7WX0

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

Summary for 7WX0

• Entry DOI: 10.2210/pdb7wx0/pdb
• Descriptor: Superoxide dismutase [Cu-Zn], ZINC ION, COPPER (II) ION, ... (4 entities in total)
• Functional Keywords: superoxide dismutase, sod, sod1, oxidoreductase, metal binding protein
• Biological source: Canis lupus familiaris (dog)
• Total number of polymer chains: 2
• Total formula weight: 31987.46

Authors

Narikiyo, S.,Furukawa, Y.,Akutsu, M. (deposition date: 2022-02-14, release date: 2023-02-15, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.4 Å)