کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8473963 | 1550415 | 2016 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
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![عکس صفحه اول مقاله: The cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position The cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position](/preview/png/8473963.png)
چکیده انگلیسی
Mutations in cardiac myosin binding protein C (cMyBP-C), a thick filament protein that modulates contraction of the heart, are a leading cause of hypertrophic cardiomyopathy (HCM). Electron microscopy and 3D reconstruction of thin filaments decorated with cMyBP-C N-terminal fragments suggest that one mechanism of this modulation involves the interaction of cMyBP-C's N-terminal domains with thin filaments to enhance their Ca2Â +-sensitivity by displacement of tropomyosin from its blocked (low Ca2Â +) to its closed (high Ca2Â +) position. The extent of this tropomyosin shift is reduced when cMyBP-C N-terminal domains are phosphorylated. In the current study, we have examined L348P, a sequence variant of cMyBP-C first identified in a screen of patients with HCM. In L348P, leucine 348 is replaced by proline in cMyBP-C's regulatory M-domain, resulting in an increase in cMyBP-C's ability to enhance thin filament Ca2Â +-sensitization. Our goal here was to determine the structural basis for this enhancement by carrying out 3D reconstruction of thin filaments decorated with L348P-mutant cMyBP-C. When thin filaments were decorated with wild type N-terminal domains at low Ca2Â +, tropomyosin moved from the blocked to the closed position, as found previously. In contrast, the L348P mutant caused a significantly larger tropomyosin shift, to approximately the open position, consistent with its enhancement of Ca2Â +-sensitization. Phosphorylated wild type fragments showed a smaller shift than unphosphorylated fragments, whereas the shift induced by the L348P mutant was not affected by phosphorylation. We conclude that the L348P mutation causes a gain of function by enhancing tropomyosin displacement on the thin filament in a phosphorylation-independent way.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 91, February 2016, Pages 141-147
Journal: Journal of Molecular and Cellular Cardiology - Volume 91, February 2016, Pages 141-147
نویسندگان
Ji Young Mun, Robert W. Kensler, Samantha P. Harris, Roger Craig,