%A Jing Wang(王静), Hua Li(李华), Xiankai Jiang(姜先凯), Bin Wu(吴斌), Jun Guo(郭俊), Xiurong Su(苏秀榕), Xingfei Zhou(周星飞), Yu Wang(王宇), Geng Wang(王耿), Heping Geng(耿和平), Zheng Jiang(姜政), Fang Huang(黄方), Gang Chen(陈刚), Chunlei Wang(王春雷), Haiping Fang(方海平), and Chenqi Xu(许琛琦) %T Peptide backbone-copper ring structure: A molecular insight into copper-induced amyloid toxicity %0 Journal Article %D 2022 %J Chin. Phys. B %R 10.1088/1674-1056/ac8920 %P 108702-108702 %V 31 %N 10 %U {https://cpb.iphy.ac.cn/CN/abstract/article_125129.shtml} %8 2022-10-16 %X Copper ions can promote amyloid diseases that are associated with amyloid peptides, such as type 2 diabetes (T2D), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, the underlying molecular mechanism remains obscure. Here we present that Cu2+ is able to specifically bind to the backbone of T2D-related human islet amyloid polypeptide (hIAPP) by forming a ring structure, which causes the reduction of Cu2+ to Cu+ to produce reactive oxygen species (ROS) and the modulation of hIAPP aggregation. Nuclear magnetic resonance spectroscopy showed that Cu2+ bound to the backbone of a turn region, His18—Ser21, which is critical for hIAPP aggregation. Ab initio calculations and x-ray absorption fine structure analyses revealed that Cu2+ simultaneously bound with both the amide nitrogen and carbonyl oxygen on the peptide backbone, resulting in a ring structure, and causing the reduction of Cu2+ to Cu+ to form a hIAPP-Cu+ complex. 2',7'-dichlorodihydrofluorescin diacetate fluorescence measurements further indicated that this complex led to enhanced ROS levels in rat insulinoma cells. Additionally, thioflavin T fluorescence and atomic force microscopy measurements denoted that the backbone-Cu ring structure largely modulated hIAPP aggregation, including the inhibition of hIAPP fibrillation and the promotion of peptide oligomerization. These findings shed new light on the molecular mechanism of Cu2+-induced amyloid toxicity involving both the enhancement of ROS and the modulation of hIAPP aggregation.