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

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.
AuthorsCampion K P Loong, Huan-Xiang Zhou, P Bryant Chase
JournalFEBS letters (FEBS Lett) Vol. 586 Issue 19 Pg. 3503-7 (Sep 21 2012) ISSN: 1873-3468 [Electronic] England
PMID22958892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Mutant Proteins
  • Recombinant Proteins
  • TPM1 protein, human
  • Tropomyosin
  • Calcium
Topics
  • Amino Acid Substitution
  • Calcium (metabolism)
  • Cardiomyopathy, Hypertrophic, Familial (genetics, physiopathology)
  • Humans
  • Microscopy, Atomic Force
  • Models, Cardiovascular
  • Models, Molecular
  • Mutant Proteins (chemistry, genetics, physiology, ultrastructure)
  • Mutation, Missense
  • Myocardial Contraction (genetics, physiology)
  • Protein Conformation
  • Recombinant Proteins (chemistry, genetics, ultrastructure)
  • Tropomyosin (chemistry, genetics, physiology, ultrastructure)

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