{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:50:26Z","timestamp":1774648226041,"version":"3.50.1"},"reference-count":27,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T00:00:00Z","timestamp":1574812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (Portugal)","award":["UID\/Multi\/04046\/2013; PTDC\/NEU-NMC\/2138\/2014; RECI\/BBB-BEP\/0104\/2012; IF\/01046\/2014; SFRH\/BD\/101171\/2014"],"award-info":[{"award-number":["UID\/Multi\/04046\/2013; PTDC\/NEU-NMC\/2138\/2014; RECI\/BBB-BEP\/0104\/2012; IF\/01046\/2014; SFRH\/BD\/101171\/2014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metal ions are well known modulators of protein aggregation and are key players in Alzheimer\u2019s Disease, being found to be associated to pathologic protein deposits in diseased brains. Therefore, understanding how metals influence amyloid aggregation is critical in establishing molecular mechanisms that underlie disease onset and progression. Here, we report data on the interaction of full-length human Tau protein with calcium and zinc ions, evidencing that Tau self-assembly is differently regulated, depending on the type of bound metal ion. We established that Tau binds 4 Zn2+ and 1 Ca2+ per monomer while using native mass spectrometry analysis, without inducing order or substantial conformational changes in the intrinsically disordered Tau, as determined by structural analysis using circular dichroism and Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopies. However, Tau aggregation is found to proceed differently in the calcium- and -zinc bound forms. While the rate of aggregation, as determined from thioflavin-T (ThT) fluorescence kinetics, is highly increased in both cases, the reaction proceeds via different mechanisms, as evidenced by the absence of the lag phase in the reaction of zinc-bound Tau. Monitoring Tau aggregation using native mass spectrometry indeed evidenced a distinct distribution of Tau conformers along the reaction, as confirmed by dynamic light scattering analysis. We propose that such differences arise from zinc binding at distinct locations within the Tau sequence that prompt both the rapid formation of seeding oligomers through interactions at high affinity sites within the repeat domains, as well as amorphous aggregation, through low affinity interactions with residues elsewhere in the sequence, including at the fuzzy coat domain.<\/jats:p>","DOI":"10.3390\/ijms20235979","type":"journal-article","created":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T11:07:00Z","timestamp":1574852820000},"page":"5979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Zinc Binding to Tau Influences Aggregation Kinetics and Oligomer Distribution"],"prefix":"10.3390","volume":"20","author":[{"given":"Guilherme G.","family":"Moreira","sequence":"first","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"given":"Joana S.","family":"Crist\u00f3v\u00e3o","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-6127","authenticated-orcid":false,"given":"Vukosava M.","family":"Torres","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"FTICR e Structural MS laboratory, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2654-6848","authenticated-orcid":false,"given":"Ana P.","family":"Carapeto","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de F\u00edsica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"given":"M\u00e1rio S.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de F\u00edsica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4883-2637","authenticated-orcid":false,"given":"Isabelle","family":"Landrieu","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Glycobiologie Structurale et Fonctionnelle, Universit\u00e9 Lille, Centre National de la Recherche Scientifique, UMR 8576, F-59000 Lille, France"}]},{"given":"Carlos","family":"Cordeiro","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"FTICR e Structural MS laboratory, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]},{"given":"Cl\u00e1udio M.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias, Universidade Lisboa, 1749-016 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"b158","DOI":"10.1136\/bmj.b158","article-title":"Alzheimer\u2019s disease","volume":"338","author":"Burns","year":"2009","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0197-4580(97)00056-0","article-title":"Frequency of stages of Alzheimer-related lesions in different age categories","volume":"18","author":"Braak","year":"1997","journal-title":"Neurobiol. aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1523\/JNEUROSCI.4637-04.2005","article-title":"Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms","volume":"25","author":"Andorfer","year":"2005","journal-title":"J. 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