N-Terminal Domains of Cardiac Myosin Binding Protein C Cooperatively Activate the Thin Filament

Cristina Risi, Betty Belknap, Eva Forgacs-Lonart, Samantha P. Harris, Gunnar F. Schröder, Howard D. White, Vitold E. Galkin

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Muscle contraction relies on interaction between myosin-based thick filaments and actin-based thin filaments. Myosin binding protein C (MyBP-C) is a key regulator of actomyosin interactions. Recent studies established that the N′-terminal domains (NTDs) of MyBP-C can either activate or inhibit thin filaments, but the mechanism of their collective action is poorly understood. Cardiac MyBP-C (cMyBP-C) harbors an extra NTD, which is absent in skeletal isoforms of MyBP-C, and its role in regulation of cardiac contraction is unknown. Here we show that the first two domains of human cMyPB-C (i.e., C0 and C1) cooperate to activate the thin filament. We demonstrate that C1 interacts with tropomyosin via a positively charged loop and that this interaction, stabilized by the C0 domain, is required for thin filament activation by cMyBP-C. Our data reveal a mechanism by which cMyBP-C can modulate cardiac contraction and demonstrate a function of the C0 domain.

Original languageEnglish (US)
Pages (from-to)1604-1611.e4
JournalStructure
Volume26
Issue number12
DOIs
StatePublished - Dec 4 2018

Keywords

  • cardiac muscle
  • cryoelectron microscopy
  • myosin binding protein C
  • thin filament

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Risi, C., Belknap, B., Forgacs-Lonart, E., Harris, S. P., Schröder, G. F., White, H. D., & Galkin, V. E. (2018). N-Terminal Domains of Cardiac Myosin Binding Protein C Cooperatively Activate the Thin Filament. Structure, 26(12), 1604-1611.e4. https://doi.org/10.1016/j.str.2018.08.007