کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1925252 | 1536354 | 2014 | 6 صفحه PDF | دانلود رایگان |
• An energy landscape was calculated for tropomyosin on the surface of F-actin.
• The energy minimum locates tropomyosin near its myosin-blocking position on F-actin.
• Tropomyosin’s myosin-induced open-position is near to the landscape’s energy maximum.
• Myosin-binding drives tropomyosin uphill over F-actin to activate thin filaments.
• Mutations distort the energy landscape in ways that explain phenotypic traits.
Muscle contraction is regulated by tropomyosin movement across the thin filament surface, which exposes or blocks myosin-binding sites on actin. Recent atomic structures of F-actin–tropomyosin have yielded the positions of tropomyosin on myosin-free and myosin-decorated actin. Here, the repositioning of α-tropomyosin between these locations on F-actin was systematically examined by optimizing the energy of the complex for a wide range of tropomyosin positions on F-actin. The resulting energy landscape provides a full-map of the F-actin surface preferred by tropomyosin, revealing a broad energy basin associated with the tropomyosin position that blocks myosin-binding. This is consistent with previously proposed low-energy oscillations of semi-rigid tropomyosin, necessary for shifting of tropomyosin following troponin-binding. In contrast, the landscape shows much less favorable energies when tropomyosin locates near its myosin-induced “open-state” position. This indicates that spontaneous movement of tropomyosin away from its energetic “ground-state” to the open-state is unlikely in absence of myosin. Instead, myosin-binding must drive tropomyosin toward the open-state to activate the thin filament. Additional energy landscapes were computed for disease-causing actin mutants that distort the topology of the actin–tropomyosin energy landscape, explaining their phenotypes. Thus, the computation of such energy landscapes offers a sensitive way to estimate the impact of mutations.
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Journal: Archives of Biochemistry and Biophysics - Volume 545, 1 March 2014, Pages 63–68