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While Cu(II) reduction is commonly attributed to unfolded or amyloid proteins, here we show that the well\u2010folded plasma protein human serum albumin (HSA) intrinsically reduces Cu(II) to Cu(I) in the absence of external reductants. Using x\u2010ray absorption spectroscopy (XAS), small\u2010angle x\u2010ray scattering (SAXS), and circular dichroism (CD), we propose a redox mechanism involving the disulphide bond Cys392\u2010Cys438 in domain III of HSA. Cu binding at the high\u2010affinity ATCUN (amino\u2010terminal copper and nickel binding site) motif might trigger conformational changes that expose this disulphide bond, enabling thiol\u2010mediated electron transfer and Cu(I) formation. Chelation with tetrathiomolybdate (TTM) impairs this reduction by restricting access to the reactive disulphide site. Comparative analysis with other globular proteins reveals that Cu reduction requires both accessible disulphide motifs and a native folded structure. Simulations and spectroscopy of SOD1 (Superoxide Dismutase 1) confirm that disulphide cleavage enhances Cu\u2010thiolate interaction, supporting a generalisable two\u2010site redox mechanism. These findings reveal a previously unrecognised mode of protein\u2010mediated copper reduction and suggest broader physiological roles for disulphide\u2010regulated redox switching in metal\u00a0homeostasis.<\/jats:p>","DOI":"10.1002\/anie.202519673","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:00:19Z","timestamp":1772964019000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein\u2010Driven Copper Redox Regulation: Uncovering the Role of Disulphide Bonds and Allosteric Modulation"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1662-8244","authenticated-orcid":false,"given":"Rebecca","family":"Sternke\u2010Hoffmann","sequence":"first","affiliation":[{"name":"PSI Center for Life Sciences Villigen PSI Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"PSI Center for Life Sciences Villigen PSI Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"PSI Center for Life Sciences Villigen PSI Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hegne","family":"Pupart","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biotechnology Tallinn University of Technology Tallinn Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Sun","sequence":"additional","affiliation":[{"name":"PSI Center for Life Sciences Villigen PSI Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan Gui\u2010Hyon","family":"Dreiser","sequence":"additional","affiliation":[{"name":"PSI Center for Photon Science Villigen PSI Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peep","family":"Palumaa","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biotechnology Tallinn University of Technology Tallinn Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2260-8493","authenticated-orcid":false,"given":"Qinghua","family":"Liao","sequence":"additional","affiliation":[{"name":"Departament de Qu\u00edmica Inorg\u00e0nica i Org\u00e0nica (Secci\u00f3 de Qu\u00edmica, (Org\u00e0nica) Institut de Qu\u00edmica Te\u00f2rica i Computacional (IQTCUB) Universitat de Barcelona Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Krack","sequence":"additional","affiliation":[{"name":"PSI Center for Scientific Computing, Theory and Data Villigen PSI Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7014-8153","authenticated-orcid":false,"given":"Jinghui","family":"Luo","sequence":"additional","affiliation":[{"name":"PSI Center for Life Sciences Villigen PSI Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.711227"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.5b00060"},{"issue":"2","key":"e_1_2_9_4_1","article-title":"Oxidative Stress Gated by Fenton and Haber Weiss Reactions and Its Association With Alzheimer's Disease","volume":"2","author":"Das T. 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