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

doi:10.1101/2023.05.12.540512

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POUNOT, Kevin

PIERSSON, Clara
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

GORING, Andrew

Langue

Document de travail - Pré-publication

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 diseases-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 radius 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 aggregation propensity of IDPs.< Réduire

Mots clés en anglais

Intrinsically disordered protein

SAXS

tau protein

amyloid

IDP conformation

URI

https://oskar-bordeaux.fr/handle/20.500.12278/200220

DOI

http://dx.doi.org/10.1101/2023.05.12.540512

Projet Européen

Cofactors at the core of tau prion behavior

Unités de recherche

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