Acidic Environment Significantly Alters Aggregation Pathway of Human Islet Amyloid Polypeptide at Negative Lipid Membrane
Acidic Environment Significantly Alters Aggregation Pathway of Human Islet Amyloid Polypeptide at Negative Lipid Membrane
复制标题
酸性环境显着改变负脂膜上人胰岛淀粉样多肽的聚集途径
DOI：
10.1021/acs.langmuir.9b03623
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发表时间：
2020
期刊：
影响因子：
3.9
通讯作者：
Shuji Ye
中科院分区：
文献类型：
--
作者：
Jiahui Zhang;Junjun Tan;Ruoqi Pei;Shuji Ye
人胰岛淀粉样多肽（human islet amyloid polypeptide，hIAPP）在细胞膜上的错误折叠和聚集与2型糖尿病（type 2 diabetes，T2 DM）的发生密切相关。这种聚集过程易受各种生理相关因素的影响，因此对条件介导的hIAPP聚集的系统研究对于彻底了解T2 DM的病理学至关重要。在这项研究中，我们结合了表面敏感的酰胺I和酰胺II的光谱信号的蛋白质骨架，同时产生的高灵敏度飞秒宽带和频产生振动光谱系统，研究环境pH值的动态结构变化的hIAPP在膜表面原位和真实的时间的影响。这样的组合可以直接区分在膜表面处的发夹样单体和低聚物/原纤维的形成。很明显，在酸性环境中，hIAPP减慢其构象演变并改变其聚集途径，导致形成非途径寡聚体。当成熟的hIAPP聚集体暴露于碱性亚相时，观察到从β-折叠寡聚体到有序β-折叠纤维状结构的部分转化。然而，当暴露于酸性环境时，hIAPP原纤维部分匡威为更松散的图案化β-折叠寡聚体结构。
The misfolding and aggregation of human islet amyloid polypeptide (hIAPP) at cell membrane has a close relationship with the development of type 2 diabetes (T2DM). This aggregation process is susceptible to various physiologically related factors, and systematic studies on condition-mediated hIAPP aggregation are therefore essential for a thorough understanding of the pathology of T2DM. In this study, we combined surface-sensitive amide I and amide II spectral signals from the protein backbone, generated simultaneously in a highly sensitive femtosecond broad-band sum frequency generation vibrational spectroscopy system, to examine the effect of environmental pH on the dynamical structural changes of hIAPP at membrane surface in situ and in real time. Such a combination can directly discriminate the formation of β-hairpin-like monomer and oligomer/fibril at the membrane surface. It is evident that, in an acidic milieu, hIAPP slows down its conformational evolution and alters its aggregation pathway, leading to the formation of off-pathway oligomers. When matured hIAPP aggregates are exposed to basic subphase, partial conversion from β-sheet oligomers into ordered β-sheet fibrillar structures is observed. When exposed to acidic environment, however, hIAPP fibrils partially converse into more loosely patterned β-sheet oligomeric structures.