{
  "abstract": "ATTR amyloidosis is caused by transthyretin (TTR) amyloid deposition, yet the sequence-encoded events linking TTR misfolding to fibril nucleation and structural polymorphism remain incompletely defined. Here, we exploit the modular organization of patient-derived TTR fibrils to investigate two components of the pathological core: an N-terminal beta-hairpin spanning residues 11-35 (N-TTR) and a larger C-terminal fragment spanning residues 57-123 (C-TTR). Both fragments independently form beta-rich amyloid fibrils, as demonstrated by electron microscopy, circular dichroism, and fluorescence spectroscopy. Yet, their activities differ markedly. N-TTR fibrils promote full-length TTR aggregation and seed in an engineered cellular biosensor platform established to detect templated TTR assembly, whereas C-TTR aggregates show no detectable templating activity. Cryo-electron microscopy reveals two N-TTR polymorphs that preserve structural features of disease-derived folds, while energetic profiling identifies N-TTR as a stabilizing hotspot within ex vivo structures, providing a basis for this templating functionality. These findings reveal a functional hierarchy among amyloidogenic segments of TTR, since distinct regions form fibrils independently, but only those with structural compatibility efficiently template the parent protein. N-TTR therefore represents an autonomous amyloidogenic segment that links local sequence propensity to TTR nucleation, templating, and fibril polymorphism.",
  "abstract_shown": true,
  "affiliations": [
    "UT Southwestern Medical Center"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "L. Gadhe"
    },
    {
      "name": "B. A. Nguyen"
    },
    {
      "name": "M. d. C. Fernandez Ramirez"
    },
    {
      "name": "K. Konstantoulea"
    },
    {
      "name": "M. Lozen"
    },
    {
      "name": "H. Tagad"
    },
    {
      "name": "A. Mendoza-Oliva"
    },
    {
      "name": "J. Vaquer-Alicea"
    },
    {
      "name": "M. I. Diamond"
    },
    {
      "name": "L. Saelices"
    },
    {
      "affs": [
        0
      ],
      "name": "N. N. Louros"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b4x64xvze0f90.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.04.749224",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749224v1.full",
  "id": "b4x64xvze0f90",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749224v1",
  "language": null,
  "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": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Amyloidosis: Diagnosis, Treatment, Outcomes"
    ]
  ],
  "openalex": "W7212084654",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749224v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/b4x64xvze0f90.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:28Z",
      "native_id": "10.64898/2026.09.04.749224",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749224v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism",
  "title_text": "An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:28Z",
  "url": "https://research.draconitic.com/paper/b4x64xvze0f90",
  "venue": "bioRxiv",
  "versions": []
}