Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy

Meera C. Viswanathan, William Schmidt, Michael J. Rynkiewicz, Karuna Agarwal, Jian Gao, Joseph Katz, William Lehman, Anthony Cammarato

Research output: Contribution to journalArticlepeer-review

Abstract

Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energetically favorable F-actin-tropomyosin configuration, with tropomyosin positioned in a location that impedes actomyosin associations and promotes relaxation. Here, we provide data that directly support a vital role for these actin residues, termed the A-triad, in tropomyosin positioning in intact functioning muscle. By examining the effects of an A295S α-cardiac actin hypertrophic cardiomyopathy-causing mutation, over a range of increasingly complex in silico, in vitro, and in vivo Drosophila muscle models, we propose that subtle A-triad-tropomyosin perturbation can destabilize thin filament regulation, which leads to hypercontractility and triggers disease. Our efforts increase understanding of basic thin filament biology and help unravel the mechanistic basis of a complex cardiac disorder.

Original languageEnglish (US)
Pages (from-to)2612-2625
Number of pages14
JournalCell Reports
Volume20
Issue number11
DOIs
StatePublished - Sep 12 2017

Keywords

  • Drosophila
  • cardiomyopathy
  • computational modeling
  • diastolic dysfunction
  • hypertrophic cardiomyopathy
  • indirect flight muscle
  • muscle regulation
  • sarcomere
  • thin filament
  • tropomyosin
  • troponin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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