Interaction between cardiac myosin-binding protein C and formin Fhod3

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 function...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2018-05, Vol.115 (19), p.E4386-E4395
Main Authors: Matsuyama, Sho, Kage, Yohko, Fujimoto, Noriko, Ushijima, Tomoki, Tsuruda, Toshihiro, Kitamura, Kazuo, Shiose, Akira, Asada, Yujiro, Sumimoto, Hideki, Takeya, Ryu
Format: Article
Language:English
Subjects:
Actin
Biological Sciences
Cardiomyopathy
Familial hypertrophic cardiomyopathy
Gene expression
Heart
Immunoglobulins
Localization
Mice
Mutation
Myosin
Myosin-binding protein C
Pathogenesis
Phenotypes
PNAS Plus
Protein C
Proteins
Sarcomeres
Studies
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1716498115