6N3B

SegA-asym, conformation of TDP-43 low complexity domain segment A asym

6N3B の概要

• エントリーDOI: 10.2210/pdb6n3b/pdb
• 関連するPDBエントリー: 6N3A 6N3B 6N3C
• EMDBエントリー: 0334 9339 9349 9350
• 分子名称: TAR DNA-binding protein 43 (1 entity in total)
• 機能のキーワード: amyloid, tdp43, als, ftld-tdp, dna binding protein, protein fibril
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 52077.97

構造登録者

Cao, Q.,Boyer, D.R.,Sawaya, M.R.,Eisenberg, D.S. (登録日: 2018-11-14, 公開日: 2019-06-26, 最終更新日: 2024-03-20)

主引用文献

Cao, Q.,Boyer, D.R.,Sawaya, M.R.,Ge, P.,Eisenberg, D.S.
Cryo-EM structures of four polymorphic TDP-43 amyloid cores.
Nat.Struct.Mol.Biol., 26:619-627, 2019

PubMed Abstract: The DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology.

PubMed: 31235914
DOI: 10.1038/s41594-019-0248-4

実験手法

ELECTRON MICROSCOPY (3.8 Å)