Structural Characterization of the C3 Domain of Cardiac Myosin Binding Protein C and Its Hypertrophic Cardiomyopathy-Related R502W Mutant

Biochemistry ◽  
2014 ◽  
Vol 53 (32) ◽  
pp. 5332-5342 ◽  
Author(s):  
Xiaolu Linda Zhang ◽  
Soumya De ◽  
Lawrence P. McIntosh ◽  
Mark Paetzel
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Structural Characterization ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

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

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

Crystal Structure of the C1 domain of Cardiac Myosin Binding Protein-C: Implications for Hypertrophic Cardiomyopathy

2008 ◽  
Vol 378 (2) ◽  
pp. 387-397 ◽  
Author(s):  
Lata Govada ◽  
Liz Carpenter ◽  
Paula C.A. da Fonseca ◽  
John R. Helliwell ◽  
Pierre Rizkallah ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Hypertrophic Cardiomyopathy ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
C1 Domain ◽  
Myosin Binding

scholarly journals Interaction between cardiac myosin-binding protein C and formin Fhod3

2018 ◽  
Vol 115 (19) ◽  
pp. E4386-E4395 ◽  
Author(s):  
Sho Matsuyama ◽  
Yohko Kage ◽  
Noriko Fujimoto ◽  
Tomoki Ushijima ◽  
Toshihiro Tsuruda ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Function ◽  
Protein C ◽  
Binding Protein ◽  
Direct Interaction ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C–binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C–binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C–null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C–null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C–null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C–related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C–mediated regulation of cardiac function via direct interaction.

scholarly journals Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy

2019 ◽  
Vol 115 (14) ◽  
pp. 1986-1997 ◽  
Author(s):  
Diederik W D Kuster ◽  
Thomas L Lynch ◽  
David Y Barefield ◽  
Mayandi Sivaguru ◽  
Gina Kuffel ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein C ◽  
Binding Protein ◽  
Force Generation ◽  
Contractile Dysfunction ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Abstract Aims A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-CΔC10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-CΔC10mutin vivo are unknown. We hypothesized that expression of cMyBP-CΔC10mut exerts a poison polypeptide effect leading to improper assembly of cardiac sarcomeres and the development of HCM. Methods and results To determine whether expression of cMyBP-CΔC10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-CΔC10mut at approximately half the level of endogenous cMyBP-C. At 12 weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-CΔC10mut (heart weight/body weight ratio: 4.43 ± 0.11 mg/g non-transgenic (NTG) vs. 5.34 ± 0.25 mg/g cMyBP-CΔC10mut, P < 0.05). Furthermore, haematoxylin and eosin, Masson’s trichrome staining, as well as second-harmonic generation imaging revealed the presence of significant fibrosis and a greater relative nuclear area in cMyBP-CΔC10mut hearts compared with NTG controls. M-mode echocardiography analysis revealed hypercontractile hearts (EF: 53.4%±2.9% NTG vs. 66.4% ± 4.7% cMyBP-CΔC10mut; P < 0.05) and early diastolic dysfunction (E/E′: 28.7 ± 3.7 NTG vs. 46.3 ± 8.4 cMyBP-CΔC10mut; P < 0.05), indicating the presence of an HCM phenotype. To assess whether these changes manifested at the myofilament level, contractile function of single skinned cardiomyocytes was measured. Preserved maximum force generation and increased Ca2+-sensitivity of force generation were observed in cardiomyocytes from cMyBP-CΔC10mut mice compared with NTG controls (EC50: 3.6 ± 0.02 µM NTG vs. 2.90 ± 0.01 µM cMyBP-CΔC10mut; P < 0.0001). Conclusion Expression of cMyBP-C protein with a modified C10 domain is sufficient to cause contractile dysfunction and HCM in vivo.

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