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

Structure. 2018 Dec 4;26(12):1604-1611.e4. doi: 10.1016/j.str.2018.08.007. Epub 2018 Sep 27.


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.

Keywords: cardiac muscle; cryoelectron microscopy; myosin binding protein C; thin filament.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism*
  • Heart / physiology*
  • Models, Molecular
  • Muscle Contraction
  • Protein Conformation
  • Protein Domains
  • Protein Stability
  • Swine
  • Tropomyosin / chemistry
  • Tropomyosin / metabolism*


  • Actins
  • Carrier Proteins
  • Tropomyosin
  • myosin-binding protein C