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Article Dans Une Revue JACS Au Année : 2023

Mutations in tau protein promote aggregation by favoring extended conformations

Résumé

Amyloid aggregation of the intrinsically disordered protein (IDP) tau is involved in several diseases, called tauopathies. Some tauopathies can be inherited due to mutations in the gene encoding tau, which might favor the formation of tau amyloid fibrils. This work aims at deciphering the mechanisms through which the disease-associated single-point mutations promote amyloid formation. We combined biochemical and biophysical characterization, notably, small-angle X-ray scattering (SAXS), to study six different FTDP-17 derived mutations. We found that the mutations promote aggregation to different degrees and can modulate tau conformational ensembles, intermolecular interactions, and liquid-liquid phase separation propensity. In particular, we found a good correlation between the aggregation lag time of the mutants and their radii of gyration. We show that mutations disfavor intramolecular protein interactions, which in turn favor extended conformations and promote amyloid aggregation. This work proposes a new connection between the structural features of tau monomers and their propensity to aggregate, providing a novel assay to evaluate the aggregation propensity of IDPs.
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Dates et versions

hal-04510750 , version 1 (19-03-2024)

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Kevin Pounot, Clara Piersson, Andrew Goring, Frédéric Rosu, Valérie Gabelica, et al.. Mutations in tau protein promote aggregation by favoring extended conformations. JACS Au, 2023, 4, pp.92-100. ⟨10.1021/jacsau.3c00550⟩. ⟨hal-04510750⟩
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