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Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+

D Szczesna1, D Ghosh, Q Li

  • 1Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33136, USA. dszczesna@med.miami.edu

The Journal of Biological Chemistry
|December 5, 2000
PubMed

Insights

Familial hypertrophic cardiomyopathy mutations in cardiac myosin light chains alter calcium binding. Some mutations disrupt calcium binding, but phosphorylation can restore it, impacting heart muscle function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Familial hypertrophic cardiomyopathy (HCM) is a genetic heart disease.
  • Mutations in regulatory light chains of human cardiac myosin are implicated in HCM.
  • Understanding these mutations' effects on protein function is crucial for disease mechanism insights.

Purpose of the Study:

  • Investigate the impact of specific familial hypertrophic cardiomyopathy mutations on human cardiac myosin regulatory light chains.
  • Characterize alterations in calcium (Ca2+) binding and phosphorylation properties.
  • Determine how these molecular changes may contribute to hypertrophic cardiomyopathy.

Main Methods:

  • Site-directed mutagenesis to introduce familial hypertrophic cardiomyopathy mutations (A13T, F18L, E22K, R58Q, P95A).
  • Biochemical assays to measure Ca2+ binding affinity (K(Ca)) and phosphorylation.
  • Circular dichroism spectroscopy to assess changes in alpha-helical content.

Main Results:

  • Mutations E22K and R58Q significantly altered Ca2+ binding; R58Q lost Ca2+ binding but regained it upon phosphorylation.
  • E22K could not be phosphorylated, and its Ca2+ binding affinity was reduced 17-fold.
  • Mutation A13T showed reduced Ca2+ affinity, but phosphorylation increased it 6-fold, reversing the wild-type effect.

Conclusions:

  • Alterations in Ca2+ binding and phosphorylation of cardiac myosin regulatory light chains due to HCM mutations can disrupt normal heart muscle function.
  • Specific mutations like E22K and R58Q directly impair Ca2+ sensitivity and/or phosphorylation.
  • These molecular dysregulations are potential contributors to the pathogenesis of hypertrophic cardiomyopathy.

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