The N-terminal fragment of human islet amyloid polypeptide is non-fibrillogenic in the presence of membranes and does not cause leakage of bilayers of physiologically relevant lipid composition
The N-terminal fragment of human islet amyloid polypeptide is non-fibrillogenic in the presence of membranes and does not cause leakage of bilayers of physiologically relevant lipid composition
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DOI：
10.1016/j.bbamem.2010.05.022
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发表时间：
2010-09-01
影响因子：
3.4
通讯作者：
Killian, J. Antoinette
中科院分区：
文献类型：
--
作者：
Khemtemourian, Lucie;Engel, Maarten F. M.;Killian, J. Antoinette
人胰岛淀粉样多肽（hIAPP）在2型糖尿病（DM 2）患者的胰岛中形成淀粉样纤维。已显示hIAPP原纤维的形成引起膜损伤，这最可能是DM 2发病过程中胰岛β细胞死亡的原因。先前的研究表明，hIAPP的N-末端部分，hIAPP（1-19），在hIAPP与脂质膜的初始相互作用中起主要作用。然而，hIAPP的N-末端部分在引起膜损伤中的确切作用尚不清楚。在这里，我们研究了hIAPP（1-19）的结构和聚集特性与膜损伤在体外通过使用膜的两性离子脂质磷脂酰胆碱（PC），阴离子脂质磷脂酰丝氨酸（PS）和这些脂质的混合物来模拟胰岛细胞膜。我们的数据显示hIAPP（1-19）在溶液中是弱原纤维形成的，并且在膜存在下不是原纤维形成的，其中它采用依赖于脂质组成并且随时间稳定的二级结构。此外，hIAPP（1-19）不能诱导PC/PS或PC双层的膜中的渗漏，表明N-末端片段本身的膜相互作用在生理学相关条件下不是膜渗漏的原因。在阴离子脂质PS的双层中，肽确实诱导膜损伤，但这种渗漏与原纤维形成无关，因为它是成熟的hIAPP。因此，阴离子脂质中hIAPP N末端片段的膜透化很可能是一个非特异性过程，通过与体内hIAPP诱导的膜损伤无关的机制发生。(C)2010年爱思唯尔。All rights reserved.
Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes mellitus (DM2). The formation of hIAPP fibrils has been shown to cause membrane damage which most likely is responsible for the death of pancreatic islet beta-cells during the pathogenesis of DM2. Previous studies have shown that the N-terminal part of hIAPP, hIAPP(1-19), plays a major role in the initial interaction of hIAPP with lipid membranes. However, the exact role of this N-terminal part of hIAPP in causing membrane damage is unknown. Here we investigate the structure and aggregation properties of hIAPP(1-19) in relation to membrane damage in vitro by using membranes of the zwitterionic lipid phosphatidylcholine (PC), the anionic lipid phosphatidylserine (PS) and mixtures of these lipids to mimic membranes of islet cells. Our data reveal that hIAPP(1-19) is weakly fibrillogenic in solution and not fibrillogenic in the presence of membranes, where it adopts a secondary structure that is dependent on lipid composition and stable in time. Furthermore, hIAPP(1-19) is not able to induce leakage in membranes of PC/PS or PC bilayers, indicating that the membrane interaction of the N-terminal fragment by itself is not responsible for membrane leakage under physiologically relevant conditions. In bilayers of the anionic lipid PS, the peptide does induce membrane damage, but this leakage is not correlated to fibril formation, as it is for mature hIAPP. Hence, membrane permeabilization by the N-terminal fragment of hIAPP in anionic lipids is most likely an aspecific process, occurring via a mechanism that is not relevant for hIAPP-induced membrane damage in vivo. (C) 2010 Elsevier By. All rights reserved.