Exploring PrP C unfolding as a critical step preceding its refolding in the context of PrP Sc propagation
Abstract
It might have been believed that elucidation of the atomistic structure of PrP Sc would lead to an immediate understanding of the mechanism of prion propagation. However, PrP Sc , now known to be a “simple” amyloid, can only template a previously unfolded polypeptide chain. Therefore, PrP Sc can easily template the disordered ~90–120 domain of an incoming PrP C molecule, but not its ~121–231 folded domain (FD). The FD needs to accommodate into the ~121–230 PrP Sc surface, an inert “procrustean bed”. Thus, a mechanism for concerted unfolding/refolding of the FD must exist, with FD unfolding as a key element. To explore how this might happen, we performed thermal unfolding of recombinant bank vole PrP C (90–231), a universal PrP Sc propagator, tracking changes at the residue level with solution NMR to pinpoint early unfolding propensity. Our data suggest that a key early event is the destabilization of the short β1-β2 assembly and that the segment contiguous to the disordered tail, ~121–140, encompassing β1 and its adjacent coils, is the most likely region to unfold first. Spectroscopic data obtained at higher temperatures suggest that portions of alpha helix α2 are likely the last elements of the FD to unfold and refold into the PrP Sc conformation. Molecular Dynamics simulations assisted the interpretation of these changes and suggest separation of α1 from the rest of the FD ensemble. Our data provide a conceivable timeline of the early events in PrP Sc -assisted conversion of PrP C and should serve as a starting framework to develop a future atomistic model of PrP Sc propagation.
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BibTeX
@article{sabzehei2026exploring,
title = {{Exploring PrP C unfolding as a critical step preceding its refolding in the context of PrP Sc propagation}},
author = {Sanaz Sabzehei and Marta Rigoli and Raúl Cacheiro and Iria Díaz-Arias and Hasier Eraña and Rubén P. Lago and Arcadio Guerra and Human Rezaei and Joaquín Castilla and Emiliano Biasini and Víctor M. Sánchez-Pedregal and Manuel Martín-Pastor and Jesús R. Requena},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = nov,
doi = {10.1073/pnas.2529837123},
url = {https://hal.science/hal-05849869v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Exploring PrP C unfolding as a critical step preceding its refolding in the context of PrP Sc propagation
AU - Sanaz Sabzehei
AU - Marta Rigoli
AU - Raúl Cacheiro
AU - Iria Díaz-Arias
AU - Hasier Eraña
AU - Rubén P. Lago
AU - Arcadio Guerra
AU - Human Rezaei
AU - Joaquín Castilla
AU - Emiliano Biasini
AU - Víctor M. Sánchez-Pedregal
AU - Manuel Martín-Pastor
AU - Jesús R. Requena
PY - 2026
DA - 2026/11/03
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2529837123
UR - https://hal.science/hal-05849869v1
AB - It might have been believed that elucidation of the atomistic structure of PrP Sc would lead to an immediate understanding of the mechanism of prion propagation. However, PrP Sc , now known to be a “simple” amyloid, can only template a previously unfolded polypeptide chain. Therefore, PrP Sc can easily template the disordered ~90–120 domain of an incoming PrP C molecule, but not its ~121–231 folded domain (FD). The FD needs to accommodate into the ~121–230 PrP Sc surface, an inert “procrustean bed”. Thus, a mechanism for concerted unfolding/refolding of the FD must exist, with FD unfolding as a key element. To explore how this might happen, we performed thermal unfolding of recombinant bank vole PrP C (90–231), a universal PrP Sc propagator, tracking changes at the residue level with solution NMR to pinpoint early unfolding propensity. Our data suggest that a key early event is the destabilization of the short β1-β2 assembly and that the segment contiguous to the disordered tail, ~121–140, encompassing β1 and its adjacent coils, is the most likely region to unfold first. Spectroscopic data obtained at higher temperatures suggest that portions of alpha helix α2 are likely the last elements of the FD to unfold and refold into the PrP Sc conformation. Molecular Dynamics simulations assisted the interpretation of these changes and suggest separation of α1 from the rest of the FD ensemble. Our data provide a conceivable timeline of the early events in PrP Sc -assisted conversion of PrP C and should serve as a starting framework to develop a future atomistic model of PrP Sc propagation.
SN - 0027-8424
SN - 1091-6490
ER -