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

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    Author
    Ly, Thu; Pappas, Christopher T.; Johnson, Dylan; Schlecht, William; Galkin, Vitold E.; Gregorio, Carol C.; Dong, Wen-Ji; Kostyukova, Alla S.
    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.
    URI
    http://hdl.handle.net/10342/8058
    Date
    2018-11-14
    Citation:
    APA:
    Ly, Thu, & Pappas, Christopher T., & Johnson, Dylan, & Schlecht, William, & Galkin, Vitold E., & Gregorio, Carol C., & Dong, Wen-Ji, & Kostyukova, Alla S.. (November 2018). Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics. , (), - . Retrieved from http://hdl.handle.net/10342/8058

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    MLA:
    Ly, Thu, and Pappas, Christopher T., and Johnson, Dylan, and Schlecht, William, and Galkin, Vitold E., and Gregorio, Carol C., and Dong, Wen-Ji, and Kostyukova, Alla S.. "Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics". . . (), November 2018. December 11, 2023. http://hdl.handle.net/10342/8058.
    Chicago:
    Ly, Thu and Pappas, Christopher T. and Johnson, Dylan and Schlecht, William and Galkin, Vitold E. and Gregorio, Carol C. and Dong, Wen-Ji and Kostyukova, Alla S., "Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics," , no. (November 2018), http://hdl.handle.net/10342/8058 (accessed December 11, 2023).
    AMA:
    Ly, Thu, Pappas, Christopher T., Johnson, Dylan, Schlecht, William, Galkin, Vitold E., Gregorio, Carol C., Dong, Wen-Ji, Kostyukova, Alla S.. Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics. . November 2018; (): . http://hdl.handle.net/10342/8058. Accessed December 11, 2023.
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