Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: A novel pathogenic mechanism for hypertrophic cardiomyopathy

Rachel K. Moore, Salwa Abdullah, Jil C Tardiff

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The majority of hypertrophic cardiomyopathy mutations in (cTnT) occur within the alpha-helical tropomyosin binding TNT1 domain. A highly charged region at the C-terminal end of TNT1 unwinds to create a flexible "hinge". While this region has not been structurally resolved, it likely acts as an extended linker between the two cTnT functional domains. Mutations in this region cause phenotypically diverse and often severe forms of HCM. Mechanistic insight, however, has been limited by the lack of structural information. To overcome this limitation, we evaluated the effects of cTnT 160-163 mutations using regulated in vitro motility (R-IVM) assays and transgenic mouse models. R-IVM revealed that cTnT mutations Δ160E, E163R and E163K disrupted weak electrostatic actomyosin binding. Reducing the ionic strength or decreasing Brownian motion rescued function. This is the first observation of HCM-linked mutations in cTnT disrupting weak interactions between the thin filament and myosin. To evaluate the in vivo effects of altering weak actomyosin binding we generated transgenic mice expressing Δ160E and E163R mutant cTnT and observed severe cardiac remodeling and profound myofilament disarray. The functional changes observed in vitro may contribute to the structural impairment seen in vivo by destabilizing myofilament structure and acting as a constant pathophysiologic stress.

Original languageEnglish (US)
Pages (from-to)21-28
Number of pages8
JournalArchives of Biochemistry and Biophysics
Volume552-553
DOIs
StatePublished - Jul 15 2014

Fingerprint

Actomyosin
Troponin
Hypertrophic Cardiomyopathy
Tropomyosin
Mutation
Brownian movement
Hinges
Myosins
Ionic strength
Myofibrils
Electrostatics
Assays
Transgenic Mice
Static Electricity
Osmolar Concentration
Observation
In Vitro Techniques

Keywords

  • Hypertrophic cardiomyopathy
  • Thin filaments
  • Troponin
  • Weak binding

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding : A novel pathogenic mechanism for hypertrophic cardiomyopathy. / Moore, Rachel K.; Abdullah, Salwa; Tardiff, Jil C.

In: Archives of Biochemistry and Biophysics, Vol. 552-553, 15.07.2014, p. 21-28.

Research output: Contribution to journalArticle

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