Aromatic interactions are not required for amyloid fibril formation by islet amyloid polypeptide but do influence the rate of fibril formation and fibril morphology
Aromatic interactions are not required for amyloid fibril formation by islet amyloid polypeptide but do influence the rate of fibril formation and fibril morphology
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DOI：
10.1021/bi0621967
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发表时间：
2007-03-20
期刊：
影响因子：
2.9
通讯作者：
Raleigh, Daniel P.
中科院分区：
文献类型：
--
作者：
Marek, Peter;Abedini, Andisheh;Raleigh, Daniel P.
淀粉样蛋白的形成与广泛的人类疾病有关，涉及一系列不同的蛋白质。人们对阐明导致淀粉样蛋白形成和有助于淀粉样纤维稳定性的相互作用有相当大的兴趣。最近的注意力集中在芳香-芳香和芳香-疏水相互作用在短到中等大小的多肽形成淀粉样蛋白中的潜在作用上。在这里，我们研究芳香族残基是否是胰岛淀粉样多肽(IAPP)形成淀粉样蛋白所必需的。IAPP负责II型糖尿病胰岛淀粉样蛋白的形成，这被认为在疾病的病理中发挥了作用。IAPP全长37个残基，含有三个芳香族残基，Phe-15、Phe-23和Tyr-37。IAPP淀粉样纤维的结构模型假设Tyr-37靠近其中一个苯丙氨酸残基，并且已知Tyr-37在纤化过程中与其中一个苯丙氨酸相互作用；然而，尚不清楚形成淀粉样蛋白是否绝对需要芳香-芳香或芳香-疏水相互作用。制备了F15L/F23L/Y37L三重突变体(IAPP-3XL)，并对其形成淀粉样蛋白的能力进行了检测。CD、硫代黄素结合分析、AFM和透射电子显微镜测量都表明，三个亮氨酸突变体很容易形成淀粉样纤维。然而，取代确实降低了原纤维的形成速度，并改变了原纤维聚集的趋势。因此，虽然芳香族残基不是IAPP形成淀粉样蛋白的绝对必要条件，但它们在纤维组装过程中确实发挥了作用。
Amyloid formation has been implicated in a wide range of human diseases, and a diverse set of proteins is involved. There is considerable interest in elucidating the interactions which lead to amyloid formation and which contribute to amyloid fibril stability. Recent attention has been focused upon the potential role of aromatic-aromatic and aromatic-hydrophobic interactions in amyloid formation by short to midsized polypeptides. Here we examine whether aromatic residues are necessary for amyloid formation by islet amyloid polypeptide (IAPP). IAPP is responsible for the formation of islet amyloid in type II diabetes which is thought to play a role in the pathology of the disease. IAPP is 37 residues in length and contains three aromatic residues, Phe-15, Phe-23, and Tyr-37. Structural models of IAPP amyloid fibrils postulate that Tyr-37 is near one of the phenylalanine residues, and it is known that Tyr-37 interacts with one of the phenylalanines during fibrillization; however, it is not known if aromatic-aromatic or aromatic-hydrophobic interactions are absolutely required for amyloid formation. An F15L/F23L/Y37L triple mutant (IAPP-3XL) was prepared, and its ability to form amyloid was tested. CD, thioflavin binding assays, AFM, and TEM measurements all show that the triple leucine mutant readily forms amyloid fibrils. The substitutions do, however, decrease the rate of fibril formation and alter the tendency of fibrils to aggregate. Thus, while aromatic residues are not an absolute requirement for amyloid formation by IAPP, they do play a role in the fibril assembly process.