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Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry

Michael J Greenberg1, Katarzyna Kazmierczak, Danuta Szczesna-Cordary

  • 1Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 22, 2010
PubMed

Insights

Familial hypertrophic cardiomyopathy (FHC) mutations in myosin regulatory light chain (RLC) reduce cardiac muscle force. These RLC mutations alter myosin

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiology

Background:

  • Familial hypertrophic cardiomyopathy (FHC) is a genetic heart disease.
  • Mutations in sarcomeric proteins, including myosin regulatory light chain (RLC), cause FHC.
  • Two FHC-associated RLC mutations, R58Q and N47K, are located near the RLC's cationic binding site.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying FHC phenotypes caused by RLC mutations.
  • To determine how RLC mutations affect myosin function and force generation.

Main Methods:

  • Reconstituted porcine cardiac myosin with recombinant human wild-type (WT) or mutant RLC (R58Q, N47K).
  • Assessed actin filament sliding velocity using the in vitro motility assay.
  • Measured myosin force and power output under varying load conditions.

Main Results:

  • Mutant RLC myosins showed reduced force and power output compared to WT or native myosin under load.
  • Unloaded motility was similar between mutant and WT myosins.
  • Mutation-induced alterations in loaded kinetics result from impaired myosin strain sensitivity of ADP affinity.

Conclusions:

  • R58Q and N47K mutations in RLC alter myosin mechanical properties, specifically in the neck region.
  • These alterations lead to abnormal load-dependent kinetics.
  • The altered kinetics may explain the FHC phenotypes observed in patients with these mutations.

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