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首页> 外文期刊>Journal of Molecular Biology >Effects of familial Alzheimer's disease mutations on the folding nucleation of the amyloid beta-protein.
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Effects of familial Alzheimer's disease mutations on the folding nucleation of the amyloid beta-protein.

机译：家族性阿尔茨海默氏病突变对淀粉样β蛋白折叠核的影响。

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摘要

The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms of Alzheimer's disease and cerebral amyloid angiopathy on the structure of the 21-30 fragment of the Alzheimer amyloid beta-protein (Abeta) is investigated by replica-exchange molecular dynamics simulations. The 21-30 segment has been shown in our earlier work to adopt a bend structure in solution that may serve as the folding nucleation site for Abeta. Our simulations reveal that the 24-28 bend motif is retained in all E22 mutants, suggesting that mutations involving residue E22 may not affect the structure of the folding nucleation site of Abeta. Enhanced aggregation in Abeta with familial Alzheimer's disease substitutions may result from the depletion of the E22-K28 salt bridge, which destabilizes the bend structure. Alternately, the E22 mutations may affect longer-range interactions outside the 21-30 segment that can impact the aggregation of Abeta. Substituting at residue D23, on the other hand, leads to the formation of a turn rather than a bend motif, implying that in contrast to E22 mutants, the D23N mutant may affect monomer Abeta folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of Abeta are fundamentally different.
机译：与意大利（E22K），北极（E22G），荷兰（E22Q）和爱荷华州（D23N）家族形式的阿尔茨海默氏病和脑淀粉样血管病相关的单个氨基酸取代对阿尔茨海默氏症21-30片段结构的影响通过复制-交换分子动力学模拟研究淀粉样蛋白β蛋白（Abeta）。在我们的早期工作中已显示21-30段在溶液中采用了弯曲结构，该结构可以用作Abeta的折叠成核位点。我们的模拟揭示了24-28弯曲基序保留在所有E22突变体中，表明涉及残基E22的突变可能不会影响Abeta折叠成核位点的结构。 E22-K28盐桥的耗尽可能导致弯曲结构的不稳定，导致家族性阿尔茨海默氏病替代引起的Abeta聚集增强。或者，E22突变可能会影响21-30节以外的更远距离的相互作用，从而影响Abeta的聚集。另一方面，取代残基D23导致形成转弯而不是弯曲基序，这意味着与E22突变体相反，D23N突变体可能影响单体Abeta折叠和随后的聚集。我们的模拟表明，E22和D23突变影响Abeta折叠和聚集的机制根本不同。

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