The aggregation of islet amyloid polypeptide (IAPP) is implicated in the pathogenesis of type 2 diabetes (T2D). In T2D, this peptide aggregates to form amyloid fibrils; the mechanism responsible for islet amyloid formation is unclear. However, it is known that the aggregation propensity of IAPP is highly related to its primary sequence. Several residues have been suggested to be critical in modulating IAPP amyloid formation, but role of the sole lysine residue at position 1 (Lys-1) in IAPP has not been discussed. In our previous study, we found that glycated IAPP can form amyloid faster than normal IAPP and induce normal IAPP to expedite the aggregation process. To gain more insight into the contribution of Lys-1 in the kinetics of fibril formation, we synthesized another two IAPP variants, K1E-IAPP and K1Nle-IAPP, in which the Lys residue was mutated to glutamate and norleucine, respectively. Interestingly, we observed that the negative or neutral charged side chain at this position was preferred for amyloid formation. The findings suggested this residue may take part in the inter- or intra-molecular interaction during IAPP aggregation, even though it was proposed not to be in part of fibril core structure. Our data also revealed that the inhibitory mechanism of some inhibitors for IAPP aggregation require reaction with Lys-1. Modifications of Lys-1, such as protein glycation, may affect the effectiveness of the inhibitory action of some potential drugs in the treatment of amyloidosis.

胰岛淀粉样多肽（IAPP）的聚集与2型糖尿病（T2D）的发病机制有关。在T2D中，该肽聚集形成淀粉样原纤维。胰岛淀粉样蛋白形成的机制尚不清楚。然而，已知IAPP的聚集倾向与其主要序列高度相关。已经提出了几个残基对调节IAPP淀粉样蛋白的形成至关重要，但是尚未讨论IAPP中位置1（Lys-1）处唯一赖氨酸残基的作用。在我们以前的研究中，我们发现糖化的IAPP可以比正常IAPP更快地形成淀粉样蛋白，并诱导正常IAPP加速聚集过程。为了进一步了解Lys-1在原纤维形成动力学中的作用，我们合成了另外两个IAPP变体K1E-IAPP和K1Nle-IAPP，其中Lys残基分别突变为谷氨酸和正亮氨酸。有趣的是，我们观察到在此位置带负电或中性的侧链对于淀粉样蛋白的形成是优选的。研究结果表明，该残基可能参与了IAPP聚集过程中的分子间或分子内相互作用，即使有人提出该残基不属于原纤维核心结构的一部分。我们的数据还揭示了某些抑制剂对IAPP聚集的抑制机制需要与Lys-1反应。Lys-1的修饰（例如蛋白质糖基化）可能会影响某些潜在药物在治疗淀粉样变性中的抑制作用的有效性。研究结果表明，该残基可能参与了IAPP聚集过程中的分子间或分子内相互作用，即使有人提出该残基不属于原纤维核心结构的一部分。我们的数据还表明，某些抑制剂对IAPP聚集的抑制机制需要与Lys-1反应。Lys-1的修饰（例如蛋白质糖基化）可能会影响某些潜在药物在治疗淀粉样变性中的抑制作用的有效性。研究结果表明，该残基可能参与了IAPP聚集过程中的分子间或分子间相互作用，即使有人提出该残基不属于原纤维核心结构的一部分。我们的数据还表明，某些抑制剂对IAPP聚集的抑制机制需要与Lys-1反应。Lys-1的修饰（例如蛋白质糖基化）可能会影响某些潜在药物在治疗淀粉样变性中的抑制作用的有效性。