Role of zinc in human islet amyloid polypeptide aggregation.
Role of zinc in human islet amyloid polypeptide aggregation.
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DOI：
10.1021/ja1007867
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发表时间：
2010-07-07
影响因子：
15
通讯作者：
Ramamoorthy, Ayyalusamy
中科院分区：
文献类型：
--
作者：
Brender, Jeffrey R.;Hartman, Kevin;Nanga, Ravi Prakash Reddy;Popovych, Nataliya;Bea, Roberto de la Salud;Vivekanandan, Subramanian;Marsh, E. Neil G.;Ramamoorthy, Ayyalusamy
人胰岛淀粉样多肽（Human Islet Amyloid Polypeptide，hIAPP）是一种存在于II型糖尿病患者胰岛细胞中的高度淀粉样蛋白。由于hIAPP在某些条件下对β细胞具有高度毒性，因此已提出hIAPP与II型糖尿病患者中β细胞和胰岛素分泌的丧失有关。围绕该肽的一个有趣的问题是，在其储存的分泌颗粒中发现的高浓度下，毒性和易于聚集的hIAPP肽如何保持在安全状态。我们在这里显示，锌，这是在分泌颗粒中发现的毫摩尔浓度，显着抑制hIAPP淀粉样纤维形成的浓度类似于那些在细胞外环境中发现的。锌对hIAPP原纤维形成具有双重作用：其在较低浓度下增加纤维形成的滞后时间并降低hIAPP向现有纤维的添加速率，而在较高浓度下具有相反的作用。在酸性pH下的实验，其部分中和了锌结合后的电荷变化，表明抑制主要是由于His18处的静电效应。从NMR实验确定的hIAPP的高分辨率结构证实锌结合到His18，并表明锌诱导IAPP的二级结构在推定的IAPP螺旋中间体的His18附近的局部破坏。锌对hIAPP的聚集和毒性形式的形成的抑制提供了最近发现的将锌转运到分泌颗粒中的SLC30A8锌转运蛋白中的有害突变与II型糖尿病之间的联系之间的可能机制。
Human Islet Amyloid Polypeptide (hIAPP) is a highly amyloidogenic protein found in islet cells of patients with type II diabetes. Because hIAPP is highly toxic to beta-cells under certain conditions, it has been proposed that hIAPP is linked to the loss of beta-cells and insulin secretion in type II diabetics. One of the interesting questions surrounding this peptide is how the toxic and aggregation prone hIAPP peptide can be maintained in a safe state at the high concentrations that are found in the secretory granule where it is stored. We show here zinc, which is found at millimolar concentrations in the secretory granule, significantly inhibits hIAPP amyloid fibrillogenesis at concentrations similar to those found in the extracellular environment. Zinc has a dual effect on hIAPP fibrillogenesis: it increases the lag-time for fiber formation and decreases the rate of addition of hIAPP to existing fibers at lower concentrations, while having the opposite effect at higher concentrations. Experiments at an acidic pH which partially neutralizes the change in charge upon zinc binding show inhibition is largely due to an electrostatic effect at His18. High-resolution structures of hIAPP determined from NMR experiments confirm zinc binding to His18 and indicate zinc induces localized disruption of the secondary structure of IAPP in the vicinity of His18 of a putative helical intermediate of IAPP. The inhibition of the formation of aggregated and toxic forms of hIAPP by zinc provides a possible mechanism between the recent discovery of linkage between deleterious mutations in the SLC30A8 zinc transporter, which transports zinc into the secretory granule, and type II diabetes.
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