Lipid membranes modulate the structure of islet amyloid polypeptide
Lipid membranes modulate the structure of islet amyloid polypeptide
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DOI：
10.1021/bi050840w
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发表时间：
2005-09-13
期刊：
影响因子：
2.9
通讯作者：
Langen, R
中科院分区：
文献类型：
--
作者：
Jayasinghe, SA;Langen, R
胰岛淀粉样多肽（IAPP）是一种由37个氨基酸残基组成的蛋白质，在II型糖尿病的发病机制中起重要作用。尽管越来越多的证据表明IAPP毒性中存在膜相互作用，但膜结合形式尚未得到很好的表征。在这里，我们使用圆二色性（CD）和荧光光谱研究的分子细节的相互作用的IAPP与脂质膜的不同组合物。在含有带负电荷的磷脂酰丝氨酸（PS）的膜的存在下，我们观察到IAPP聚集体的形成显着加速。这种加速强烈调制的PS浓度和离子强度，也观察到生理相关的PS浓度。加入含有PS的膜后立即获得的IAPP的CD光谱显示了长度约为15-19个残基的α-螺旋构象的特征。在与膜一起孵育较长时间后，IAPP产生β-折叠构象的CD光谱特征。总之，我们的CD和荧光数据表明，促进弱稳定的α-螺旋构象的条件可能会促进IAPP聚集。IAPP-膜相互作用和新的膜结合的α-螺旋构象在IAPP聚集的潜在作用进行了讨论。
The 37-residue islet amyloid polypeptide (IAPP) is thought to play an important role in the pathogenesis of type II diabetes. Despite a growing body of evidence implicating membrane interaction in IAPP toxicity, the membrane-bound form has not yet been well characterized. Here we used circular dichroism (CD) and fluorescence spectroscopy to investigate the molecular details of the interaction of IAPP with lipid membranes of varying composition. In the presence of membranes containing negatively charged phosphatidylserine (PS), we observed significant acceleration in the formation of IAPP aggregates. This acceleration is strongly modulated by the PS concentration and ionic strength, and is also observed at physiologically relevant PS concentrations. CD spectra of IAPP obtained immediately after the addition of membranes containing PS revealed features characteristic of an alpha-helical conformation approximately similar to 15-19 residues in length. After a longer incubation with membranes, IAPP gave rise to CD spectra characteristic of a beta-sheet conformation. Taken together, our CD and fluorescence data indicate that conditions that promote weakly stable a-helical conformations may promote IAPP aggregation. The potential roles of IAPP-membrane interaction and the novel membrane-bound a-helical conformation in IAPP aggregation are discussed.