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Here it is reported that the universal energy molecule ATP is another substrate for \u03b1\u2010synuclein amyloid chemical catalysis. To reveal the underlying mechanism, the high\u2010resolution cryo\u2010EM structure of the amyloids in the presence of ATP is solved. The structure reveals a type 1A amyloid fold with an additional \u03b2\u2010strand involving residues 16\u201022 that wraps around the ATP, creating an enclosed cavity at the interface of the protofilaments. Mutations of putative ATP\u2010interacting residues in the cavity and the additional \u03b2\u2010strand showed that replacing any one of Lys21, Lys23, Lys43, Lys45, and Lys60 with Ala reduced amyloid\u2010mediated ATPase activity. High\u2010resolution structural analysis of Lys21Ala \u03b1\u2010synuclein amyloids in the presence of ATP reveals the same fold as wild\u2010type \u03b1\u2010synuclein amyloids but without the extra \u03b2\u2010strand and with ATP oriented differently. It is concluded that positively\u2010charged side chains, along with ordering of the N\u2010terminal part into a \u03b2\u2010strand, enclosing the cavity, are essential parameters governing ATP hydrolysis by \u03b1\u2010synuclein amyloids. Amyloid\u2010catalyzed ATP hydrolysis may hamper ATP\u2010dependent rescue systems near amyloid deposits in vivo.<\/jats:p>","DOI":"10.1002\/advs.202508441","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T19:32:48Z","timestamp":1760643168000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["ATP Hydrolysis by \u03b1\u2010Synuclein Amyloids is Mediated by Enclosing \u03b2\u2010Strand"],"prefix":"10.1002","volume":"12","author":[{"given":"Lukas","family":"Frey","sequence":"first","affiliation":[{"name":"ETH Z\u00fcrich Institute of Molecular Physical Science  Z\u00fcrich 8092 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiamma Ayelen","family":"Buratti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Chalmers University of Technology  Gothenburg 412 96 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Chalmers University of Technology  Gothenburg 412 96 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shraddha","family":"Parate","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Chalmers University of Technology  Gothenburg 412 96 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjeet","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Chalmers University of Technology  Gothenburg 412 96 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Riek","sequence":"additional","affiliation":[{"name":"ETH Z\u00fcrich Institute of Molecular Physical Science  Z\u00fcrich 8092 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1058-1964","authenticated-orcid":false,"given":"Pernilla","family":"Wittung\u2010Stafshede","sequence":"additional","affiliation":[{"name":"Department of Life Sciences Chalmers University of Technology  Gothenburg 412 96 Sweden"},{"name":"Department of Chemistry Rice University  Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061516-045115"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.013"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2013.09.010"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.4161\/pri.4.4.13676"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar050073t"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00069a001"},{"key":"e_1_2_8_4_3","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(97)00891-4"},{"key":"e_1_2_8_4_4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.23.8628"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-191790"},{"key":"e_1_2_8_6_1","first-page":"S219","volume":"84","author":"John A.","year":"2018","journal-title":"Ann. 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