{
  "abstract": "Tau assembles into fibrillar aggregates that are pathological hallmarks of a group of neurodegenerative diseases collectively called tauopathies. Templated aggregation of naive 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 (IDP), 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 hotspots 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": [
    "Northwestern University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "C.-T. Han"
    },
    {
      "name": "K. Tsay"
    },
    {
      "name": "S. Lobo"
    },
    {
      "name": "S. Najafi"
    },
    {
      "name": "K. Monahan"
    },
    {
      "name": "E. Hong"
    },
    {
      "name": "M. S. Shell"
    },
    {
      "name": "J.-E. Shea"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Han"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bskzmpptnxy4n.bib",
  "cited_by": 1,
  "doi": "10.64898/2026.08.04.742883",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.04.742883v3.full",
  "id": "bskzmpptnxy4n",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.04.742883v3",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7202099824",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.04.742883v3.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/bskzmpptnxy4n.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:30Z",
      "native_id": "10.64898/2026.08.04.742883",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.04.742883v3"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "A water-pinning hotspot drives templated tau aggregation",
  "title_text": "A water-pinning hotspot drives templated tau aggregation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:30Z",
  "url": "https://research.draconitic.com/paper/bskzmpptnxy4n",
  "venue": "bioRxiv",
  "versions": []
}