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

Michael J. Greenberg, Katarzyna Kazmierczak, Danuta Szczesna-Cordary, Jeffrey R. Moore

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in sarcomeric proteins including the myosin regulatory light chain (RLC). Two such FHC mutations, R58Q and N47K, located near the cationic binding site of the RLC, have been identified from population studies. To examine the molecular basis for the observed phenotypes, we exchanged endogenous RLC from native porcine cardiac myosin with recombinant human ventricular wild type (WT) or FHC mutant RLC and examined the ability of the reconstituted myosin to propel actin filament sliding using the in vitro motility assay. We find that, whereas the mutant myosins are indistinguishable from the controls (WT or native myosin) under unloaded conditions, both R58Q- and N47K-exchanged myosins show reductions in force and power output compared with WT or native myosin. We also show that the changes in loaded kinetics are a result of mutation-induced loss of myosin strain sensitivity of ADP affinity. Wepropose that the R58Q and N47K mutations alter the mechanical properties of the myosin neck region, leading to altered load-dependent kinetics that may explain the observed mutant-induced FHC phenotypes.

Original languageEnglish
Pages (from-to)17403-17408
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number40
DOIs
StatePublished - Oct 5 2010

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Myosin Light Chains
Myosins
Cardiomyopathies
Biochemistry
Familial Hypertrophic Cardiomyopathy
Mutation
Light
Cardiac Myosins
Phenotype
Actin Cytoskeleton
Adenosine Diphosphate
Neck
Swine
Binding Sites
Population

Keywords

  • Familial hypertrophic cardiomyopathy
  • In vitro motility
  • Load-dependent kinetics
  • N47K
  • R58Q

ASJC Scopus subject areas

  • General

Cite this

Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry. / Greenberg, Michael J.; Kazmierczak, Katarzyna; Szczesna-Cordary, Danuta; Moore, Jeffrey R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 40, 05.10.2010, p. 17403-17408.

Research output: Contribution to journalArticle

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