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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease
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Pauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease

机译：鲍林（Pau​​ling）和科里（Corey）的α折叠片状结构可能定义了淀粉样疾病中的原纤维淀粉样生成中间物

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摘要

Transthyretin, β_2-microglobulin, lysozyme, and the prion protein are four of the best-characterized proteins implicated in amyloid disease. Upon partial acid denaturation, these proteins undergo conformational change into an amyloidogenic intermediate that can self-assemble into amyloid fibrils. Many experiments have shown that pH-mediated changes in structure are required for the formation of the amyloidogeneic intermediate, but it has proved impossible to characterize these conformational changes at high resolution using experimental means. To probe these conformational changes at atomic resolution, we have performed molecular dynamics simulations of these proteins at neutral and low pH. In low-pH simulations of all four proteins, we observe the formation of α-pleated sheet secondary structure, which was first proposed by L. Pauling and R. B. Corey [(1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. In all β-sheet proteins, transthyretin and β_2-microglobu-lin, α-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, α-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of α-pleated sheet structure may be a common conformational transition in amyloidosis.
机译：运甲状腺素蛋白，β_2-微球蛋白，溶菌酶和the病毒蛋白是淀粉样蛋白病中最典型的四个蛋白。在部分酸变性后，这些蛋白质发生构象变化，成为淀粉样蛋白生成中间体，该中间体可以自组装为淀粉样蛋白原纤维。许多实验表明，淀粉样遗传中间体的形成需要pH介导的结构变化，但是事实证明不可能使用实验手段在高分辨率下表征这些构象变化。为了以原子分辨率探测这些构象变化，我们在中性和低pH下对这些蛋白质进行了分子动力学模拟。在所有四种蛋白质的低pH模拟中，我们观察到形成了α-折叠薄片的二级结构，该结构最初是由L. Pauling和R. B. Corey [（1951）Proc。 Natl。学院科学USA 37，251-256]。在所有β-折叠蛋白，运甲状腺素蛋白和β_2-微球蛋白中，α-折叠的折叠结构形成在探测淀粉样蛋白生成条件的氢交换实验中受到高度保护的链上。在溶菌酶和the病毒蛋白中，在蛋白质的特定区域中形成了α-折叠，这与淀粉样生成有关。我们建议α-折叠片状结构的形成可能是淀粉样变性中常见的构象转变。

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