7WX0

E40K variant of Cu/Zn-superoxide dismutase from dog (Canis familiaris)

7WX0 の概要

• エントリーDOI: 10.2210/pdb7wx0/pdb
• 分子名称: Superoxide dismutase [Cu-Zn], ZINC ION, COPPER (II) ION, ... (4 entities in total)
• 機能のキーワード: superoxide dismutase, sod, sod1, oxidoreductase, metal binding protein
• 由来する生物種: Canis lupus familiaris (dog)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31987.46

構造登録者

Narikiyo, S.,Furukawa, Y.,Akutsu, M. (登録日: 2022-02-14, 公開日: 2023-02-15, 最終更新日: 2024-11-06)

主引用文献

Hashimoto, K.,Watanabe, S.,Akutsu, M.,Muraki, N.,Kamishina, H.,Furukawa, Y.,Yamanaka, K.
Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy-linked E40K mutation.
J.Biol.Chem., 299:104798-104798, 2023

PubMed Abstract: Canine degenerative myelopathy (DM), a fatal neurodegenerative disease in dogs, shares clinical and genetic features with amyotrophic lateral sclerosis, a human motor neuron disease. Mutations in the SOD1 gene encoding Cu/Zn superoxide dismutase (SOD1) cause canine DM and a subset of inherited human amyotrophic lateral sclerosis. The most frequent DM causative mutation is homozygous E40K mutation, which induces the aggregation of canine SOD1 but not of human SOD1. However, the mechanism through which canine E40K mutation induces species-specific aggregation of SOD1 remains unknown. By screening human/canine chimeric SOD1s, we identified that the humanized mutation of the 117th residue (M117L), encoded by exon 4, significantly reduced aggregation propensity of canine SOD1. Conversely, introducing a mutation of leucine 117 to methionine, a residue homologous to canine, promoted E40K-dependent aggregation in human SOD1. M117L mutation improved protein stability and reduced cytotoxicity of canine SOD1. Furthermore, crystal structural analysis of canine SOD1 proteins revealed that M117L increased the packing within the hydrophobic core of the β-barrel structure, contributing to the increased protein stability. Our findings indicate that the structural vulnerability derived intrinsically from Met 117 in the hydrophobic core of the β-barrel structure induces E40K-dependent species-specific aggregation in canine SOD1.

PubMed: 37156398
DOI: 10.1016/j.jbc.2023.104798

実験手法

X-RAY DIFFRACTION (1.4 Å)