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Effect of cardiac myosin-binding protein C on stability of the thick filament

G McClellan1, I Kulikovskaya, J Flavigny

  • 1Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6085, USA.

Journal of Molecular and Cellular Cardiology
|September 24, 2004
PubMed

Insights

Cardiac myosin-binding protein C (cMyBP-C) is crucial for heart muscle function. The C5 region of cMyBP-C specifically regulates calcium sensitivity and cardiac contractility by interacting with myosin.

Area of Science:

  • Cardiovascular Physiology
  • Muscle Biology
  • Protein Structure-Function Relationships

Background:

  • Cardiac myosin-binding protein C (cMyBP-C) is a key regulatory protein in cardiac muscle, distinct from its skeletal counterpart.
  • cMyBP-C comprises 11 modules (C0-C10) and possesses unique structural features, including phosphorylation sites and an extended C5 region.
  • Intramolecular interactions within the C5-C10 region of cMyBP-C, specifically between C5-C8 and C7-C10, are implicated in its function.

Purpose of the Study:

  • To investigate the role of the C5 region of cardiac myosin-binding protein C (cMyBP-C) in regulating cardiac muscle contractility.
  • To determine how specific interactions involving the C5 module influence calcium sensitivity and myosin structure.

Main Methods:

  • Utilized isolated skinned cardiac trabeculae for functional assays.
  • Incubated trabeculae with recombinant cMyBP-C fragments, specifically targeting the C5 region.
  • Assessed changes in calcium sensitivity, protein extraction, and maximum calcium-activated force.

Main Results:

  • Low concentrations (2-10 µM) of C5 or C5-containing fragments reversibly reduced calcium sensitivity without myofibrillar protein extraction.
  • Fragments lacking the C5 region (C2-C4) had no significant effect on cardiac trabeculae function.
  • Higher concentrations (>10 µM) of C5 led to irreversible loss of cMyBP-C and myosin heavy chain, reducing maximum force.

Conclusions:

  • The C5 region of cMyBP-C is essential for maintaining the structural arrangement of myosin, thereby setting cardiac contractile properties.
  • cMyBP-C, particularly its C5 module, plays a critical role in stabilizing the thick filament and modulating myosin head interaction with actin.
  • Disruption of cMyBP-C structure, especially the C5 region, impairs cardiac function, highlighting its importance in heart muscle physiology.

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