Phospholipid catalysis of diabetic amyloid assembly
Phospholipid catalysis of diabetic amyloid assembly
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DOI：
10.1016/j.jmb.2004.06.086
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发表时间：
2004-08-27
影响因子：
5.6
通讯作者：
Miranker, AD
中科院分区：
文献类型：
--
作者：
Knight, JD;Miranker, AD
胰岛淀粉样多肽（IAPP）是一种37个残基的激素，在II型糖尿病（NIDDM）患者的内分泌胰腺中形成细胞毒性淀粉样纤维。细胞毒性的潜在来源是IAPP对脂质膜的破坏，如在体外观察到的。NIDDM期间淀粉样蛋白形成的原因尚不清楚，体外发生膜破坏的机制也不清楚。在这里，我们使用动力学研究结合评估的脂质结合和电子显微镜，以调查IAPP与磷脂双层的相互作用和IAPP纤维上的膜的形态学效应。IAPP的原纤维形成由合成的和人组织来源的磷脂催化，导致原纤维形成速率增加> 10倍。这种现象的分子基础包括对膜的浓度和电荷密度的强烈依赖性。IAPP与混合阴离子（DOPG）和两性离子（DOPC）含量的脂质膜结合。结合的过渡发生在生理相关的阴离子含量范围内。通过IAPP的膜结合发生在与原纤维形成相比较短的时间尺度上，并且通过蛋白质的N端而不是C端的有序相互作用导致组装成类磷脂状态。与无脂质体原纤维形成相比，这些组装导致脂质体的总体形态变化和早期纤维外观的改变。当纤维从膜表面解离时，完整的双层表面再生。这些发现提供了膜不稳定的结构机制，并表明脂质代谢的变化可以诱导IAPP纤维的形成在NIDDM。(C)2004爱思唯尔有限公司保留所有权利。
Islet amyloid polypeptide (IAPP) is a 37-residue hormone that forms cytotoxic amyloid fibers in the endocrine pancreas of patients with type II diabetes (NIDDM). A potential origin for cytotoxicity is disruption of lipid membranes by IAPP as has been observed in vitro. The cause of amyloid formation during NIDDM is not known, nor is the mechanism by which membrane disruption occurs in vitro. Here, we use kinetic studies in conjunction with assessments of lipid binding and electron microscopy to investigate the interactions of IAPP with phospholipid bilayers and the, morphological effects of membranes on IAPP fibers. Fibrillogenesis of IAPP is catalyzed by synthetic and human tissue-derived phospholipids, leading to > tenfold increases in the rate of fibrillogenesis. The molecular basis of this phenomenon includes a strong dependence on the concentration and charge density of the membrane. IAPP binds to lipid membranes of mixed anionic (DOPG) and zwitterionic (DOPC) content. The transition for binding occurs over a physiologically relevant range of anionic content. Membrane binding by IAPP occurs on timescales that are short compared to fibrillogenesis and results in assembly into preamyloid states via ordered interactions at the N but not C terminus of the protein. These assemblies lead both to gross morphological changes in liposomes and to alterations in the appearance of early fibers when compared to liposome-free fibril formation. Intact bilayer surfaces are regenerated upon dissociation of fibers from the membrane surface. These findings offer a structural mechanism of membrane destabilization and suggest that changes in lipid metabolism could induce IAPP fiber formation in NIDDM. (C) 2004 Elsevier Ltd. All rights reserved.