The deposition of human islet amyloid polypeptide (hIAPP) within β-cells is implicated in the etiology of type 2 diabetes mellitus (T2Dm). It was reported that heme could bind to hIAPP. We speculate that binding may affect the aggregation of hIAPP. In this study, UV–vis spectroscopy was used to detect the interaction pattern between the heme and hIAPP. ThT and Bis-ANS fluorescence assay, circular dichroism spectroscopy, gel electrophoresis assay, and transmission electron microscopy were employed to study the effect of heme on the aggregation of hIAPP. We found that heme dramatically inhibited hIAPP aggregation, even partially dismantled hIAPP aggregates by preventing its conformational changes. Moreover, a similar inhibitory effect was also observed on mutant hIAPP. In the compared group, the inhibitory effects of protoporphyrin on hIAPP and its mutants aggregation were weaker. Similarly, its effect on the dismantlement of the aggregates was also weaker. On the basis of these results, we revealed that the heme iron center was not required for the inhibitory effect on hIAPP but affected the binding affinity of heme to hIAPP. Besides Arg11 and His18, other hydrophobic residues of hIAPP may also play important roles in heme binding. Our results may help to develop an in-depth understanding of the interaction between heme and hIAPP, which would be helpful in designing new therapeutic strategies against T2Dm.

中文翻译：

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血红素对hIAPP原纤化的强抑制作用

人胰岛淀粉样多肽（hIAPP）在β细胞内的沉积与2型糖尿病（T2Dm）的病因有关。据报道，血红素可以与hIAPP结合。我们推测结合可能会影响hIAPP的聚集。在这项研究中，紫外可见光谱被用来检测血红素和hIAPP之间的相互作用模式。ThT和Bis-ANS荧光分析，圆二色光谱，凝胶电泳分析和透射电子显微镜用于研究血红素对hIAPP聚集的影响。我们发现血红素通过阻止其构象变化而显着抑制了hIAPP聚集，甚至部分拆除了hIAPP聚集。此外，还观察到了对突变hIAPP的类似抑制作用。在比较组中 原卟啉对hIAPP及其突变体聚集的抑制作用较弱。同样，它对骨料分解的影响也较弱。基于这些结果，我们揭示了血红素铁中心不是抑制hIAPP所必需的，但影响了血红素与hIAPP的结合亲和力。除Arg11和His18外，hIAPP的其他疏水残基也可能在血红素结合中起重要作用。我们的结果可能有助于深入了解血红素与hIAPP之间的相互作用，这将有助于设计针对T2Dm的新治疗策略。我们发现，血红素铁中心不是抑制hIAPP所必需的，但会影响血红素与hIAPP的结合亲和力。除Arg11和His18外，hIAPP的其他疏水残基也可能在血红素结合中起重要作用。我们的结果可能有助于深入了解血红素与hIAPP之间的相互作用，这将有助于设计针对T2Dm的新治疗策略。我们发现，血红素铁中心不是抑制hIAPP所必需的，但会影响血红素与hIAPP的结合亲和力。除Arg11和His18外，hIAPP的其他疏水残基也可能在血红素结合中起重要作用。我们的结果可能有助于深入了解血红素与hIAPP之间的相互作用，这将有助于设计针对T2Dm的新治疗策略。