ReviewCu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance☆
Graphical abstract
Introduction
In the last decades, the discovery of a common characteristic to different diseases is leading the research on their development. Neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s and prion diseases share with type II diabetes mellitus (T2D) the misfolding of specific proteins or peptides, which causes the deposition of amyloid fibrils and plaques in different tissues [1]. Furthermore, metal ions dyshomeostasis has been linked to AD, PD and T2D and could be a key factor in their development as they can greatly impact the aggregation and the redox activity of the implicated peptides and proteins [2], [3], [4]. Several studies have found a relatively high concentration of metal ions (Zn, Cu and Fe) in aggregates such as senile plaques (AD) formed by the amyloid-β (Aβ) peptide [5], [6], [7], [8], [9], and Lewy’s bodies (PD) formed by α-synuclein (αSyn) protein [10]; and a probable correlation between amyloid deposits formation of islet amyloid polypeptide (IAPP, amylin), Zn deficiency and T2D [11]. Nevertheless, there is still no clear evidence of the in vivo metal-binding to Aβ, αSyn and IAPP upstream of the aggregates. One parameter to take into account is the relatively low binding constant for these peptides and protein, which makes metal-binding a low probability scenario in the cytosol [12]. However, interaction between Cu and Zn and intrinsically disordered peptides/proteins (IDPs) could be plausible in the extracellular space. In the case of AD, a “labile copper pool” was proposed [13]. Similarly, spots where high concentration of metal ions, especially loosely bound metals, would be present such as in β-cells in the pancreas could be key for the interaction of IDPs and these metal ions. Moreover, some deregulation of the metal ions' concentration might need to occur, which would increase the available metal ions, and hence permit metal binding to Aβ, αSyn and IAPP.
In this review, we will focus on Cu and Zn, due to their relatively high concentration in the synaptic cleft in the brain and β-cells of the pancreas. The coordination chemistry of Zn(II) and Cu(II/I) have been studied since more than two decades, at least for Aβ. Thus, we do not go into past controversies, which mainly concern the native structure of amyloid-β. We just report the most accepted structures (and refer to past reviews) and concentrate on the most recent advancements often obtained on mutations or modified forms of the peptides/proteins. A general perspective of the metal-induced aggregation and ROS production will be covered in Sections 3 Impact of Cu and Zn on the aggregation of Aβ, αSyn and IAPP, 4 Production of reactive oxygen species catalyzed by Cu-peptides, aiming to compare the last data for the three peptides and protein. Surely this work will complete the reviews that aimed to cover the interaction of metal ions and amyloidogenic peptides individually. Moreover, we aim at outlining their coordination not only to Aβ, αSyn and IAPP, the main disordered peptides and proteins of the mentioned diseases; but also, to the mutated peptides which cause familial pathologies, and the murine peptides, which show different aggregating propensity features in vivo (Table 1). Studying how these mutations impact the coordination of metals ions, and consequently their aggregation and ROS production could be an important step to help elucidate this very interesting chemistry.
Section snippets
Coordination of Cu and Zn to amyloid-β, α-synuclein and IAPP and their mutants
The coordination of metal ions to the different amyloidogenic peptides and proteins has been thoroughly studied. There is still debate regarding some coordination modes. Nonetheless, in the next paragraphs the different coordination modes, including the most accepted and the new ones, proposed for Aβ, αSyn, IAPP and their mutated and murine homologues will be outlined (Table 1). In order to give a more global understanding of Cu and Zn binding to these peptides and protein, their association
Common ground
Metal ions such as Cu and Zn can impact the aggregation of intrinsically disordered peptides and proteins, either by changing the kinetics of the process or the morphologies of the aggregates formed (Fig. 4). The influence of the metal ions in the aggregation of IDPs’ has been thoroughly reviewed in the last years (especially for Aβ) [1], [3], [12], [85], [125], [126], [127], [128], [129], including an article in this special issue [130].
Literature in the field of aggregation of amyloidogenic
Introduction and biological relevance:
Cu-ions can be very efficient catalysts for the reduction of dioxygen resulting in the generation of reactive oxygen species (ROS, like HO, H2O2 and O2−) [179], [180], [181], [182], [183]. An overproduction of ROS induces oxidative stress. Oxidative stress has been observed in several amyloidogenic diseases, including AD, PD and diabetes [184], [185], [186], [187]. However, it is not known to what extent or if at all the complexes of Cu with amyloidogenic peptides and proteins (Aβ, αSyn and
General conclusions
In the present review, we have described the coordination modes of Cu and Zn ions to three peptides and protein of biological interest: Aβ, αSyn and IAPP and to their familial and murine mutants. General coordination trends are shared by these peptides: (i) when available and close to other binding amino-acid residues, the N-terminal amine is the preferred anchoring sites for Cu(II), else His residues serve as the anchoring residues. As N ligands, His and deprotonated amide groups from the
Acknowledgements
The ERC aLzINK grant (ERC-StG-638712) is acknowledged for financial support (granted to C.H.). We acknowledge financial support from the University of Strasbourg Institute for Advanced Study (USIAS; to P.G., C.H. and P.F.), University of Strasbourg (IDEX program, PhD grant to A.S.) and the Frontier Research in Chemistry Foundation of Strasbourg (Installation grant to P.F.).
Conflicts of interest
None.
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This is a contribution to the special issue from the Applied Biological Chemistry Conference Summer 2017 handled by Crans and Gale.