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Dilated cardiomyopathy mutations in alpha-tropomyosin inhibit its movement during the ATPase cycle

Yurii S Borovikov1, Olga E Karpicheva, Galina A Chudakova

  • 1Laboratory of Mechanisms of Cell Motility, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Avenue, 194064 St. Petersburg, Russia. boroviko@mail.cytspb.rssi.ru

Biochemical and Biophysical Research Communications
|February 19, 2009
PubMed

Insights

Dilated cardiomyopathy (DCM) mutations in alpha-tropomyosin alter its position and actin affinity on muscle thin filaments. These structural changes explain reduced Ca2+-sensitivity and activation observed in DCM patients.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Dilated cardiomyopathy (DCM) is a severe heart condition.
  • Mutations in alpha-tropomyosin, specifically Glu40Lys and Glu54Lys, are linked to DCM.
  • These mutations impair cardiac muscle function by decreasing thin filament Ca2+-sensitivity.

Purpose of the Study:

  • To elucidate the molecular mechanisms behind the functional deficits caused by Glu40Lys and Glu54Lys alpha-tropomyosin mutations.
  • To correlate structural changes in tropomyosin with observed functional impairments in DCM.

Main Methods:

  • Labeling wild-type and mutant (Glu40Lys, Glu54Lys) alpha-tropomyosin with a fluorescent probe at Cys190.
  • Incorporating labeled tropomyosin into ghost muscle fibers.
  • Utilizing polarized fluorimetry to measure tropomyosin position on the thin filament and its actin affinity throughout the ATPase cycle.

Main Results:

  • Both DCM-associated mutations shifted tropomyosin towards the thin filament periphery.
  • Mutations altered tropomyosin's affinity for actin.
  • The amplitude of tropomyosin movement during the ATPase cycle was reduced, and in some stages, reversed.

Conclusions:

  • Structural alterations in tropomyosin, including altered position and actin binding, underlie the reduced Ca2+-sensitivity and activation in DCM.
  • These findings provide a molecular basis for understanding alpha-tropomyosin-linked dilated cardiomyopathy.

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