Effects of familial Alzheimer's disease mutations on the folding nucleation of the amyloid β-protein
Effects of familial Alzheimer's disease mutations on the folding nucleation of the amyloid β-protein
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DOI：
10.1016/j.jmb.2008.05.069
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发表时间：
2008-08-01
影响因子：
5.6
通讯作者：
Shea, Joan-Emma
中科院分区：
文献类型：
--
作者：
Krone, Mary Griffin;Baumketner, Andrij;Shea, Joan-Emma
通过复制交换分子动力学模拟研究了与意大利（E22 K）、北极（E22 G）、荷兰（E22 Q）和爱荷华州（D23 N）阿尔茨海默病和脑淀粉样血管病家族形式相关的单个氨基酸取代对阿尔茨海默淀粉样β蛋白（A β）21-30片段结构的影响。在我们早期的工作中，21-30段已经显示在溶液中采用弯曲结构，其可以作为A β的折叠成核位点。我们的模拟显示，24-28弯曲基序保留在所有E22突变体，这表明涉及残基E22的突变可能不会影响A β的折叠成核位点的结构。在具有家族性阿尔茨海默病置换的A β中增强的聚集可能是由于E22-K28盐桥的耗尽，其使弯曲结构不稳定。或者，E22突变可能会影响21-30片段以外的更长范围的相互作用，这可能会影响A β的聚集。另一方面，在残基D23处的取代导致形成转角而不是弯曲基序，这意味着与E22突变体相反，D23 N突变体可能影响单体A β折叠和随后的聚集。我们的模拟表明，E22和D23突变影响A β折叠和聚集的机制是根本不同的。(C)2008爱思唯尔有限公司保留所有权利。
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 (A beta) 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 A beta. 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 A beta. Enhanced aggregation in A beta 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 A beta. 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 A beta folding and subsequent aggregation. Our simulations suggest that the mechanisms by which E22 and D23 mutations affect the folding and aggregation of A beta are fundamentally different. (C) 2008 Elsevier Ltd. All rights reserved.