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Patient\u2010derived amyloid fibrils are formed from light chain variable domain residues in non\u2010native conformations, highlighting a requirement that light chains unfold from their native structures in order to aggregate. However, mechanistic studies of amyloid formation have primarily focused on the self\u2010assembly of natively unstructured peptides, and the role of native state unfolding is less well understood. Using a well\u2010studied light chain variable domain protein known as WIL, which readily aggregates in vitro under conditions where the native state predominates, we asked how the protein concentration and addition of pre\u2010formed fibril \u201cseeds\u201d alter the kinetics of aggregation. Monitoring aggregation with thioflavin T fluorescence revealed a distinctly non\u2010linear dependence on concentration, with a maximum aggregation rate observed at 8\u2009\u03bcM protein. This behavior is consistent with formation of alternate aggregate structures in the early phases of amyloid formation. Addition of N\u2010 or C\u2010terminal peptide tags, which did not greatly affect the folding or stability of the protein, altered the concentration dependence of aggregation. Aggregation rates increased in the presence of pre\u2010formed seeds, but this effect did not eliminate the delay before aggregation and became saturated when the proportion of seeds added was greater than 1 in 1600. The complexity of aggregation observed in vitro highlights how multiple species may contribute to amyloid pathology in patients.<\/jats:p>","DOI":"10.1002\/pro.4871","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T13:48:14Z","timestamp":1702648094000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Kinetic evidence for multiple aggregation pathways in antibody light chain variable domains"],"prefix":"10.1002","volume":"33","author":[{"given":"Sherry","family":"Wong","sequence":"first","affiliation":[{"name":"Boston University Amyloidosis Center, Boston University Chobanian and Avedisian School of Medicine  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeline E.","family":"West","sequence":"additional","affiliation":[{"name":"Boston University Amyloidosis Center, Boston University Chobanian and Avedisian School of Medicine  Boston 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