Solid-state NMR as a method to reveal structure and membrane-interaction of amyloidogenic proteins and peptides.
Solid-state NMR as a method to reveal structure and membrane-interaction of amyloidogenic proteins and peptides.
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DOI：
10.1016/j.bbamem.2007.03.025
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发表时间：
2007-08
期刊：
影响因子：
--
通讯作者：
A. Naito;I. Kawamura
中科院分区：
文献类型：
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作者：
A. Naito;I. Kawamura
鉴于许多医学和生化方面，了解淀粉样原纤维的形成非常重要。淀粉样原纤维的结构测定已使用电子显微镜进行了广泛研究。随后，固态核磁共振波谱已被认识到不仅是确定微观分子结构而且是确定宏观分子堆积的最重要手段。淀粉样原纤维的分子结构首先被预测为平行 β-片层结构，随后，通过固态核磁共振波谱进一步细化为 Aβ(1-40) 为具有双层对准平行 β-片层结构的交叉 β-片层。另一方面，已报道 Aβ-淀粉样蛋白和其他淀粉样蛋白形成肽的短片段具有反平行 β-折叠结构。已经使用多种方法研究了淀粉样原纤维形成的动力学研究，并使用两步自催化反应机制来解释原纤维形成。最近，通过电子显微镜（EM）图像观察到了稳定的中间体或原纤维。一些中间体具有与成熟原纤维相同的微观结构，并随后转变为成熟原纤维。关于淀粉样蛋白原纤维形成的另一个重要研究是确定与脂质膜的相互作用，因为淀粉样肽在膜界面从淀粉样蛋白前体蛋白上裂解，并且据报道淀粉样蛋白脂质相互作用与细胞毒性有关。最后讨论了如何抑制淀粉样原纤维的形成。首先，据报道，正确设计的化合物通过与淀粉样肽相互作用而具有抑制淀粉样原纤维形成的能力。其次，研究表明定点突变可以抑制淀粉样原纤维的形成。这些抑制剂是通过了解固态核磁共振确定的原纤维结构而开发的。
It is important to understand the Amyloid fibril formation in view of numerous medical and biochemical aspects. Structural determination of amyloid fibril has been extensively studied using electron microscopy. Subsequently, solid state NMR spectroscopy has been realized to be the most important means to determine not only microscopic molecular structure but also macroscopic molecular packing. Molecular structure of amyloid fibril was first predicted to be parallel β-sheet structure, and subsequently, was further refined for Aβ(1–40) to be cross β-sheet with double layered in register parallel β-sheet structure by using solid state NMR spectroscopy. On the other hand, anti-parallel β-sheet structure has been reported to short fragments of Aβ-amyloid and other amyloid forming peptides. Kinetic study of amyloid fibril formation has been studied using a variety of methods, and two-step autocatalytic reaction mechanism used to explain fibril formation. Recently, stable intermediates or proto-fibrils have been observed by electron microscope (EM) images. Some of the intermediates have the same microscopic structure as the matured fibril and subsequently change to matured fibrils. Another important study on amyloid fibril formation is determination of the interaction with lipid membranes, since amyloid peptide are cleaved from amyloid precursor proteins in the membrane interface, and it is reported that amyloid lipid interaction is related to the cytotoxicity. Finally it is discussed how amyloid fibril formation can be inhibited. Firstly, properly designed compounds are reported to have inhibition ability of amyloid fibril formation by interacting with amyloid peptide. Secondly, it is revealed that site directed mutation can inhibit amyloid fibril formation. These inhibitors were developed by knowing the fibril structure determined by solid state NMR.