Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics
Pappas, Christopher T
Galkin, Vitold E
Gregorio, Carol C
Kostyukova, Alla S
AffiliationUniv Arizona, Dept Cellular & Mol Med
Univ Arizona, Sarver Mol Cardiovasc Res Program
MetadataShow full item record
PublisherAMER SOC CELL BIOLOGY
CitationLy, 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.
JournalMOLECULAR BIOLOGY OF THE CELL
Rights© 2019 Ly et al. This article is distributed by The American Society for Cell Biology under license from the author(s).
Collection InformationThis 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 email@example.com.
AbstractMissense 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.
VersionFinal published version
SponsorsNational Institutes of Health (NIH) [GM120137, R01HL123078]; American Heart Association Predoctoral Fellowship [17PRE33680008]; NIH/National Institute of General Medical Sciences [T32 GM008336]
- The cardiomyopathy-associated K15N mutation in tropomyosin alters actin filament pointed end dynamics.
- Authors: Colpan M, Ly T, Grover S, Tolkatchev D, Kostyukova AS
- Issue date: 2017 Sep 15
- Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments.
- Authors: Robinson P, Griffiths PJ, Watkins H, Redwood CS
- Issue date: 2007 Dec 7
- Structural destabilization of tropomyosin induced by the cardiomyopathy-linked mutation R21H.
- Authors: Ly T, Krieger I, Tolkatchev D, Krone C, Moural T, Samatey FA, Kang C, Kostyukova AS
- Issue date: 2018 Feb
- <i>TNNT2</i> mutations in the tropomyosin binding region of TNT1 disrupt its role in contractile inhibition and stimulate cardiac dysfunction.
- Authors: Madan A, Viswanathan MC, Woulfe KC, Schmidt W, Sidor A, Liu T, Nguyen TH, Trinh B, Wilson C, Madathil S, Vogler G, O'Rourke B, Biesiadecki BJ, Tobacman LS, Cammarato A
- Issue date: 2020 Aug 4
- Leiomodin creates a leaky cap at the pointed end of actin-thin filaments.
- Authors: Tolkatchev D, Smith GE Jr, Schultz LE, Colpan M, Helms GL, Cort JR, Gregorio CC, Kostyukova AS
- Issue date: 2020 Sep