Conformational Switching within Individual Amyloid Fibrils
Conformational Switching within Individual Amyloid Fibrils
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DOI：
10.1074/jbc.m900533200
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发表时间：
2009-05-22
影响因子：
4.8
通讯作者：
Baskakov, Ilia V.
中科院分区：
文献类型：
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作者：
Makarava, Natallia;Ostapchenko, Valeriy G.;Baskakov, Ilia V.
淀粉样蛋白原纤维的关键结构组分是高度有序的晶体样交叉β片层核心。构象上不同的淀粉样蛋白结构可以在相同的氨基酸序列内形成。一般认为，单个原纤维由构象均匀的交叉β结构组成。使用哺乳动物重组朊病毒蛋白（PrP），我们发现，与常见的看法相反，淀粉样蛋白是能够容纳一个显着的构象转换内个别原纤维。构象开关发生时，作为前体底物在原纤化反应中使用的PrP变体的氨基酸序列是不兼容的应变特异性构象的原纤化模板。尽管基质和模板之间的氨基酸序列不匹配，个别原纤维招募异源PrP变体;然而，原纤维伸长通过构象适应进行，导致个别原纤维内淀粉样蛋白菌株的变化。这项研究说明了淀粉样蛋白结构的高适应潜力，并表明，个别原纤维内的构象转换可能占适应淀粉样蛋白菌株的异源底物。这项工作提出了一个新的机制解释的应变转换现象，并说明了淀粉样蛋白结构的进化方向。这项研究还提供了一个直接的例证，即自我复制的淀粉样蛋白结构的催化活性最终并不与它们的模板效应相结合。
A key structural component of amyloid fibrils is a highly ordered, crystalline-like cross-beta-sheet core. Conformationally different amyloid structures can be formed within the same amino acid sequence. It is generally assumed that individual fibrils consist of conformationally uniform cross-beta-structures. Using mammalian recombinant prion protein (PrP), we showed that, contrary to common perception, amyloid is capable of accommodating a significant conformational switching within individual fibrils. The conformational switch occurred when the amino acid sequence of a PrP variant used as a precursor substrate in a fibrillation reaction was not compatible with the strain-specific conformation of the fibrillar template. Despite the mismatch in amino acid sequences between the substrate and template, individual fibrils recruited the heterologous PrP variant; however, the fibril elongation proceeded through a conformational adaptation, resulting in a change in amyloid strain within individual fibrils. This study illustrates the high adaptation potential of amyloid structures and suggests that conformational switching within individual fibrils may account for adaptation of amyloid strains to a heterologous substrate. This work proposes a new mechanistic explanation for the phenomenon of strain conversion and illustrates the direction in evolution of amyloid structures. This study also provides a direct illustration that catalytic activity of self-replicating amyloid structures is not ultimately coupled with their templating effect.