Copper binding and protein aggregation: a journey from the brain to the human lens

Metal ions have been implicated in several proteinopathies associated to degenerative and neurodegenerative diseases. While the molecular mechanisms for protein aggregation are still under investigation, recent findings from Cryo-EM point out to polymorphisms in aggregates obtained from patients, as compared to those formed in vitro, suggesting that several factors may impact aggregation in vivo. One of these factors could be the direct binding of metal ions to the proteins engaged in aggregate formation. In this opinion article, three case studies are discussed to address the question of how metal ion binding to a peptide or protein may impact its conformation, folding, and aggregation, and how this may be relevant in understanding the polymorphic nature of the aggregates related to disease. Specifically, the impact of Cu²⁺ ions in the amyloid aggregation of amyloid-β and amylin (or IAPP- islet amyloid polypeptide) are discussed and then contrasted to the case of Cu²⁺-induced non-amyloid aggregation of human lens γ-crystallin proteins. For the intrinsically disordered peptides amyloid-β and IAPP, the impact of Cu²⁺ ion binding is highly dependent on the relative location of the metal binding site and the hydrophobic regions involved in β-sheet folding and amyloid formation. Further structural studies of how Cu²⁺ binding impacts amyloid aggregation pathways and the molecular structure of the final amyloid fibril, both, in vitro and in vivo, will certainly shed light into the molecular origins of the polymorphisms observed in diseased tissue. Finally, contrasting these cases to that of Cu²⁺-induced non-amyloid aggregation of γ-crystallins, it is evident that, although the impact in aggregation - and the nature of the aggregate - may differ in each system, at the molecular level there is a competition between metal ion coordination and the stability of β-sheet structures. Considering the importance of the β-sheet fold in biology, it is fundamental to understand the energetics and molecular details behind such competition. This opinion article aims to highlight future research directions in the field that can help tackle the important question of how metal ion binding may impact protein folding and aggregation and how this relates to disease.