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Chin. Phys. B, 2022, Vol. 31(10): 108702    DOI: 10.1088/1674-1056/ac8920

Peptide backbone-copper ring structure: A molecular insight into copper-induced amyloid toxicity

Jing Wang(王静)1,†, Hua Li(李华)2,†, Xiankai Jiang(姜先凯)3,†,‡, Bin Wu(吴斌)2, Jun Guo(郭俊)2, Xiurong Su(苏秀榕)1, Xingfei Zhou(周星飞)1, Yu Wang(王宇)4, Geng Wang(王耿)4, Heping Geng(耿和平)4, Zheng Jiang(姜政)4, Fang Huang(黄方)5, Gang Chen(陈刚)4,6,§, Chunlei Wang(王春雷)7, Haiping Fang(方海平)8, and Chenqi Xu(许琛琦)2,9,¶
1. Faculty of Science, Ningbo University, Ningbo 315211, China;
2. National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
3. School of Sciences, Changzhou Institute of Technology, Changzhou, 213032, China;
4. Shanghai Synchrotron Radiation Facility, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China;
5. Center for Bioengineering and Biotechnology, China University of Petroleum (Huadong), Qingdao 266580, China;
6. School of Physical Science and Technology, ShanghaiTech University, Shanghai 200031, China;
7. Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China;
8. School of Physics and National Engineering Research Center of Industrial Wastewater Detoxication and Resource Recovery, East China University of Science and Technology, Shanghai 200031, China;
9. School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
Abstract  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.
Keywords:  interactions between metal ion and protein      quantum chemistry calculation      protein aggregation      amyloid diseases  
Received:  02 July 2022      Revised:  03 August 2022      Accepted manuscript online: 
PACS:  87.15.-v (Biomolecules: structure and physical properties) (Protein-ligand interactions) (Electronic structure and bonding characteristics)  
  68.37.Ps (Atomic force microscopy (AFM))  
Fund: Project supported by the National Natural Science Foundation of China (Grant Nos. 12074208 and 11375256), the Natural Science Foundation of Jiangsu Province (Grant No. BK20200176), the Natural Science Foundation of Jiangsu Higher Education Institutions of China (Grant Nos. 20KJB140020 and 19KJB140005), Fundamental Research Project from Changzhou Science and Technology (Grant No. CJ20200029), and the Jiangsu Province High-level Innovative and Entrepreneurial Talents Introduction Plan.
Corresponding Authors:  Xiankai Jiang, Gang Chen, Chenqi Xu     E-mail:;;

Cite this article: 

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) Peptide backbone-copper ring structure: A molecular insight into copper-induced amyloid toxicity 2022 Chin. Phys. B 31 108702

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