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

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.

Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides

“…9 ), which is a common ROS effect. Earlier studies have shown that bound redox-active Cu ions can initiate dityrosine formation, both in Aβ and other peptides and proteins 96 , 122 – 125 , 152 , 156 , 157 . It is therefore not surprising that a similar effect is observed for Ni(II) ions, especially as the NMR results indicate that Tyr10 is one of the Ni(II) binding ligands (Fig.…”