A Tetramer Derived from Islet Amyloid Polypeptide

Aggregation of the islet amyloid polypeptide (IAPP) to form fibrils and oligomers is important in the progression of type 2 diabetes. This article describes X-ray crystallographic and solution-state NMR studies of peptides derived from residues 11–17 of IAPP that assemble to form tetramers. Incorporation of residues 11–17 of IAPP (RLANFLV) into a macrocyclic β-sheet peptide results in a monomeric peptide that does not self-assemble to form oligomers. Mutation of Arg11 to the uncharged isostere citrulline gives peptide homologues that assemble to form tetramers in both the crystal state and in aqueous solution. The tetramers consist of hydrogen-bonded dimers that sandwich together through hydrophobic interactions. The tetramers share several features with structures reported for IAPP fibrils and demonstrate the importance of hydrogen bonding and hydrophobic interactions in the oligomerization of IAPP-derived peptides.胰岛淀粉样多肽（islet amyloid polypeptide, IAPP）聚集形成原纤维与寡聚体的过程，与2型糖尿病的病情进展密切相关。本文针对IAPP第11至17位残基衍生的、可组装形成四聚体的肽段，展开了X射线晶体学与溶液态核磁共振（nuclear magnetic resonance, NMR）研究。将IAPP第11至17位残基（RLANFLV）引入大环β折叠肽中，可得到无法自组装形成寡聚体的单体肽段。将第11位精氨酸（Arg11）突变为不带电荷的等排体瓜氨酸（citrulline）后，所得到的肽类同源物可在晶体状态与水溶液中均组装形成四聚体。此类四聚体由通过氢键结合的二聚体构成，这些二聚体通过疏水相互作用堆叠结合。该四聚体结构与已报道的IAPP原纤维结构存在多项共同特征，同时证实了氢键与疏水相互作用在IAPP衍生肽段的寡聚化过程中的重要性。