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

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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 CryoEM 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 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,