7Q3U

Cryo-EM structure of TDP43 core peptide amyloid fiber

Summary for 7Q3U

• Entry DOI: 10.2210/pdb7q3u/pdb
• EMDB information: 13795
• Descriptor: TAR DNA-binding protein 43 (1 entity in total)
• Functional Keywords: tdp-43, amyloid, neurodegeneration, helical, cryo-em, rna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 5
• Total formula weight: 40213.43

Authors

Nazarov, S. (deposition date: 2021-10-28, release date: 2023-03-22, Last modification date: 2023-10-04)

Primary citation

Kumar, S.T.,Nazarov, S.,Porta, S.,Maharjan, N.,Cendrowska, U.,Kabani, M.,Finamore, F.,Xu, Y.,Lee, V.M.,Lashuel, H.A.
Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage.
Nat.Neurosci., 26:983-996, 2023

PubMed Abstract: Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge of the sequence and structural determinants of its aggregation and neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit sequence and morphological features similar to those of brain-derived TDP-43 filaments. We show that TDP-43 filaments contain a β-sheet-rich helical amyloid core that is fully buried by the flanking structured domains of the protein. We demonstrate that the proteolytic cleavage of TDP-43 filaments and exposure of this amyloid core are necessary for propagating TDP-43 pathology and enhancing the seeding of brain-derived TDP-43 aggregates. Only TDP-43 filaments with exposed amyloid core efficiently seeded the aggregation of endogenous TDP-43 in cells. These findings suggest that inhibiting the enzymes mediating cleavage of TDP-43 aggregates represents a viable disease-modifying strategy to slow the progression of amyotrophic lateral sclerosis and other TDP-43 proteinopathies.

PubMed: 37248338
DOI: 10.1038/s41593-023-01341-4

Experimental method

ELECTRON MICROSCOPY (3.7 Å)