Transthyretin can denature by an alternative pathway

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-09-08
DOI
https://doi.org/10.1073/pnas.2536532123
Primary Topic
Amyloidosis: Diagnosis, Treatment, Outcomes
Type
article
Field-Weighted Citation Impact
0.00

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article

Transthyretin can denature by an alternative pathway

Jan-Hannes Schäfer, Martin Gruebele, Gabriel C. Lander, Marcus Jäger et al.
Proceedings of the National Academy of Sciences
Amyloidosis: Diagnosis, Treatment, Outcomes
article

Transthyretin can denature by an alternative pathway

Jan-Hannes Schäfer, Martin Gruebele, Gabriel C. Lander, Marcus Jäger, Evan T. Powers, Jeffery W. Kelly
article en

Abstract

Transthyretin (TTR) is a kinetically stable protein in the bloodstream, cerebrospinal fluid, and in the eye, whose aggregation causes a prominent human amyloid disease, TTR amyloidosis (ATTR). Dissociation of the wild-type TTR tetramer into metastable dimers is rate-limiting for aggregation at acidic pH and unfolding in denaturant solutions at neutral pH. However, this "canonical dimer" pathway of denaturation is not the only one accessible under conditions possibly relevant to amyloid disease. At pH-values reached in the late endosome and lysosome (pH 4.0 to 5.0), as well as with perturbing mutations at neutral pH, a second denaturation pathway becomes accessible involving a more expanded transition state. This "alternative unfolding" pathway is evident via a characteristic switch to a steeper slope in the plot of the log-transformed unfolding rate constant vs. the urea concentration. Using mutations, we identify globally distributed locations in the protein that are sensitive to pathway-switching and correlate them with structural information. We show that flux along the alternative denaturation pathway becomes kinetically competitive in a subset of variants under mildly acidic conditions. A small-molecule kinetic stabilizer of TTR decreases flux along the canonical denaturation pathway, and exhibits reduced influence on denaturation by the alternative pathway. We present a "universal" plot allowing classification of TTR mutants to either pathway, and suggest a mechanism by which the two pathways operate. We speculate that the existence of an alternative unfolding pathway could allow for rapid protein degradation and turnover of kinetically stable TTR under acidic conditions in the autolysosome.

Proceedings of the National Academy of SciencesVol. 123(37)
Scripps Research Institute (US), University of Illinois Urbana-Champaign (US), Illinois College (US)
Deutsche Forschungsgemeinschaft, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 18%
Amyloidosis: Diagnosis, Treatment, Outcomes
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