Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics
Author
Ly, ThuPappas, Christopher T
Johnson, Dylan
Schlecht, William
Colpan, Mert
Galkin, Vitold E
Gregorio, Carol C
Dong, Wen-Ji
Kostyukova, Alla S
Affiliation
Univ Arizona, Dept Cellular & Mol MedUniv Arizona, Sarver Mol Cardiovasc Res Program
Issue Date
2019-01-15
Metadata
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AMER SOC CELL BIOLOGYCitation
Ly, T., Pappas, C. T., Johnson, D., Schlecht, W., Colpan, M., Galkin, V. E., ... & Kostyukova, A. S. (2019). Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics. Molecular biology of the cell, 30(2), 268-281.Journal
MOLECULAR BIOLOGY OF THE CELLRights
© 2019 Ly et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.ISSN
1939-4586PubMed ID
30462572Version
Final published versionSponsors
National Institutes of Health (NIH) [GM120137, R01HL123078]; American Heart Association Predoctoral Fellowship [17PRE33680008]; NIH/National Institute of General Medical Sciences [T32 GM008336]Additional Links
https://www.molbiolcell.org/doi/full/10.1091/mbc.E18-06-0406ae974a485f413a2113503eed53cd6c53
10.1091/mbc.E18-06-0406
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Except where otherwise noted, this item's license is described as © 2019 Ly et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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