Pauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease
Pauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease
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DOI：
10.1073/pnas.0401781101
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发表时间：
2004-08-10
影响因子：
11.1
通讯作者：
Daggett, V
中科院分区：
文献类型：
--
作者：
Armen, RS;DeMarco, ML;Daggett, V
转甲状腺素、β(2)-微球蛋白、溶菌酶和普恩蛋白是与淀粉样变性疾病有关的四种最典型的蛋白质。在部分酸变性后，这些蛋白质发生构象变化，形成淀粉样蛋白中间体，可以自我组装成淀粉样蛋白纤维。许多实验表明，pH介导的结构变化是形成淀粉样蛋白中间体所必需的，但事实证明，不可能用实验手段在高分辨率下表征这些构象变化。为了在原子分辨率下探索这些构象变化，我们对这些蛋白质在中性和低pH条件下进行了分子动力学模拟。在对所有四种蛋白质的低pH模拟中，我们观察到了由L.Pauling和R.B.Corey[(1951)Proc]最先提出的α-折叠片状二级结构的形成。娜塔莉。阿卡德科学公司。美国37,251-256]。在所有的β-折叠蛋白中，转甲状腺素和β(2)-微球蛋白，在探索淀粉样变性条件的氢交换实验中，在高度保护的链上形成了折叠的片状结构。在溶菌酶和Prion蛋白中，在蛋白质的特定区域形成了与淀粉样蛋白转化有关的阿尔法片。我们认为，α-褶皱片状结构的形成可能是淀粉样变性的一种常见构象转变。
Transthyretin, beta(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 alpha-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 beta-sheet proteins, transthyretin and beta(2)-Microglobulin, a-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, alpha-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of alpha-pleated sheet structure may be a common conformational transition in amyloidosis.