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The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

Suman Nag1, Darshan V Trivedi1, Saswata S Sarkar1

  • 1Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA.

Nature Structural & Molecular Biology
|May 9, 2017
PubMed

Insights

Hypertrophic cardiomyopathy (HCM) may stem from more accessible myosin heads. Myosin tail (S2) and MyBP-C interactions, regulated by phosphorylation and HCM mutations, influence this accessibility.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease.
  • Mutations in β-cardiac myosin and myosin-binding protein-C (MyBP-C) are primary causes of HCM.
  • Existing explanations for HCM-related hypercontractility are insufficient.

Purpose of the Study:

  • To investigate the role of myosin head accessibility in HCM-related hypercontractility.
  • To explore the functional regulation of human β-cardiac myosin by its tail (S2) and MyBP-C.

Main Methods:

  • Assessed actin-activated human β-cardiac myosin ATPase activity.
  • Investigated binding interactions between myosin subfragments (S1, S2) and MyBP-C.
  • Examined the effects of phosphorylation and HCM mutations on these interactions.

Main Results:

  • Demonstrated S2-dependent regulation of myosin ATPase activity.
  • Confirmed binding of S2 and MyBP-C to S1.
  • Showed that phosphorylation and specific HCM mutations weaken S1-S2 and S1-MyBP-C interactions.

Conclusions:

  • Propose that HCM hypercontractility results from increased accessible myosin heads (S1).
  • Suggest a structural model where S2 and MyBP-C interactions sequester myosin.
  • Highlight the impact of phosphorylation and HCM mutations on myosin regulation.

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