):  
Frederic V. Schwäbe ◽  
Emanuel K. Peter ◽  
Manuel H. Taft ◽  
Dietmar J. Manstein
Keyword(s):  
Molecular Dynamics ◽  
Hypertrophic Cardiomyopathy ◽  
Protein Interactions ◽  
Protein C ◽  
Binding Protein ◽  
Regulatory Protein ◽  
Double Mutation ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Cardiac myosin-binding protein C (MyBPC) is a thick-filament associated regulatory protein in the sarcomere. It regulates the sensitive contractile system of the myocardium by acting as a mechanical tether, sensitizing the thin filament or modulating myosin motor activity. Mutations in the MYBPC3 gene are a frequent cause for the development of hypertrophic cardiomyopathy, the most frequent cardiac disorder. Recently, the monoallelic double mutation MYBPC3Δ25bp/D389V has been discovered as a subset of the common MYBPC3Δ25bp variant in South Asia. MYBPC3Δ25bp/D389V carriers exhibit hyperdynamic features, which are considered an early finding for the development of hypertrophic cardiomyopathy. Using correlation-guided molecular dynamics simulations sampling, we show that the D389V mutation shifts the conformational distribution of the C2 domain of MyBPC. We further applied biochemical approaches to probe the effects of the D389V mutation on structure, thermostability and protein-protein interactions of MyBPC C2. The melting temperature (Tm) of MyBPC C2 D389V is decreased by 4 to 7 °C compared to wild type while the interaction of the C0-C2 domains with myosin and actin remains unchanged. Additionally, we utilized steered molecular dynamics (SMD) simulations to investigate the altered unfolding pathway of MyBPC C2 D389V. Based on our data, we propose a pathomechanism for the development of HCM in MYBPC3Δ25bp and MYBPC3Δ25bp/D389V carriers.

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

The carboxyl terminus of myosin binding protein C (MyBP-C, C-protein) specifies incorporation into the A-band of striated muscle

1996 ◽  
Vol 109 (1) ◽  
pp. 101-111 ◽  
Author(s):  
R. Gilbert ◽  
M.G. Kelly ◽  
T. Mikawa ◽  
D.A. Fischman
Keyword(s):  
Amino Acids ◽  
Protein C ◽  
Binding Protein ◽  
Thick Filament ◽  
Binding Domain ◽  
C Protein ◽  
Amino Terminal ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Myosin binding protein-C (MyBP-C), also known as C-protein, is a major constituent of the thick filaments of vertebrate striated muscles. The protein, approximately 130 kDa, consists of a series of 10 globular motifs (numbered I to X) each of approximately 90–100 amino acids, bearing resemblance to the C2-set of immunoglobins (Ig C2) and to the fibronectin type III (FnIII) motifs. Using pure preparations of myosin and MyBP-C, it has been demonstrated that the major myosin binding domain of MyBP-C resides within the C-terminal Ig C2 motif (motif X). However, in the context of the in vivo thick filament, it is uncertain if the latter domain is sufficient to target MyBP-C correctly to the A-band or if other regions of the molecule are required for this process. To answer this question, cultures of skeletal muscle myoblasts were transfected with expression plasmids encoding seven truncation mutants of MyBP-C, and their targeting to the A-band investigated by immunofluorescence microscopy. To distinguish the recombinant proteins from endogenous MyBP-C, a myc epitope was inserted at each amino terminus. Recombinant MyBP-C exhibited an identical distribution in the sarcomere to that of native MyBP-C; i.e. it was found exclusively in the C-zone of the A-band. A mutant encoding the C-terminal 372 amino acids, but lacking motifs I-VI (termed delta 1–6), also targeted correctly to the A-band. This fragment, which is composed of two Ig C2 and two FnIII motifs, was the minimal protein fragment required for correct A-band incorporation. Larger amino-terminal deletions or deletion of motif X, the myosin binding domain, abolished all localization to the A-band. One construct (delta 10) lacking only motif X strongly inhibited myofibril assembly. We conclude that the myosin binding domain of MyBP-C, although essential, is not sufficient for correct incorporation into the A-band and that motifs VII to IX are required for this process. The data suggest a topological model in which MyBP-C is associated with the thick filament through its C terminus.

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.

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