The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme A biological perspective
The irreversible binding of amyloid peptide substrates to insulin-degrading enzyme A biological perspective
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DOI：
10.4161/pri.2.2.6710
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发表时间：
2008-04-01
期刊：
影响因子：
2.3
通讯作者：
Castano, Eduardo M.
中科院分区：
文献类型：
--
作者：
de Tullio, Matias B.;Morelli, Laura;Castano, Eduardo M.
胰岛素降解酶（Insulin-degradingenzyme，IDE）是一种保守的Zn ~（2+）金属内肽酶，参与胰岛素降解和阿尔茨海默病（Alzheimer 'sdisease，AD）脑内淀粉样β肽（amyloidbetapeptide，A β）稳态水平的维持。我们最近证明IDE和A β能够形成化学计量且极其稳定的复合物，这就提出了关于这种独特的蛋白质-肽相互作用在生理和病理条件下的作用的几种有趣的可能性。这些包括IDE作为其蛋白水解活性的“死端伴侣”替代物的保护性细胞功能，以及A β与IDE的不可逆结合对其作为水痘带状疱疹病毒受体的作用的潜在影响。在病理背景下，胰岛素信号转导及其与AD发病机制的关系的影响进行了讨论。此外，我们的研究结果值得进一步研究淀粉样蛋白生成肽和其他锌2+金属肽酶与IDE样折叠和底物构象依赖的识别机制之间可能的一般和新的相互作用。
Insulin-degrading enzyme (IDE) is a conserved Zn2+ metalloendopeptidase involved in insulin degradation and in the maintenance of brain steady-state levels of amyloid beta peptide (A beta) of Alzheimer's disease (AD). Our recent demonstration that IDE and A beta are capable of forming a stoichiometric and extremely stable complex raises several intriguing possibilities regarding the role of this unique protein-peptide interaction in physiological and pathological conditions. These include a protective cellular function of IDE as a "dead-end chaperone" alternative to its proteolytic activity and the potential impact of the irreversible binding of A beta to IDE upon its role as a varicella zoster virus receptor. In a pathological context, the implications for insulin signaling and its relationship to AD pathogenesis are discussed. Moreover, our findings warrant further research regarding a possible general and novel interaction between amyloidogenic peptides and other Zn2+ metallopeptidases with an IDE-like fold and a substrate conformation-dependent recognition mechanism.