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Transition metals such as copper and zinc have been suggested to enhance the toxicity of circulating soluble LCs. We show here how divalent metal ions influence the aggregation behavior of the patient\u2010derived \u03bb\u2010III AL variable domain FOR005. We characterize metal binding across dimeric, monomeric, oligomeric, and fibril aggregation states, using solution\u2010 and MAS solid\u2010state NMR spectroscopy, as well as molecular dynamics (MD) simulations. Zn\n                    <jats:sup>2+<\/jats:sup>\n                    and Cu\n                    <jats:sup>2+<\/jats:sup>\n                    reduce the lag time for fibril formation. In the dimer, the Cu\n                    <jats:sup>2+<\/jats:sup>\n                    binding site involves the side chains of residues D91 from protomer 1 and H96 from protomer 2. The accelerated aggregation kinetics induced by Cu\n                    <jats:sup>2+<\/jats:sup>\n                    arises from differential stabilization of oligomeric intermediate states, either through depletion of off\u2010pathway intermediates or shortened lifetimes of on\u2010pathway species. We find that Cu\n                    <jats:sup>2+<\/jats:sup>\n                    does not bind to a specific site but interacts nonspecifically with the protein fibrils. We hypothesize that a decrease of the cytosolic free pool of ions perturbs the cellular ion homeostasis in cardiomyocytes which in turn can result in dysregulated metabolic function.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70460","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T12:00:57Z","timestamp":1784030457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic Insights Into Metal Binding in the Aggregation Pathway of an Immunoglobulin Light Chain Protein"],"prefix":"10.1002","volume":"27","author":[{"given":"Tejaswini","family":"Pradhan","sequence":"first","affiliation":[{"name":"Bayerisches NMR Zentrum (BNMRZ) at Department of Bioscience TUM School of Natural Sciences Technische Universit\u00e4t M\u00fcnchen  Garching Germany"},{"name":"Helmholtz\u2010Zentrum M\u00fcnchen (HMGU), Deutsches Forschungszentrum f\u00fcr Gesundheit und Umwelt, Institute of Structural Biology (STB)  Neuherberg Germany"},{"name":"Centre of Biomedical Research (CBMR) Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS) Campus  Lucknow Uttar Pradesh India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9055-7897","authenticated-orcid":false,"given":"Riddhiman","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Bayerisches NMR Zentrum (BNMRZ) at Department of Bioscience TUM School of Natural Sciences Technische Universit\u00e4t M\u00fcnchen  Garching Germany"},{"name":"Helmholtz\u2010Zentrum M\u00fcnchen (HMGU), Deutsches Forschungszentrum f\u00fcr Gesundheit und Umwelt, Institute of Structural Biology (STB)  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Leonhard\u2010Preu","sequence":"additional","affiliation":[{"name":"Institute of 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