5WHN

Crystal structure of the segment, NFGAFS, from the low complexity domain of TDP-43, residues 312-317

5WHN の概要

• エントリーDOI: 10.2210/pdb5whn/pdb
• 分子名称: Segment of TAR DNA-binding protein 43 (1 entity in total)
• 機能のキーワード: amyloid, larks, tdp-43, protein fibril
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 641.67

構造登録者

Guenther, E.L.,Sawaya, M.R.,Eisenberg, D.S. (登録日: 2017-07-17, 公開日: 2018-04-25, 最終更新日: 2023-10-04)

主引用文献

Guenther, E.L.,Cao, Q.,Trinh, H.,Lu, J.,Sawaya, M.R.,Cascio, D.,Boyer, D.R.,Rodriguez, J.A.,Hughes, M.P.,Eisenberg, D.S.
Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.
Nat. Struct. Mol. Biol., 25:463-471, 2018

PubMed Abstract: The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation.

PubMed: 29786080
DOI: 10.1038/s41594-018-0064-2

実験手法

X-RAY DIFFRACTION (1.1 Å)