Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation.
Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation.
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hIAPP 二聚体的构象整体：深入了解绿茶提取物抑制 hIAPP 聚集的分子机制。
DOI：
10.1038/srep33076
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发表时间：
2016-09-13
影响因子：
4.6
通讯作者：
Wei G
中科院分区：
文献类型：
--
作者：
Mo Y;Lei J;Sun Y;Zhang Q;Wei G
在II型糖尿病中，早期沿着人胰岛淀粉样多肽（hIAPP）聚集形成的小寡聚体是导致细胞死亡的原因。发现表没食子儿茶素没食子酸酯（EGCG），一种绿色茶提取物，抑制hIAPP纤维化。然而，最小的hIAPP寡聚体-二聚体的抑制机制和构象分布大多未知。在此，我们进行了广泛的复制交换分子动力学模拟hIAPP二聚体与和没有EGCG分子。扩展的hIAPP二聚体构象，与离子迁移率-质谱所观察到的碰撞截面值相似，在我们的模拟中观察到。值得注意的是，这些二聚体采用三链反平行β-折叠，并含有先前报道的β-发夹淀粉样蛋白前体。我们发现，EGCG的结合强烈地阻断了肽间疏水和芳香堆积的相互作用，这些相互作用是肽间β-折叠形成的原因，而肽内相互作用是β-发夹形成的关键，从而消除了三链β-折叠结构，并导致形成富含卷曲的构象。疏水、芳香堆积、阳离子-π和氢键相互作用共同促成了EGCG诱导的构象转变。本研究在原子水平上提供了hIAPP二聚体的构象系综和EGCG抑制hIAPP聚集的分子机制。
Small oligomers formed early along human islet amyloid polypeptide (hIAPP) aggregation is responsible for the cell death in Type II diabetes. The epigallocatechin gallate (EGCG), a green tea extract, was found to inhibit hIAPP fibrillation. However, the inhibition mechanism and the conformational distribution of the smallest hIAPP oligomer – dimer are mostly unknown. Herein, we performed extensive replica exchange molecular dynamic simulations on hIAPP dimer with and without EGCG molecules. Extended hIAPP dimer conformations, with a collision cross section value similar to that observed by ion mobility-mass spectrometry, were observed in our simulations. Notably, these dimers adopt a three-stranded antiparallel β-sheet and contain the previously reported β-hairpin amyloidogenic precursor. We find that EGCG binding strongly blocks both the inter-peptide hydrophobic and aromatic-stacking interactions responsible for inter-peptide β-sheet formation and intra-peptide interaction crucial for β-hairpin formation, thus abolishes the three-stranded β-sheet structures and leads to the formation of coil-rich conformations. Hydrophobic, aromatic-stacking, cation-π and hydrogen-bonding interactions jointly contribute to the EGCG-induced conformational shift. This study provides, on atomic level, the conformational ensemble of hIAPP dimer and the molecular mechanism by which EGCG inhibits hIAPP aggregation.
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人类 IAPP 中淀粉样蛋白的形成机制：二聚体具有 β 链单体-单体界面。
影响因子：
15
作者：
Dupuis NF;Wu C;Shea JE;Bowers MT
通讯作者：
Bowers MT
淀粉样蛋白生成被脯氨酸取代所消除，但通过脂质结合而增强。
影响因子：
4.3
作者：
Jiang, Ping;Xu, Weixin;Mu, Yuguang
通讯作者：
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影响因子：
2.9
作者：
Fox, Ayano;Snollaerts, Thibaut;Casanova, Camille Errecart;Calciano, Anastasia;Nogaj, Luiza A.;Moffet, David A.
通讯作者：
Moffet, David A.
影响因子：
5.6
作者：
Kayed, R;Bernhagen, J;Kapurniotu, A
通讯作者：
Kapurniotu, A
影响因子：
3.4
作者：
Chiu, Chi-cheng;Singh, Sadanand;de Pablo, Juan J.
通讯作者：
de Pablo, Juan J.