{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T08:43:31Z","timestamp":1789548211320,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,9,21]],"date-time":"2015-09-21T00:00:00Z","timestamp":1442793600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["GM110577"],"award-info":[{"award-number":["GM110577"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"GAANN"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\u03b2\u2010synuclein (\u03b2S) is a homologue of \u03b1\u2010synuclein (\u03b1S), the major protein component of Lewy bodies in patients with Parkinson's disease. In contrast to \u03b1S, \u03b2S does not form fibrils, mitigates \u03b1S toxicity <jats:italic>in vivo<\/jats:italic> and inhibits \u03b1S fibril formation <jats:italic>in vitro<\/jats:italic>. Previously a missense mutation of \u03b2S, P123H, was identified in patients with Dementia with Lewy Body disease. The single P123H mutation at the C\u2010terminus of \u03b2S is able to convert \u03b2S from a nontoxic to a toxic protein that is also able to accelerate formation of inclusions when it is in the presence of \u03b1S <jats:italic>in vivo<\/jats:italic>. To elucidate the molecular mechanisms of these processes, we compare the conformational properties of the monomer forms of \u03b1S, \u03b2S and P123H\u2010\u03b2S, and the effects on fibril formation of coincubation of \u03b1S with \u03b2S, and with P123H\u2010\u03b2S. NMR residual dipolar couplings and secondary structure propensities show that the P123H mutation of \u03b2S renders it more flexible C\u2010terminal to the mutation site and more \u03b1S\u2010like. <jats:italic>In vitro<\/jats:italic> Thioflavin T fluorescence experiments show that P123H\u2010\u03b2S accelerates \u03b1S fibril formation upon coincubation, as opposed to wild type \u03b2S that acts as an inhibitor of \u03b1S aggregation. When P123H\u2010\u03b2S becomes more \u03b1S\u2010like it is unable to perform the protective function of \u03b2S, which suggests that the extended polyproline II motif of \u03b2S in the C\u2010terminus is critical to its nontoxic nature and to inhibition of \u03b1S upon coincubation. These studies may provide a basis for understanding which regions to target for therapeutic intervention in Parkinson's disease.<\/jats:p>","DOI":"10.1002\/pro.2798","type":"journal-article","created":{"date-parts":[[2015,9,2]],"date-time":"2015-09-02T19:31:22Z","timestamp":1441222282000},"page":"286-294","source":"Crossref","is-referenced-by-count":16,"title":["The loss of inhibitory C\u2010terminal conformations in disease associated P123H \u03b2\u2010synuclein"],"prefix":"10.1002","volume":"25","author":[{"given":"Maria K.","family":"Janowska","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology Rutgers University Piscataway New Jersey 08854"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Baum","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology Rutgers University Piscataway New Jersey 08854"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,9,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.67"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2001.047"},{"key":"e_1_2_6_4_1","first-page":"REVIEWS3002.","article-title":"The synucleins","volume":"3","author":"George JM","year":"2002","journal-title":"Genome Biol"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(95)90302-X"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0169-328X(94)90187-2"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-09-03214.2000"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.073181508"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.09.039"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi300558q"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109541200"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-009-5246-8"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-813X(02)00029-3"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00462-7"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302349"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl242"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi020604a"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2007.05733.x"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.11.6469"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000139870.14385.3C"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1101"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703711200"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct300241t"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201802109"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111971200"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411805200"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.051803606"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.2217\/fnl.12.5"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.07.009"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.062465306"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi3001825"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja055538p"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja067482k"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407146102"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.149"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.06.063"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010907200"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.2174\/156720509788486491"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600211"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105343200"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi1010927"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi048453u"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(02)00154-4"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.86"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2008.07.004"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412621200"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.554667"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja203979j"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2088"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja001068h"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075018"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi5003025"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0739-6260(91)90050-A"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/25.17.3389"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_2_6_56_1","volume-title":"AMBER 2015","author":"Case DA","year":"2015"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10286"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpro.2798","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.2798","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T19:43:23Z","timestamp":1694634203000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.2798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,21]]},"references-count":56,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,1]]}},"alternative-id":["10.1002\/pro.2798"],"URL":"https:\/\/doi.org\/10.1002\/pro.2798","archive":["Portico"],"relation":{},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"value":"0961-8368","type":"print"},{"value":"1469-896X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9,21]]}}}