7PY2

Structure of pathological TDP-43 filaments from ALS with FTLD

7PY2 の概要

• エントリーDOI: 10.2210/pdb7py2/pdb
• EMDBエントリー: 13708
• 分子名称: TAR DNA-binding protein 43 (1 entity in total)
• 機能のキーワード: tdp-43, als, amyotrophic lateral sclerosis, ftd, frontotemporal dementia, ftld, frontotemporal lobar degeneration, amyloid, filament, fibril, neurodegenerative, neurodegeneration, protein fibril
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 179138.97

構造登録者

Arseni, D.,Hasegawa, H.,Murzin, A.G.,Kametani, F.,Arai, M.,Yoshida, M.,Falcon, B. (登録日: 2021-10-08, 公開日: 2021-12-15, 最終更新日: 2024-07-17)

主引用文献

Arseni, D.,Hasegawa, M.,Murzin, A.G.,Kametani, F.,Arai, M.,Yoshida, M.,Ryskeldi-Falcon, B.
Structure of pathological TDP-43 filaments from ALS with FTLD.
Nature, 601:139-143, 2022

PubMed Abstract: The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD). It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282-360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts β-strand length, which results in an absence of β-sheet stacking that is associated with cross-β amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.

PubMed: 34880495
DOI: 10.1038/s41586-021-04199-3

実験手法

ELECTRON MICROSCOPY (2.59 Å)