SHENOY, Jayakrishna; EL MAMMERI, Nadia; DUTOUR, Antoine; BERBON, Melanie; SAAD, Ahmad; LENDS, Alons; MORVAN, Estelle; GRELARD, Axelle; LECOMTE, Sophie; KAUFFMANN, Brice; THEILLET, Francois-Xavier; HABENSTEIN, Birgit; LOQUET, Antoine

doi:10.1111/febs.15159

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SHENOY, Jayakrishna
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

EL MAMMERI, Nadia

Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

DUTOUR, Antoine
Chimie et Biologie des Membranes et des Nanoobjets [CBMN]

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Article de revue

Ce document a été publié dans

Febs Journal. 2019

Résumé en anglais

The TAR DNA-binding protein (TDP-43) self-assembles into prion-like aggregates considered to be the structural hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we use a combination of electron microscopy, X-ray fiber diffraction, Fourier-transform infrared spectroscopy analysis, and solid-state NMR spectroscopy to investigate the molecular organization of different TDP constructs, namely the full-length TDP-43 (1-414), two C-terminal fragments [TDP-35 (90-414) and TDP-16 (267-414)], and a C-terminal truncated fragment (TDP-43 increment GaroS2), in their fibrillar state. Although the different protein constructs exhibit similar fibril morphology and a typical cross-beta signature by X-ray diffraction, solid-state NMR indicates that TDP-43 and TDP-35 share the same polymorphic molecular structure, while TDP-16 encompasses a well-ordered amyloid core. We identified several residues in the so-called C-terminal GaroS2 (368-414) domain that participates in the rigid core of TDP-16 fibrils, underlining its importance during the aggregation process. Our findings demonstrate that C-terminal fragments can adopt a different molecular conformation in isolation or in the context of the full-length assembly, suggesting that the N-terminal domain and RRM domains play an important role in the TDP-43 amyloid transition.< Réduire

Mots clés en anglais

amyloid

amyotrophic lateral sclerosis

frontotemporal dementia

solid-state NMR

TDP-43

URI

https://oskar-bordeaux.fr/handle/20.500.12278/4357

DOI

http://dx.doi.org/10.1111/febs.15159

Project ANR

Advanced Materials by Design - ANR-10-IDEX-03-02/10-LABX-0042
Nanostructures biologiques et synthétiques étudiées par Résonance Magnétique Nucléaire du Solide

Unités de recherche

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