{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:46:07Z","timestamp":1791834367932,"version":"4.3.4"},"reference-count":63,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:p>\n                    Tau assembles into fibrillar aggregates that are pathological hallmarks of a group of neurodegenerative diseases collectively called tauopathies. Templated aggregation of na\u00efve tau to seeding-competent fibrils that proceed from cell to cell is a key driver of prion-like progression of tauopathies. This study tests the hypothesis that tau, an intrinsically disordered protein, achieves in-register stacking to form seed-competent fibrils by a pinning action of tau to each other and\/or the seed surface via a single dominant hotspot to avoid mismatch in tau stacking to fibrils. Structured solvation water has been proposed to be a signature of such hot spots at both the tau fibril-end surface and soluble tau monomers. Although jR2R3-P301L tau exhibits a heterogeneous hydration landscape in its intrinsically disordered state, with enhanced water structuring near the P301L mutation site, it is unclear whether a localized hotspot exists at the fibril end surface and surface water facilitates the initial contacts in templated aggregation. Using rapid\n                    <jats:sup>1<\/jats:sup>\n                    H-\n                    <jats:sup>15<\/jats:sup>\n                    N SOFAST-HMQC NMR to track seed-induced aggregation of jR2R3-P301L in real time, complemented by molecular dynamics simulation of fibril surface hydration, we identify a residue-specific pinning hotspot that is prone to dewetting followed by sequential folding and incorporation of the remaining segment in a two-step dock-and-lock process. Site-specific spin labeling further demonstrates that blocking this pinning hotspot disrupts templated aggregation, leading to shorter fibrils. The identification of a dominant pinning site will facilitate the rational design of binders to effectively disrupt fibril extension or serve as diagnostic or therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2611158123","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:03:09Z","timestamp":1791831789000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["A water-pinning hot spot drives templated tau aggregation"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0924-3617","authenticated-orcid":false,"given":"Chung-Ta","family":"Han","sequence":"first","affiliation":[{"name":"Department of Chemistry, Northwestern University","place":["Evanston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Tsay","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02t274463","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry and Biochemistry, University of California","place":["Santa Barbara"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1162-8798","authenticated-orcid":false,"given":"Samuel","family":"Lobo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02t274463","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemical Engineering, University of California","place":["Santa Barbara"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeed","family":"Najafi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02t274463","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry and Biochemistry, University of California","place":["Santa Barbara"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Monahan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Northwestern University","place":["Evanston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9227-7847","authenticated-orcid":false,"given":"Erica","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Northwestern University","place":["Evanston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0439-1534","authenticated-orcid":false,"given":"M. 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