Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics

Thu Ly, Christopher T. Pappas, Dylan Johnson, William Schlecht, Mert Colpan, Vitold E. Galkin, Carol Gregorio, Wen Ji Dong, Alla S. Kostyukova

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Missense mutations K15N and R21H in striated muscle tropomyosin are linked to dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Tropomyosin, together with the troponin complex, regulates muscle contraction and, along with tropomodulin and leiomodin, controls the uniform thin-filament lengths crucial for normal sarcomere structure and function. We used Förster resonance energy transfer to study effects of the tropomyosin mutations on the structure and kinetics of the cardiac troponin core domain associated with the Ca2+-dependent regulation of cardiac thin filaments. We found that the K15N mutation desensitizes thin filaments to Ca2+ and slows the kinetics of structural changes in troponin induced by Ca2+ dissociation from troponin, while the R21H mutation has almost no effect on these parameters. Expression of the K15N mutant in cardiomyocytes decreases leiomodin's thin-filament pointed-end assembly but does not affect tropomodulin's assembly at the pointed end. Our in vitro assays show that the R21H mutation causes a twofold decrease in tropomyosin's affinity for F-actin and affects leiomodin's function. We suggest that the K15N mutation causes DCM by altering Ca2+-dependent thin-filament regulation and that one of the possible HCM-causing mechanisms by the R21H mutation is through alteration of leiomodin's function.

Original languageEnglish (US)
Pages (from-to)268-281
Number of pages14
JournalMolecular Biology of the Cell
Volume30
Issue number2
DOIs
StatePublished - Jan 15 2019

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Tropomyosin
Cardiomyopathies
Troponin
Mutation
Tropomodulin
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Dissociative Disorders
Sarcomeres
Striated Muscle
Energy Transfer
Missense Mutation
Muscle Contraction
Cardiac Myocytes
Actins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics. / Ly, Thu; Pappas, Christopher T.; Johnson, Dylan; Schlecht, William; Colpan, Mert; Galkin, Vitold E.; Gregorio, Carol; Dong, Wen Ji; Kostyukova, Alla S.

In: Molecular Biology of the Cell, Vol. 30, No. 2, 15.01.2019, p. 268-281.

Research output: Contribution to journalArticle

Ly, Thu ; Pappas, Christopher T. ; Johnson, Dylan ; Schlecht, William ; Colpan, Mert ; Galkin, Vitold E. ; Gregorio, Carol ; Dong, Wen Ji ; Kostyukova, Alla S. / Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics. In: Molecular Biology of the Cell. 2019 ; Vol. 30, No. 2. pp. 268-281.
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AU - Colpan, Mert

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AU - Dong, Wen Ji

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