{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:45:56Z","timestamp":1791557156634,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T00:00:00Z","timestamp":1710201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK\u2010029023"],"award-info":[{"award-number":["DK\u2010029023"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pathogenic huntingtin exon\u20101 protein (htt<jats:sup>ex1<\/jats:sup>), characterized by an expanded polyglutamine tract located between the N\u2010terminal amphiphilic region and a C\u2010terminal polyproline\u2010rich domain, forms fibrils that accumulate in neuronal inclusion bodies, and is associated with a fatal, autosomal dominant neurodegenerative condition known as Huntington's disease. Here a complete kinetic model is described for aggregation\/fibril formation of a htt<jats:sup>ex1<\/jats:sup> construct with a 35\u2010residue polyglutamine repeat, htt<jats:sup>ex1<\/jats:sup>Q<jats:sub>35<\/jats:sub>. Using exchange NMR spectroscopy, it is previously shown that the reversible formation of a sparsely\u2010populated tetramer of the N\u2010terminal amphiphilic domain of htt<jats:sup>ex1<\/jats:sup>Q<jats:sub>35<\/jats:sub>, comprising a <jats:italic>D<\/jats:italic><jats:sub>2<\/jats:sub> symmetric four\u2010helix bundle, occurs on the microsecond time\u2010scale and is a prerequisite for subsequent nucleation and fibril formation on a time scale that is many orders of magnitude slower (hours). Here a unified kinetic model of htt<jats:sup>ex1<\/jats:sup>Q<jats:sub>35<\/jats:sub> aggregation is developed in which fast, reversible tetramerization is directly linked to slow irreversible fibril formation via conversion of pre\u2010equilibrated tetrameric species to \u201cactive\u201d, chain elongation\u2010capable nuclei by conformational re\u2010arrangement with a finite, monomer\u2010independent rate. The unified model permits global quantitative analysis of reversible tetramerization and irreversible fibril formation from a time series of <jats:sup>1<\/jats:sup>H\u2010<jats:sup>15<\/jats:sup>N correlation spectra recorded during the course of htt<jats:sup>ex1<\/jats:sup>Q<jats:sub>35<\/jats:sub> aggregation.<\/jats:p>","DOI":"10.1002\/advs.202309217","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T02:59:46Z","timestamp":1710298786000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Nucleation of Huntingtin Aggregation Proceeds via Conformational Conversion of Pre\u2010Formed, Sparsely\u2010Populated Tetramers"],"prefix":"10.1002","volume":"11","author":[{"given":"Francesco","family":"Torricella","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health  Bethesda MD 20892\u20100520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitali","family":"Tugarinov","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health  Bethesda MD 20892\u20100520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3809-1027","authenticated-orcid":false,"given":"G. Marius","family":"Clore","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health  Bethesda MD 20892\u20100520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,12]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.5"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.2006.00335.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70245-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00041.2009"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1992"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.0c00450"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1521933113"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2020.06.021"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja110715f"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b00281"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15462"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.009"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02360-2"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821216116"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922264117"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.0c01636"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2207690119"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b11441"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja051306e"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10858-005-4425-x"},{"key":"e_1_2_8_21_1","volume-title":"Themodynamics of the Polymerization of Proteins","author":"Oosawa F.","year":"1975"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.010"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.71.12.4864"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(85)90175-5"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(80)84962-9"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2305823120"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1218402110"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-020-0452-1"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922267117"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.5.1942"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8290964"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c04786"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi500300c"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155747"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.42301"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2253"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197809"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu830"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1137\/S1064827594276424"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202309217","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T20:54:31Z","timestamp":1759784071000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202309217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,12]]},"references-count":39,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2024,6]]}},"alternative-id":["10.1002\/advs.202309217"],"URL":"https:\/\/doi.org\/10.1002\/advs.202309217","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,12]]},"assertion":[{"value":"2023-11-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2309217"}}