Strong Inhibitory Effect of Heme on hIAPP Fibrillation
Strong Inhibitory Effect of Heme on hIAPP Fibrillation
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血红素对 hIAPP 颤动有较强的抑制作用
DOI：
10.1021/acs.chemrestox.7b00170
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发表时间：
2017
影响因子：
4.1
通讯作者：
Gao Zhonghong
中科院分区：
文献类型：
--
作者：
Wu Jinming;Zhao Jie;Yang Zhen;Li Hailing;Gao Zhonghong
人胰岛淀粉样多肽(HIAPP)在β细胞内的沉积与2型糖尿病(T2 DM)的发病有关。据报道，血红素能与hIAPP结合。我们推测，结合可能影响hIAPP的聚集。在本研究中，利用紫外可见光谱检测了血红素与hIAPP的相互作用模式。采用THT和BIS-ANS荧光分析、圆二色光谱、凝胶电泳法和透射电子显微镜研究了血红素对hIAPP聚集的影响。我们发现，血红素显著地抑制了hIAPP的聚集，甚至通过阻止其构象变化来部分地分解hIAPP聚集体。此外，对突变型hIAPP也有类似的抑制作用。在对照组中，原卟啉对hIAPP及其突变体聚集的抑制作用较弱。同样，它对骨料的分解作用也较弱。在这些结果的基础上，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发挥重要作用。我们的结果可能有助于深入了解血红素和hIAPP之间的相互作用，这将有助于设计新的治疗T2 DM的策略。
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.