Conformational polymorphism and cellular toxicity of IAPP and βAP domains
Conformational polymorphism and cellular toxicity of IAPP and βAP domains
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DOI：
10.1016/j.jsb.2008.12.011
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发表时间：
2009-05-01
影响因子：
3
通讯作者：
Malar, E. J. Padma
中科院分区：
文献类型：
--
作者：
Andrews, Maneesha E.;Inayathullah, N. Mohammed;Malar, E. J. Padma
阿尔茨海默病中淀粉样蛋白沉积物的主要成分是β-淀粉样蛋白多肽，而在11型糖尿病中，沉积物主要由胰岛淀粉样蛋白多肽组成。这些淀粉样蛋白形成多肽由高度多态性的结构域组成，其根据微环境采取不同的构象，包括无规卷曲、螺旋和β链。我们已经研究了IAPP和β AP的主要纤维形成组分，并证明这些肽在不同微环境中的构象多态性与细胞毒性和蛋白酶体抑制活性相关。在用三氟乙醇（TFE）处理时，肽片段经历从无规卷曲到螺旋构象的结构转变。尽管这些结构域具有相同的总淀粉样蛋白结构特征，但它们的蛋白酶体活性不同。我们发现，即使是四肽具有显着的蛋白酶体抑制活性，表明淀粉样蛋白的形成参与了全长和片段肽的较小聚集体的增强寿命，这可以解释这些序列的毒性。(C)2009 Elsevier Inc. All rights reserved.
The principal component of the amyloid deposits in Alzheimer's disease is the beta-amyloid polypeptide, while in type 11 diabetes the deposits consist primarily of Islet amyloid polypeptide. These amyloid forming polypeptides consist of highly polymorphic domains, which take different conformations including random coil, helical and beta strand depending upon the microenvironment. We have studied major fibril-forming components of IAPP and beta AP and demonstrated that conformational polymorphism of these peptides in different microenvironments correlate with cellular toxicity and proteasomal inhibitory activity. On treating with trifluoroethanol (TFE) the peptide fragments undergo structural transition from a random coil to a helical conformation. Even though these domains share the same gross amyloid structural characteristic, their proteasomal activities differ. We found that even the tetrapeptides have significant proteasomal inhibitory activity indicating that the amyloid formation is involved in the enhanced life of the smaller aggregates of full-length and fragment peptides, which could explain the toxicity of these sequences. (C) 2009 Elsevier Inc. All rights reserved.