An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism
- 1UT Southwestern Medical Center
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.
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BibTeX
@misc{gadhe2026nterminal,
title = {{An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism}},
author = {L. Gadhe and B. A. Nguyen and M. d. C. Fernandez Ramirez and K. Konstantoulea and M. Lozen and H. Tagad and A. Mendoza-Oliva and J. Vaquer-Alicea and M. I. Diamond and L. Saelices and N. N. Louros},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749224},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749224v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - An N-terminal ATTR Fibril Segment Promotes Transthyretin Amyloid Nucleation and Polymorphism
AU - L. Gadhe
AU - B. A. Nguyen
AU - M. d. C. Fernandez Ramirez
AU - K. Konstantoulea
AU - M. Lozen
AU - H. Tagad
AU - A. Mendoza-Oliva
AU - J. Vaquer-Alicea
AU - M. I. Diamond
AU - L. Saelices
AU - N. N. Louros
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749224
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749224v1
AB - 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.
ER -