Conformations of islet amyloid polypeptide monomers in a membrane environment: implications for fibril formation.
Conformations of islet amyloid polypeptide monomers in a membrane environment: implications for fibril formation.
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DOI：
10.1371/journal.pone.0047150
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Huo S
中科院分区：
文献类型：
--
作者：
Duan M;Fan J;Huo S
胰岛淀粉样多肽(IAPP)形成的淀粉样纤维与II型糖尿病有关。IAPP的毒性机制之一是造成膜损伤。据报道，S20G人IAPP致死突变可导致II型糖尿病的早期发病和体外高淀粉样蛋白形成倾向。由于S20G突变体的聚集速度异常快，因此在实验上很难表征其单体状态的结构特征。计算工作是对实验研究的补充。我们对膜中人类变异体的单体状态进行了一系列分子动力学模拟。通过与实验数据的广泛比较，我们的模拟得到了验证。我们发现，His18的螺旋破坏在两个人类变种中都是共同的。在其中一个构象家族中观察到S20G突变体的L状基序。这个在18岁时弯曲的图案类似于IAPP纤维的整体拓扑结构。S20G IAPP在类纤维拓扑中的构象预组织为S20G IAPP的快速聚集提供了可能的解释。
The amyloid fibrils formed by islet amyloid polypeptide (IAPP) are associated with type II diabetes. One of the proposed mechanisms of the toxicity of IAPP is that it causes membrane damage. The fatal mutation of S20G human IAPP was reported to lead to early onset of type II diabetes and high tendency of amyloid formation in vitro. Characterizing the structural features of the S20G mutant in its monomeric state is experimentally difficult because of its unusually fast aggregation rate. Computational work complements experimental studies. We performed a series of molecular dynamics simulations of the monomeric state of human variants in the membrane. Our simulations are validated by extensive comparisons with experimental data. We find that a helical disruption at His18 is common to both human variants. An L-shaped motif of S20G mutant is observed in one of the conformational families. This motif that bends at His18 resembles the overall topology of IAPP fibrils. The conformational preorganization into the fibril-like topology provides a possible explanation for the fast aggregation rate of S20G IAPP.
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