POUNOT, Kevin; PIERSSON, Clara; GORING, Andrew; ROSU, Frédéric; GABELICA, Valérie; WEIK, Martin; HAN, Songi; FICHOU, Yann

doi:10.1021/jacsau.3c00550

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Pounot et al. - 2024 - Mutations in Tau Protein Promote Aggregation by Fa (1).pdf (2.959Mo)

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POUNOT, Kevin
Dynamiques Chromatiniennes et Transitions Développementales [ChromDev]
Institut Européen de Chimie et Biologie [IECB]

PIERSSON, Clara
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]
Institut Européen de Chimie et Biologie [IECB]

GORING, Andrew
University of California [Los Angeles] [UCLA]

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Article de revue

Ce document a été publié dans

JACS Au. 2023-12-19, vol. 4, p. 92-100

Résumé en anglais

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.< Réduire

URI

https://oskar-bordeaux.fr/handle/20.500.12278/199205

DOI

http://dx.doi.org/10.1021/jacsau.3c00550

Projet Européen

Cofactors at the core of tau prion behavior

Unités de recherche

CBMN : Chimie & de Biologie des Membranes & des Nano-objets - UMR 5248