Low pH Acts as Inhibitor of Membrane Damage Induced by Human Islet Amyloid Polypeptide
Low pH Acts as Inhibitor of Membrane Damage Induced by Human Islet Amyloid Polypeptide
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DOI：
10.1021/ja205007j
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发表时间：
2011-10-05
影响因子：
15
通讯作者：
Killian, J. Antoinette
中科院分区：
文献类型：
--
作者：
Khemtemourian, Lucie;Domenech, Elena;Killian, J. Antoinette
人胰岛淀粉样多肽（TAPP）是2型糖尿病患者胰岛淀粉样沉积物的主要成分。合成后，IAPP在约5.5的pH下储存在胰腺的β细胞颗粒中，并在7.4的pH下释放到细胞外区室中。为了深入了解IAPP的性质和膜相互作用的pH差异的可能后果，我们在这里比较了IAPP的聚集和构象行为以及IAPP-膜相互作用在pH 5.5和pH 7.4。我们的数据表明，低pH值会降低溶液中和膜存在下原纤维的形成速率。我们通过CD光谱观察到，这些动力学差异与肽的构象行为变化直接相关。从机理上讲，在pH 5.5和pH 7.4下发生的过程似乎相似。在这两个pH值下，我们发现IAPP原纤维生长的动力学曲线与IAPP诱导的膜损伤的动力学曲线相匹配，并且两者的特征在于滞后期和S形转变。此外，单层研究以及固态NMR实验表明，作为pH值的函数的动力学和构象行为的差异是不是由于不同的模式膜插入。我们的研究表明，低pH值可以防止分泌颗粒中IAPP的聚集和膜损伤，最有可能是通过影响肽的电离特性。
Human islet amyloid polypeptide (TAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus. After synthesis, IAPP is stored in the beta-cell granules of the pancreas at a pH of approximately 5.5 and released into the extracellular compartment at a pH of 7.4. To gain insight into the possible consequences of pH differences for properties and membrane interaction of IAPP, we here compared the aggregational and conformational behavior of IAPP as well as IAPP-membrane interactions at pH 5.5 and pH 7.4. Our data reveal that a low pH decreases the rate of fibril formation both in solution and in the presence of membranes. We observed by CD spectroscopy that these differences in kinetics are directly linked to changes in the conformational behavior of the peptide. Mechanistically, the processes that occur at pH 5.5 and pH 7.4 appear to be similar. At both pH values, we found that the kinetic profile of IAPP fibril growth matches the kinetic profile of IAPP-induced membrane damage, and that both are characterized by a lag phase and a sigmoidal transition. Furthermore, monolayer studies as well as solid-state NMR experiments indicate that the differences in kinetics and conformational behavior as function of pH are not due to a different mode of membrane insertion. Our study suggests that a low pH prevents aggregation and membrane damage of IAPP in the secretory granules, most likely by affecting the ionization properties of the peptide.