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We tested the ability of <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/firstglance.jmol.org\/fg.htm?mol=3DEO\">cpSRP43<\/jats:ext-link>, a small, robust, ATP\u2010 and cofactor\u2010independent plant chaperone built from an ARD, to antagonize disease\u2010linked protein aggregation. <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/firstglance.jmol.org\/fg.htm?mol=3DEO\">cpSRP43<\/jats:ext-link> delays the aggregation of multiple proteins including the amyloid beta peptide (A\u03b2) associated with Alzheimer's disease and \u03b1\u2010synuclein associated with Parkinson's disease. Kinetic modeling and biochemical analyses show that <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/firstglance.jmol.org\/fg.htm?mol=3DEO\">cpSRP43<\/jats:ext-link> targets early oligomers during A\u03b2 aggregation, preventing their transition to a self\u2010propagating nucleus on the fibril surface. Accordingly, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/firstglance.jmol.org\/fg.htm?mol=3DEO\">cpSRP43<\/jats:ext-link> rescued neuronal cells from the toxicity of extracellular A\u03b242 aggregates. The substrate\u2010binding domain of <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/firstglance.jmol.org\/fg.htm?mol=3DEO\">cpSRP43<\/jats:ext-link>, composed primarily of the ARD, is necessary and sufficient to prevent A\u03b242 aggregation and protect cells against A\u03b242 toxicity. This work provides an example in which an ARD chaperone non\u2010native to mammalian cells harbors anti\u2010amyloidal activity, which may be exploited for bioengineering.<\/jats:p>","DOI":"10.1002\/pro.4728","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T18:07:10Z","timestamp":1689098830000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An ankyrin repeat chaperone targets toxic oligomers during amyloidogenesis"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8573-8818","authenticated-orcid":false,"given":"Arpit","family":"Gupta","sequence":"first","affiliation":[{"name":"Division of Chemistry and Chemical Engineering California Institute of Technology  Pasadena California 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