Dzwolak Wojciech, Pecul Magdalena
Institute of High Pressure Physics, Polish Academy of Sciences, Sokolowska 29/37, 01-142 Warsaw, Poland.
FEBS Lett. 2005 Dec 5;579(29):6601-3. doi: 10.1016/j.febslet.2005.10.048. Epub 2005 Nov 9.
Since it was implicated in a number of neurodegenerative conditions, such as Alzheimer disease, formation of beta-sheet-rich protein fibrils (amyloids) has been drawing a lot of attention. One of elusive aspects of amyloidogenesis concerns the mechanisms of specific binding of molecules such as Congo red, or Thioflavin T by amyloid fibrils. A comprehensive understanding of these docking interactions is needed, however, for the sake of furthering biochemical studies and developing molecular, pharmacological strategies preventing proliferation of amyloids in vivo. Through the application of circular dichroism, here we show that upon binding to insulin fibrils, a twisted conformation is enforced in molecules of Thioflavin T, manifested in a strong negative Cotton effect around 450 nm, which is supported by density functional theory-based calculations. This finding may lead to circular dichroism of Thioflavin T becoming a new diagnostic technique for protein fibrils, complementary to fluorescence spectroscopy.
由于富含β-折叠的蛋白质纤维（淀粉样蛋白）与包括阿尔茨海默病在内的多种神经退行性疾病有关，其形成一直备受关注。淀粉样蛋白生成难以捉摸的一个方面涉及刚果红或硫黄素T等分子与淀粉样纤维特异性结合的机制。然而，为了推进生化研究并开发防止淀粉样蛋白在体内增殖的分子和药理学策略，需要全面了解这些对接相互作用。通过圆二色性的应用，我们在此表明，硫黄素T分子与胰岛素纤维结合后，会形成扭曲构象，在450nm左右表现出强烈的负科顿效应，基于密度泛函理论的计算也证实了这一点。这一发现可能使硫黄素T的圆二色性成为一种用于蛋白质纤维的新诊断技术，作为荧光光谱法的补充。
