The polypeptide hormone islet amyloid polypeptide (IAPP) forms islet amyloid in type 2 diabetes, a process which contributes to pancreatic β-cell dysfunction and death. Not all species form islet amyloid, and the ability to do so correlates with the primary sequence. Humans form islet amyloid, but baboon IAPP has not been studied. The baboon peptide differs from human IAPP at three positions containing K1I, H18R, and A25T substitutions. The K1I substitution is a rare example of a replacement in the N-terminal region of amylin. The effect of this mutation on amyloid formation has not been studied, but it reduces the net charge, and amyloid prediction programs suggest that it should increase amyloidogenicity. The A25T replacement involves a nonconservative substitution in a region of IAPP that is believed to be important for aggregation, but the effects of this replacement have not been examined. The H18R point mutant has been previously shown to reduce aggregation in vitro. Baboon amylin forms amyloid on the same timescale as human amylin in vitro and exhibits similar toxicity toward cultured β-cells. The K1I replacement in human amylin slightly reduces toxicity, whereas the A25T substitution accelerates amyloid formation and enhances toxicity. Photochemical cross-linking reveals that the baboon amylin, like human amylin, forms low-order oligomers in the lag phase of amyloid formation. Ion-mobility mass spectrometry reveals broadly similar gas phase collisional cross sections for human and baboon amylin monomers and dimers, with some differences in the arrival time distributions. Preamyloid oligomers formed by baboon amylin, but not baboon amylin fibers, are toxic to cultured β-cells. The toxicity of baboon oligomers and lack of significantly detectable toxicity with exogenously added amyloid fibers is consistent with the hypothesis that preamyloid oligomers are the most toxic species produced during IAPP amyloid formation.

中文翻译：

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狒狒 IAPP 的分析提供了对人类 IAPP 的淀粉样蛋白原性和细胞毒性的洞察

多肽激素胰岛淀粉样多肽 (IAPP) 在 2 型糖尿病中形成胰岛淀粉样蛋白，这一过程会导致胰腺 β 细胞功能障碍和死亡。并非所有物种都形成胰岛淀粉样蛋白，并且这样做的能力与一级序列相关。人类形成胰岛淀粉样蛋白，但尚未研究狒狒IAPP。狒狒肽在包含 K1I、H18R 和 A25T 取代的三个位置与人类 IAPP 不同。K1I 取代是胰淀素 N 端区域取代的罕见例子。尚未研究这种突变对淀粉样蛋白形成的影响，但它减少了净电荷，淀粉样蛋白预测程序表明它应该增加淀粉样蛋白的生成。A25T 替代涉及 IAPP 区域中的非保守替代，该区域被认为对聚集很重要，但这种替代的影响尚未得到检验。H18R 点突变体先前已被证明可减少体外聚集。狒狒淀粉样蛋白在体外形成淀粉样蛋白的时间与人淀粉样蛋白相同，对培养的 β 细胞表现出相似的毒性。人胰淀素中的 K1I 替代物略微降低了毒性，而 A25T 替代物会加速淀粉样蛋白的形成并增强毒性。光化学交联表明狒狒淀粉样蛋白与人淀粉样蛋白一样，在淀粉样蛋白形成的滞后阶段形成低级寡聚体。离子迁移质谱法揭示了人和狒狒胰淀素单体和二聚体的气相碰撞截面大体相似，但到达时间分布存在一些差异。由狒狒胰淀素形成的前淀粉样寡聚体，而不是狒狒胰淀素纤维，对培养的 β 细胞有毒。狒狒低聚物的毒性和外源添加的淀粉样蛋白纤维没有明显可检测到的毒性与前淀粉样蛋白低聚物是 IAPP 淀粉样蛋白形成过程中产生的毒性最强的物种的假设一致。