Probing ion channel activity of human islet amyloid polypeptide (amylin).
Probing ion channel activity of human islet amyloid polypeptide (amylin).
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DOI：
10.1016/j.bbamem.2012.08.012
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发表时间：
2012-12
影响因子：
3.4
通讯作者：
Zheng, Jie
中科院分区：
文献类型：
--
作者：
Zhao, Jun;Luo, Yin;Jang, Hyunbum;Yu, Xiang;Wei, Guanghong;Nussinov, Ruth;Zheng, Jie
人胰岛淀粉样多肽（hIAPP或胰淀素）与细胞膜的相互作用与II型糖尿病中胰岛β细胞的功能障碍和死亡相关。hIAPP在膜中形成不依赖受体的通道被视为在胰岛β细胞中诱导离子稳态失衡和毒性的膜损伤机制之一。在此，我们利用分子建模和分子动力学模拟研究了hIAPP通道在1,2 - 二油酰基 - sn - 甘油 - 3 - 磷酸胆碱（DOPC）双层膜中的动态结构、离子传导性以及膜相互作用。我们使用由核磁共振得出的β - 链 - 转角 - β - 链基序作为构建模块，通过计算构建了一系列具有不同大小和拓扑结构的环状hIAPP结构。在模拟的脂质环境中，通道失去了其初始的连续β - 折叠网络，并分解为寡聚亚基，这些亚基仍然松散地结合形成异质的通道构象。通道的形状、形态和尺寸与通过原子力显微镜获得的甜甜圈状图像以及为β - 淀粉样蛋白（Aβ）、β2 - 微球蛋白衍生的K3肽和抗菌肽PG - 1的基于β - 发夹的通道所构建的模型通道相符。此外，所有通道都诱导多种离子从膜下层向上层定向渗透穿过双层膜。这种相似性表明，松散结合的β - 结构基序可能是有毒的、不受调控的通道的一个普遍特征。在缺乏hIAPP通道在膜中的实验性高分辨率原子结构的情况下，本研究首次尝试描绘hIAPP通道的一些主要结构特征，以便更好地理解淀粉样蛋白毒性的起源以及药物制剂的开发。
Interactions of human islet amyloid polypeptide (hIAPP or amylin) with the cell membrane are correlated with the dysfunction and death of pancreatic islet β-cells in type II diabetes. Formation of receptor-independent channels by hIAPP in membrane is regarded as one of the membrane-damaging mechanisms that induce ion homeostasis and toxicity in islet β-cells. Here, we investigate the dynamic structure, ion conductivity, and membrane interactions of hIAPP channels in the DOPC bilayer using molecular modeling and molecular dynamics simulations. We use the NMR-derived β-strand-turn-β-strand motif as a building block to computationally construct a series of annular-like hIAPP structures with different sizes and topologies. In the simulated lipid environments, the channels lose their initial continuous β-sheet network and break into oligomeric subunits, which are still loosely associated to form heterogeneous channel conformations. The channels’ shapes, morphologies and dimensions are compatible with the doughnut-like images obtained by atomic force microscopy, and with those of modeled channels for Aβ, the β2-microglobulin-derived K3 peptides, and the β-hairpin-based channels of antimicrobial peptide PG-1. Further, all channels induce directional permeability of multiple ions across the bilayers from the lower to the upper leaflet. This similarity suggests that loosely-associated β-structure motifs can be a general feature of toxic, unregulated channels. In the absence of experimental high-resolution atomic structures of hIAPP channels in the membrane, this study represents a first attempt to delineate some of the main structural features of the hIAPP channels, for a better understanding of the origin of amyloid toxicity and the development of pharmaceutical agents.
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影响因子：
3.7
作者：
Jo S;Kim T;Im W
通讯作者：
Im W
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
影响因子：
--
作者：
Åkesson, B;Panagiotidis, G;Lundquist, I
通讯作者：
Lundquist, I
影响因子：
4.1
作者：
Kalé, L;Skeel, R;Schulten, K
通讯作者：
Schulten, K
影响因子：
3.3
作者：
Jang, Hyunbum;Arce, Fernando Teran;Ramachandran, Srinivasan;Capone, Ricardo;Lal, Ratnesh;Nussinov, Ruth
通讯作者：
Nussinov, Ruth