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Even if many amyloidogenic proteins can bind copper ions as monomers, little is known about copper interactions with the resulting amyloid fibers. Here, we investigate copper interactions with \u03b1\u2010synuclein, the amyloid\u2010forming protein in Parkinson's disease. Copper (Cu(II)) binds tightly to monomeric \u03b1\u2010synuclein in vitro involving the N\u2010terminal amine and the side chain of His50. Using purified protein and biophysical methods in vitro, we reveal that copper ions are readily incorporated into the formed amyloid fibers when present at the start of aggregation reactions, and the metal ions also bind if added to pre\u2010formed amyloids. Efficient incorporation is observed for \u03b1\u2010synuclein variants with perturbation of either one of the high\u2010affinity monomer copper\u2010binding residues (i.e., N\u2010terminus or His50) whereas a variant with both N\u2010terminal acetylation and His50 substituted with Ala does not incorporate any copper into the amyloids. Both the morphology of the resulting \u03b1\u2010synuclein amyloids (amyloid fiber pitch, secondary structure, proteinase sensitivity) and the copper chemical properties (redox activity, chemical potential) are altered when copper is incorporated into amyloids. We speculate that copper chelation by \u03b1\u2010synuclein amyloids contributes to the observed copper dys\u2010homeostasis (e.g., reduced bioavailable levels) in Parkinson's disease patients. At the same time, amyloid\u2010copper interactions may be protective to neuronal cells as they will shield aberrantly free copper ions from promotion of toxic reactive oxygen species.<\/jats:p>","DOI":"10.1002\/pro.4956","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T06:09:22Z","timestamp":1711001362000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Copper ion incorporation in \u03b1\u2010synuclein amyloids"],"prefix":"10.1002","volume":"33","author":[{"given":"Gulshan","family":"Walke","sequence":"first","affiliation":[{"name":"Department of Life Sciences Chalmers University of Technology  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjeet","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Chalmers University of Technology  Gothenburg 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