کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1925179 | 1536348 | 2014 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: A novel pathogenic mechanism for hypertrophic cardiomyopathy
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: A novel pathogenic mechanism for hypertrophic cardiomyopathy Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: A novel pathogenic mechanism for hypertrophic cardiomyopathy](/preview/png/1925179.png)
چکیده انگلیسی
The majority of hypertrophic cardiomyopathy mutations in (cTnT) occur within the alpha-helical tropomyosin binding TNT1 domain. A highly charged region at the C-terminal end of TNT1 unwinds to create a flexible “hinge”. While this region has not been structurally resolved, it likely acts as an extended linker between the two cTnT functional domains. Mutations in this region cause phenotypically diverse and often severe forms of HCM. Mechanistic insight, however, has been limited by the lack of structural information. To overcome this limitation, we evaluated the effects of cTnT 160-163 mutations using regulated in vitro motility (R-IVM) assays and transgenic mouse models. R-IVM revealed that cTnT mutations Î160E, E163R and E163K disrupted weak electrostatic actomyosin binding. Reducing the ionic strength or decreasing Brownian motion rescued function. This is the first observation of HCM-linked mutations in cTnT disrupting weak interactions between the thin filament and myosin. To evaluate the in vivo effects of altering weak actomyosin binding we generated transgenic mice expressing Î160E and E163R mutant cTnT and observed severe cardiac remodeling and profound myofilament disarray. The functional changes observed in vitro may contribute to the structural impairment seen in vivo by destabilizing myofilament structure and acting as a constant pathophysiologic stress.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Archives of Biochemistry and Biophysics - Volumes 552â553, 15 Juneâ1 July 2014, Pages 21-28
Journal: Archives of Biochemistry and Biophysics - Volumes 552â553, 15 Juneâ1 July 2014, Pages 21-28
نویسندگان
Rachel K. Moore, Salwa Abdullah, Jil C. Tardiff,