Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor.
Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor.
复制标题
DOI：
10.1021/ja903814q
复制
发表时间：
2009-12-30
影响因子：
15
通讯作者：
Bowers, Michael T.
中科院分区：
文献类型：
--
作者：
Dupuis, Nicholas F.;Wu, Chun;Shea, Joan-Emma;Bowers, Michael T.
人类胰岛淀粉样多肽（IAPP）寡聚化越来越被认为是II型糖尿病的主要致病过程。本文采用离子迁移率质谱（IMS-MS）和全原子复制交换分子动力学（REMD）模拟相结合的方法研究了IAPP单体的结构特征。在IMS实验中观察到人类IAPP单体的三个不同的构象家族，根据我们的模拟结果确定其中两个为脱水溶液结构：一个是扩展的β-发夹结构家族，另一个是紧凑的螺旋-线圈结构家族。延伸的β-发夹家族在拓扑结构上与Tycko及其同事发表的固态核磁共振纤维结构中的肽构象相似。在非淀粉样变性大鼠IAPP的实验和模拟中都没有发现它，提示它可能在人类IAPP的纤颤通路中起重要作用。此外，pH依赖性研究表明，在pH 8.0时，β-发夹结构家族的相对丰度显著增强。这一观察结果与体外高pH下纤维性颤动的增加率一致，并为体内pH依赖性纤维性颤动提供了可能的解释。这篇论文，据我们所知，提出了IAPP肽β-发夹构象显著种群的第一个实验证据。这与文献中先前的建议一致，即富含β片的低聚物是由有序的β发夹组装而成，而不是由盘绕结构组装而成。
Oligomerization of human Islet Amyloid Polypeptide (IAPP) has been increasingly considered a primary pathogenic process in Type II Diabetes. Here structural features of the IAPP monomer have been probed using a combination of Ion Mobility Mass Spectrometry (IMS-MS) and all-atom Replica Exchange Molecular Dynamics (REMD) simulations. Three distinct conformational families of human IAPP monomer are observed in IMS experiments and two of them are identified as dehydrated solution structures based on our simulation results: one is an extended β-hairpin structural family and the second is a compact helix-coil structural family. The extended β-hairpin family is topologically similar to the peptide conformation in the solid state NMR fibril structure published by Tycko and coworkers. It is absent in both experiments and simulations performed on the non-amyloidogenic rat IAPP suggesting it may play an important role in the fibrillation pathway of human IAPP. In addition, pH dependence studies show the relative abundance of the β-hairpin structural family is significantly enhanced at pH 8.0. This observation is consistent with the increased rate of fibrillation at high pH in vitro and offers a possible explanation of the pH dependent fibrillation in vivo. This paper, to the best of our knowledge, presents the first experimental evidence of a significant population of β-hairpin conformers for the IAPP peptide. It is consistent with a previous suggestion in the literature that β-sheet rich oligomers are assembled from ordered β-hairpins, rather than from coiled structures.
登录
查看更多内容
影响因子：
3.5
作者：
BETSHOLTZ, C;CHRISTMANSSON, L;WESTERMARK, P
通讯作者：
WESTERMARK, P
影响因子：
15
作者：
Gidden, J;Ferzoco, A;Bowers, MT
通讯作者：
Bowers, MT
影响因子：
15
作者：
Bernstein, SL;Wyttenbach, T;Bowers, MT
通讯作者：
Bowers, MT
影响因子：
1.8
作者：
Baker, Erin Shammel;Bernstein, Summer L.;Bowers, Michael T.
通讯作者：
Bowers, Michael T.
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P