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β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity

Arjun S Adhikari1,2, Darshan V Trivedi1,2, Saswata S Sarkar1,2

  • 1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Nature Communications
|June 20, 2019
PubMed

Insights

Hypertrophic cardiomyopathy mutations disrupt myosin

Area of Science:

  • Molecular biology
  • Cardiovascular research
  • Biochemistry

Background:

  • Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals, causing heart hyper-contractility.
  • Approximately 40% of HCM cases stem from mutations in human β-cardiac myosin.
  • Previous research on HCM mutations' effects on myosin activity lacked clear molecular-level explanations for hypercontractility.

Purpose of the Study:

  • To investigate how specific HCM mutations impact the functional accessibility of myosin heads.
  • To explore the molecular mechanisms underlying HCM-related hypercontractility.
  • To determine if disrupting intramolecular interactions in myosin contributes to HCM.

Main Methods:

  • Functional analysis of four distinct HCM mutations (R249Q, H251N, D382Y, R719W) in human β-cardiac myosin.
  • Examination of mutations at the myosin head-tail and head-head interfaces within the interacting heads motif (IHM).
  • Assessment of the impact of these mutations on the number of myosin heads accessible for actin interaction.

Main Results:

  • Four specific HCM mutations significantly increase the number of myosin heads available for actin binding.
  • These mutations are located at critical interfaces (head-tail and head-head) within the interacting heads motif (IHM).
  • Disruption of intramolecular interactions within the sequestered IHM state is implicated.

Conclusions:

  • HCM mutations can alter myosin activity by disrupting intramolecular interactions in the IHM.
  • This disruption leads to increased functional accessibility of myosin heads, potentially causing molecular-level hypercontractility.
  • The findings offer a molecular explanation for HCM pathogenesis.

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