Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.
Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.
复制标题
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。
DOI：
10.1371/journal.pcbi.1000357
复制
发表时间：
2009-04
影响因子：
4.3
通讯作者：
Mu, Yuguang
中科院分区：
文献类型：
--
作者：
Jiang, Ping;Xu, Weixin;Mu, Yuguang
采用显式溶剂模型全原子复制交换分子动力学（REMD）模拟研究了脂类分子对人胰岛淀粉样多肽hIAPP20-29高度淀粉样蛋白片段聚集的影响及其相应的大鼠序列。hIAPP20-29片段聚集成部分有序的β-片低聚物，然后进行大的构象重组，转化为寄存器内和寄存器外混合模式的平行/反平行β-片低聚物。脂质尾部与23-25位残基之间的疏水相互作用稳定了有序的β-片结构，表明脂质分子在hIAPP20-29自组装中起催化作用。具有三个脯氨酸残基的大鼠IAPP变体保持非结构化胶束状低聚物，这与实验研究中观察到的非淀粉样变性行为一致。我们的研究提供了脂质分子对IAPP肽聚集的催化功能的原子分辨率描述。在过去二十年中，被诊断患有糖尿病的人从3000万增加到2.46亿。2型糖尿病的一个标志是胰岛淀粉样蛋白的形成，它由人类胰岛淀粉样蛋白多肽（90%）和脂质分子（10%）组成。在对抗疾病的长期努力中，在原子水平上理解肽聚集和脂质分子之间的相互作用是很重要的。在本研究中，我们使用分子动力学模拟来探索脂质分子对有毒肽段自组装过程的影响。此外，采用非淀粉样变性啮齿动物序列的阴性对照模拟也进行了评估模拟方案的鲁棒性。我们的研究提供了脂质分子在淀粉样蛋白形成过程中催化作用的一般图景。
The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20–29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics (REMD) simulations with explicit solvent model. hIAPP20–29 fragments aggregate into partially ordered β-sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel β-sheet oligomers in mixed in-register and out-of-register patterns. The hydrophobic interaction between lipid tails and residues at positions 23–25 is found to stabilize the ordered β-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20–29 self-assembly. The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies. Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides. People diagnosed with diabetes have increased from 30 million to 246 million over the last two decades. One hallmark of type 2 diabetes is the formation of amyloid in the pancreatic islet, which is composed of human islet amyloid polypeptide (90%) and lipid molecules (10%). In the long-lasting endeavors against the disease, it is important to understand, at the atomic level, the interaction between peptide aggregation and lipid molecules. In this study, we use molecular dynamics simulations to explore the influence of lipid molecules on the self-assembly process of toxic peptide segments. Moreover, a negative control simulation, employing the non-amyloidogenic rodent sequence, is also performed to evaluate the robustness of the simulation protocol. Our study provides a generic picture of the catalytic role of lipid molecules in the process of amyloidogenesis.
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影响因子：
3.5
作者：
BETSHOLTZ, C;CHRISTMANSSON, L;WESTERMARK, P
通讯作者：
WESTERMARK, P
影响因子：
5.6
作者：
Domanov, Yegor A.;Kinnunen, Paavo K. J.
通讯作者：
Kinnunen, Paavo K. J.
DOI：
10.1016/s0006-291x(88)80538-2
发表时间：
1988-09-15
影响因子：
3.1
作者：
GLENNER, GG;EANES, ED;WILEY, CA
通讯作者：
WILEY, CA
影响因子：
15
作者：
Brender, Jeffrey R.;Lee, Edgar L.;Ramamoorthy, Ayyalusamy
通讯作者：
Ramamoorthy, Ayyalusamy
DOI：
10.1073/pnas.84.23.8628
发表时间：
1987-12-01
影响因子：
11.1
作者：
COOPER, GJS;WILLIS, AC;REID, KBM
通讯作者：
REID, KBM