Familial hypertrophic cardiomyopathy related E180G mutation increases flexibility of human cardiac α-tropomyosin

FEBS Lett. 2012 Sep 21;586(19):3503-7. doi: 10.1016/j.febslet.2012.08.005. Epub 2012 Aug 14.

Abstract

α-Tropomyosin (αTm) is central to Ca(2+)-regulation of cardiac muscle contraction. The familial hypertrophic cardiomyopathy mutation αTm E180G enhances Ca(2+)-sensitivity in functional assays. To investigate the molecular basis, we imaged single molecules of human cardiac αTm E180G by direct probe atomic force microscopy. Analyses of tangent angles along molecular contours yielded persistence length corresponding to ~35% increase in flexibility compared to wild-type. Increased flexibility of the mutant was confirmed by fitting end-to-end length distributions to the worm-like chain model. This marked increase in flexibility can significantly impact systolic and possibly diastolic phases of cardiac contraction, ultimately leading to hypertrophy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Calcium / metabolism
  • Cardiomyopathy, Hypertrophic, Familial / genetics*
  • Cardiomyopathy, Hypertrophic, Familial / physiopathology
  • Humans
  • Microscopy, Atomic Force
  • Models, Cardiovascular
  • Models, Molecular
  • Mutant Proteins / chemistry*
  • Mutant Proteins / genetics*
  • Mutant Proteins / physiology
  • Mutant Proteins / ultrastructure
  • Mutation, Missense
  • Myocardial Contraction / genetics
  • Myocardial Contraction / physiology
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / ultrastructure
  • Tropomyosin / chemistry*
  • Tropomyosin / genetics*
  • Tropomyosin / physiology
  • Tropomyosin / ultrastructure

Substances

  • Mutant Proteins
  • Recombinant Proteins
  • TPM1 protein, human
  • Tropomyosin
  • Calcium