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. 2018 Sep 15:375:38-55.
doi: 10.1016/j.ccr.2018.04.007.

Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance

Elena Atrián-Blasco  1   2 , Paulina Gonzalez  3   4 , Alice Santoro  3   4 , Bruno Alies  5 , Peter Faller  3   4 , Christelle Hureau  1   2
Affiliations

Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance

Elena Atrián-Blasco et al. Coord Chem Rev. .

Abstract

Several diseases share misfolding of different peptides and proteins as a key feature for their development. This is the case of important neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and type II diabetes mellitus. Even more, metal ions such as copper and zinc might play an important role upon interaction with amyloidogenic peptides and proteins, which could impact their aggregation and toxicity abilities. In this review, the different coordination modes proposed for copper and zinc with amyloid-β, α-synuclein and IAPP will be reviewed as well as their impact on the aggregation, and ROS production in the case of copper. In addition, a special focus will be given to the mutations that affect metal binding and lead to familial cases of the diseases. Different modifications of the peptides that have been observed in vivo and could be relevant for the coordination of metal ions are also described.

Keywords: Amyloid-β; amylin; copper; familial mutations; zinc; α-synuclein.

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Conflict of interest statement

Conflicts of interest: none.

Figures

Fig. 1
Fig. 1
Main coordination modes of (A) hAβwt (for Cu(II), Cu(I) and Zn(II)) and (B) mAβ for Cu(II) at physiological pH and for Zn(II).
Fig. 2
Fig. 2
Cu(II) and Cu(I) coordination to (A) α-synuclein, (B) Ac-α-synuclein and (C) β-synuclein.
Fig. 3
Fig. 3
(A) Representation of the two Cu(II) coordination models proposed for hIAPP with His18 as anchoring ligand, towards the C-terminal (left) and N-terminal (right). (B) Two different propositions for Zn(II) binding to monomeric hIAPP.
Fig. 4
Fig. 4
Schematic representation of some of the morphologies found in the aggregation pathway and off-pathway (amorphous aggregates) of amyloid peptides followed by ThT fluorescence assay and their TEM and AFM images. The most common techniques used to study the aggregation are listed.
Fig. 5
Fig. 5
Schematic mechanism of the ROS production by Cu-amyloidogenic peptides/proteins complexes in the presence of ascorbate (Asc) and dioxygen. Amyloidogenic peptides and proteins considered in this work are Aβ, αSyn and IAPP.
Fig. 6
Fig. 6
Schematic representation of the different coordination geometries around the Cu center in the equilibrium between the “resting state” (for Cu(II) on the left and Cu(I) on the right) and the “in between state”. While for Cu(II) a square planar geometry is favored, Cu(I) prefers a diagonal or tetrahedral geometry. In the “in between state”, where the electron transfer between the Cu and the substrate occurs, we can imagine a highly similar coordination sphere for Cu(II) and Cu(I) in which the substrate is involved. In this way a low re-organization energy would be needed. Aβ, αSyn and IAPP are flexible peptides thus able to adapt to the Cu coordination requirements.
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