{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:57:33Z","timestamp":1790776653232,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["CRG\/2018\/004960"],"award-info":[{"award-number":["CRG\/2018\/004960"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>\n                    Tau protein is found abundantly in neurofibrillary tangles in Alzheimer's disease (AD). The longest human tau isoform (2N4R) has 44 lysine residues. Several lysine\u2010based post\u2010translational modifications (PTMs) such as glycation, acetylation, ubiquitination, and sumoylation have been implicated not only in AD, but also in other tauopathies. Carbamylation is one such lysine neutralizing age\u2010related nonenzymatic PTM which can modulate the aggregation propensity of tau. In this work, we have studied the aggregation potential of lysine\u2010rich regions of tau upon carbamylation which do not aggregate in their native form. Using an array of biophysical and microscopic analyses, such as ThT kinetic assay, fluorescence microscopy, Congo red staining, and scanning electron microscopy, we demonstrate that peptides derived from four of five such regions exhibit robust fibrillar amyloid formation. These regions are found in the N\u2010terminal projection domain that encompasses proline\u2010rich domain (148\u2013153 and 223\u2013230), repeat domain R1 (253\u2013260), as well as fibrillary core region (368\u2013378), and can be described as hidden aggregation hot\u2010spots which become activated upon carbamylation. We have further compared the impact of carbamylation with acetylation on the aggregation propensity of lysine\u2010rich peptide (\n                    <jats:sup>254<\/jats:sup>\n                    KKVAVV\n                    <jats:sup>259<\/jats:sup>\n                    ) using biophysical experiments and molecular dynamics simulations and deduced that carbamylation is a much stronger driver of aggregation than acetylation. Our findings may offer more insight into amyloid fibrils' interaction with hidden aggregation\u2010prone nucleating sequences that act as hot\u2010spots for inducing tau fibrillation.\n                  <\/jats:p>","DOI":"10.1111\/febs.16284","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T02:35:49Z","timestamp":1637289349000},"page":"2562-2577","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Charge neutralization of lysine via carbamylation reveals hidden aggregation hot\u2010spots in tau protein flanking regions"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7945-4886","authenticated-orcid":false,"given":"Joshna","family":"Gadhavi","sequence":"first","affiliation":[{"name":"Department of Biological Engineering Indian Institute of Technology Gandhinagar  India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumedha","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering Indian Institute of Technology Gandhinagar  India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tulika","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Biotechnology Birla Institute of Technology  Ranchi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7365-7455","authenticated-orcid":false,"given":"Alok","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Biotechnology Birla Institute of Technology  Ranchi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9136-3875","authenticated-orcid":false,"given":"Sharad","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering Indian Institute of Technology Gandhinagar  India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006247"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb03390.x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2010.12.023"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature23002"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2020.05.011"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.13.4884"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.39578"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.611285"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-78161-0"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.10.029"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi500006v"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051360"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10040232"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-020-09878-8"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2018.07.030"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12154-009-0027-5"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/10.3.355"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky497"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_11_21_1","unstructured":"The PyMOL Molecular Graphics System Version 2.0.Schr\u00f6dinger LLC. 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