Islet amyloid polypeptide (IAPP), a 37 residue polypeptide, is the main protein component of islet amyloid deposits produced in the pancreas in Type 2 diabetes. Human IAPP contains five serine residues at positions 19, 20, 28, 29, and 34. Models of the IAPP amyloid fibril indicate a structure composed of two closely aligned columns of IAPP monomers with each monomer contributing to two intermolecular β-strands. Ser 19 and Ser 20 are in the partially ordered β-turn region, which links the two strands, whereas Ser 28, Ser 29, and Ser 34 are in the core region of the amyloid fibril. Ser 29 is involved in contacts between the two columns of monomers and is the part of the steric zipper interface. We undertook a study of individual serine substitutions with the hydrophobic isostere 2-aminobutyric acid (2-Abu) to examine the site-specific role of serine side chains in IAPP amyloid formation. All five variants formed amyloid. The Ser 19 to 2-Abu mutant accelerates amyloid formation by a factor of 3 to 4, while the Ser 29 to 2-Abu mutation modestly slows the rate of amyloid formation. 2-Abu replacements at the other sites had even smaller effects. The data demonstrate that the cross-column interactions made by residue 29 are not essential for amyloid formation and also show that cross-strand networks of hydrogen-bonded Ser side chains, so called Ser-ladders, are not required for IAPP amyloid formation. The effect of the Ser 19 to 2-Abu mutant suggests that residues in this region are important for amyloid formation by IAPP.

中文翻译：

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胰岛淀粉样蛋白多肽在淀粉样蛋白形成中丝氨酸侧链相互作用的差异作用。

胰岛淀粉样蛋白多肽（IAPP）是37个残基的多肽，是2型糖尿病胰腺中产生的胰岛淀粉样蛋白沉积的主要蛋白质成分。人IAPP在位置19、20、28、29和34处含有5个丝氨酸残基。IAPP淀粉样蛋白原纤维的模型表明，该结构由两个IAPP单体紧密排列的列组成，每个单体都贡献了两个分子间的β链。Ser 19和Ser 20在连接两个链的部分有序的β-turn区域中，而Ser 28，Ser 29和Ser 34在淀粉样蛋白原纤维的核心区域中。Ser 29参与两列单体之间的接触，是空间拉链界面的一部分。我们进行了一个单独的丝氨酸取代疏水等排异构体2-氨基丁酸（2-Abu）的研究，以检查丝氨酸侧链在IAPP淀粉样蛋白形成中的位点特异性作用。所有五个变体形成淀粉样蛋白。Ser 19到2-Abu突变体将淀粉样蛋白形成的速度提高了3到4倍，而Ser 29到2-Abu突变体则适度地减慢了淀粉样蛋白的形成速度。其他地点的2-Abu替代品产生的影响甚至更小。数据表明，残基29产生的跨柱相互作用对于淀粉样蛋白的形成不是必不可少的，并且还表明IAPP淀粉样蛋白的形成不需要氢键合的Ser侧链的跨链网络，即所谓的Ser-ladders。Ser 19到2-Abu突变体的影响表明，该区域的残基对于IAPP形成淀粉样蛋白很重要。