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 spec-troscopy 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.

Jing Wang;Hua Li;Xiankai Jiang;Bin Wu;Jun Guo;Xiurong Su;Xingfei Zhou;Yu Wang;Geng Wang;Heping Geng;Zheng Jiang;Fang Huang;Gang Chen;Chunlei Wang;Haiping Fang;Chenqi Xu

Faculty of Science,Ningbo University,Ningbo 315211,China;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;School of Sciences,Changzhou Institute of Technology,Changzhou,213032,China;Shanghai Synchrotron Radiation Facility,Shanghai Institute of Applied Physics,Chinese Academy of Sciences,Shanghai 201800,China;Center for Bioengineering and Biotechnology,China University of Petroleum(Huadong),Qingdao 266580,China;School of Physical Science and Technology,ShanghaiTech University,Shanghai 200031,China;Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai 201210,China;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;School of Life Science and Technology,ShanghaiTech University,Shanghai 200031,China

中国物理B（英文版）

[1]Jing Wang;Hua Li;Xiankai Jiang;Bin Wu;Jun Guo;Xiurong Su;Xingfei Zhou;Yu Wang;Geng Wang;Heping Geng;Zheng Jiang;Fang Huang;Gang Chen;Chunlei Wang;Haiping Fang;Chenqi Xu-.Peptide backbone-copper ring structure:A molecular insight into copper-induced amyloid toxicity)[J].中国物理B（英文版）,2022(10):324-332

Cu2+is,Cu2+to,Cu+to,Cu2+bound,His18,Ser21,Cu2+simultaneously,Cu+complex,dichlorodihydrofluorescin,thioflavin

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