Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15-28 fragment of the Alzheimer amyloid-β protein
Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15-28 fragment of the Alzheimer amyloid-β protein
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DOI：
10.1073/pnas.0708193105
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发表时间：
2008-04-22
影响因子：
11.1
通讯作者：
Shea, Joan-Emma
中科院分区：
文献类型：
--
作者：
Baumketner, Andrij;Krone, Mary Griffin;Shea, Joan-Emma
淀粉样原纤维，淀粉样β蛋白（A β）的大型有序聚集体，是阿尔茨海默病（AD）的临床标志。淀粉样β蛋白的聚集特性可以受到位置22和23处的单点突变的强烈影响。Dutch突变涉及在位置22（E22 Q）处的取代，并导致A β E22 Q肽在前肌原纤维上的沉积速率增加。我们研究了E22 Q突变对A β肽折叠和聚集的两个关键区域的影响，通过A β肽15-28片段的复制交换分子动力学模拟。A β 15-28肽颗粒包括22-28区域，该区域构成A β肽的最具结构的部分（E22-K28弯曲），以及中心疏水簇（CHC）（片段17-21），A β单体沉积到原纤维上的主要对接位点。我们的模拟表明，22-28弯曲被保存在A β（15-28）的肽和CHC，这主要是非结构化的，与这个弯曲区域的相互作用。E22 Q突变不影响弯曲的结构，但削弱了CHC和弯曲之间的相互作用。这导致CHC中β结构的数量增加。我们的原纤维伸长反应的分析表明，CHC采用β-链构象的过渡态合奏，和E22 Q突变增加聚集率，通过降低A β单体沉积到原纤维上的障碍。从我们的模拟，这种增强的纤维化过程的热力学签名是在很好的协议与实验观察。
Amyloid fibrils, large ordered aggregates of amyloid beta proteins (A beta), are clinical hallmarks of Alzheimer's disease (AD). The aggregation properties of amyloid beta proteins can be strongly affected by single-point mutations at positions 22 and 23. The Dutch mutation involves a substitution at position 22 (E22Q) and leads to increased deposition rates of the A beta E22Q peptide onto preseeded fibrils. We investigate the effect of the E22Q mutation on two key regions involved in the folding and aggregation of the A beta pepticle through replica exchange molecular dynamics simulations of the 15-28 fragment of the A beta pepticle. The A beta 15-28 pepticle encompasses the 22-28 region that constitutes the most structured part of the A beta peptide (the E22-K28 bend), as well as the central hydrophobic cluster (CHC) (segment 17-21), the primary docking site for A beta monomers depositing onto fibrils. Our simulations show that the 22-28 bend is preserved in the A beta(15-28) pepticle and that the CHC, which is mostly unstructured, interacts with this bend region. The E22Q mutation does not affect the structure of the bend but weakens the interactions between the CHC and the bend. This leads to an increased population of beta-structure in the CHC. Our analysis of the fibril elongation reaction reveals that the CHC adopts a beta-strand conformation in the transition state ensemble, and that the E22Q mutation increases aggregation rates by lowering the barrier for A beta monomer deposition onto a fibril. Thermodynamic signatures of this enhanced fibrillization process from our simulations are in good agreement with experimental observations.