Natural tri- to hexapeptides self-assemble in water to amyloid β-type fiber aggregates by unexpected α-helical intermediate structures
Natural tri- to hexapeptides self-assemble in water to amyloid β-type fiber aggregates by unexpected α-helical intermediate structures
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DOI：
10.1073/pnas.1014796108
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发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Hauser, Ulrich A.
中科院分区：
文献类型：
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作者：
Hauser, Charlotte A. E.;Deng, Rensheng;Hauser, Ulrich A.
许多致命的神经退行性疾病如阿尔茨海默氏病、帕金森病、朊病毒相关疾病和非神经退行性疾病如II型糖尿病的特征在于异常淀粉样蛋白纤维聚集体，这表明共同的发病机制。我们已经发现，一类系统设计的天然三肽至六肽，具有特征性的顺序基序，可以模拟纤维组装和进一步缩合成淀粉样蛋白原纤维的过程，可能是通过意想不到的二聚体α-螺旋中间结构。新型肽类的特征序列基序由极性头部加帽的疏水性降低的脂肪族氨基酸尾部组成。据我们所知，所研究的脂肪族三肽是迄今报道的最短的天然存在的氨基酸序列，可以采用α-螺旋结构并促进淀粉样蛋白的形成。我们提出的逐步组装过程与特征构象的变化，从无规卷曲α-螺旋中间体终止在交叉β肽结构。圆二色性和X-射线纤维衍射分析证实了肽在水中的浓度依赖性构象变化。分子动力学模拟肽在水中的行为揭示单体反平行配对二聚体结构的互补结构排列，进一步聚集和稳定凝聚成卷曲的纤维。超小的尺寸和动态的组装过程使这种新的肽类淀粉样蛋白的形成机制，其进化和致病性的研究一个很好的模型系统。在限定条件下改变组装结构的性质的能力将揭示操纵致病性淀粉样蛋白聚集体以预防或控制聚集体形成的策略。
Many fatal neurodegenerative diseases such as Alzheimer's, Parkinson, the prion-related diseases, and non-neurodegenerative disorders such as type II diabetes are characterized by abnormal amyloid fiber aggregates, suggesting a common mechanism of pathogenesis. We have discovered that a class of systematically designed natural tri- to hexapeptides with a characteristic sequential motif can simulate the process of fiber assembly and further condensation to amyloid fibrils, probably via unexpected dimeric a-helical intermediate structures. The characteristic sequence motif of the novel peptide class consists of an aliphatic amino acid tail of decreasing hydrophobicity capped by a polar head. To our knowledge, the investigated aliphatic tripeptides are the shortest ever reported naturally occurring amino acid sequence that can adopt a-helical structure and promote amyloid formation. We propose the stepwise assembly process to be associated with characteristic conformational changes from random coil to alpha-helical intermediates terminating in cross-beta peptide structures. Circular dichroism and X-ray fiber diffraction analyses confirmed the concentration-dependent conformational changes of the peptides in water. Molecular dynamics simulating peptide behavior in water revealed monomer antiparallel pairing to dimer structures by complementary structural alignment that further aggregated and stably condensed into coiled fibers. The ultrasmall size and the dynamic facile assembly process make this novel peptide class an excellent model system for studying the mechanism of amyloidogenesis, its evolution and pathogenicity. The ability to modify the properties of the assembled structures under defined conditions will shed light on strategies to manipulate the pathogenic amyloid aggregates in order to prevent or control aggregate formation.