{
  "abstract": "Tau assembles into fibrillar aggregates that are pathological hallmarks of a group of neurodegenerative diseases collectively called tauopathies. Templated aggregation of naïve 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 ¹H-¹⁵N 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, Northwestern University, Evanston, IL 60208-3113.",
    "Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510.",
    "Department of Chemical Engineering, University of California, Santa Barbara, CA 93106-5080.",
    "Department of Physics, University of California, Santa Barbara, CA 93106-9530."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Chung-Ta Han",
      "orcid": "0009-0006-0924-3617"
    },
    {
      "affs": [
        1
      ],
      "name": "Karen Tsay"
    },
    {
      "affs": [
        2
      ],
      "name": "Samuel Lobo",
      "orcid": "0000-0002-1162-8798"
    },
    {
      "affs": [
        1
      ],
      "name": "Saeed Najafi"
    },
    {
      "affs": [
        0
      ],
      "name": "Kieran Monahan"
    },
    {
      "affs": [
        0
      ],
      "name": "Erica Hong",
      "orcid": "0009-0004-9227-7847"
    },
    {
      "affs": [
        2
      ],
      "name": "M Scott Shell",
      "orcid": "0000-0002-0439-1534"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Joan-Emma Shea",
      "orcid": "0000-0002-9801-9273"
    },
    {
      "affs": [
        0
      ],
      "name": "Songi Han",
      "orcid": "0000-0001-6489-6246"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e42qc2x75czg5.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2611158123",
  "fulltext_url": "https://europepmc.org/articles/PMC13684300",
  "id": "e42qc2x75czg5",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://europepmc.org/article/MED/42863048",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7221529573",
  "pdf_url": "https://europepmc.org/articles/PMC13684300?pdf=render",
  "pmcid": "PMC13684300",
  "pmid": "42863048",
  "published": "2026-10-12",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e42qc2x75czg5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:00Z",
      "native_id": "MED:42863048",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42863048"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "A water-pinning hot spot drives templated tau aggregation.",
  "title_text": "A water-pinning hot spot drives templated tau aggregation.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:00Z",
  "url": "https://research.draconitic.com/paper/e42qc2x75czg5",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}