2N4H

Solution Structure of the Q343R Mutant of TDP-43 Amyloidogenic Core Region

2N4H の概要

• エントリーDOI: 10.2210/pdb2n4h/pdb
• 関連するPDBエントリー: 2N3X 2N4G
• NMR情報: BMRB: 25668
• 分子名称: TAR DNA-binding protein 43 (1 entity in total)
• 機能のキーワード: tdp-43, amyloidogenic core region, q343r, dna binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : Q13148
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 5236.86

構造登録者

Jiang, L.,Zhao, J.,Hu, H. (登録日: 2015-06-18, 公開日: 2016-04-20, 最終更新日: 2024-05-15)

主引用文献

Jiang, L.L.,Zhao, J.,Yin, X.F.,He, W.T.,Yang, H.,Che, M.X.,Hu, H.Y.
Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation
Sci Rep, 6:23928-23928, 2016

PubMed Abstract: TDP-43 is a DNA/RNA binding protein associated with TDP-43 proteinopathies. Many mutations have been identified in the flexible C-terminal region, which is implicated in the disease pathology. We investigated four point mutations in the amyloidogenic core region (residues 311-360) of TDP-43 by biochemical and spectroscopic methods. We found that the G335D mutation enhances the aggregation and inclusion formation of TDP-43 and this mutant in TDP-35 (the C-terminal fragment of 35 kDa) exaggerates the antagonist effect on RNA processing by endogenous TDP-43; whereas Q343R gives an opposite effect. As a comparison, M337V and Q331K have very little impact on the aggregation and inclusion formation of TDP-43 or TDP-35. NMR structural analysis showed that the G335D mutant in the core region forms a loop linker between the two α-helices and promotes α-to-β transition, but Q343R loses the second helix and consequently the structural transformation. Thus, the propensity of structural transformation in the amyloidogenic core of TDP-43 determines its aggregation and inclusion formation. This study may provide a molecular mechanism of the TDP-43 proteinopathies caused by genetic mutations.

PubMed: 27030292
DOI: 10.1038/srep23928

実験手法

SOLUTION NMR