7wx1

E40K/M117L variant of Cu/Zn-superoxide dismutase from dog (Canis familiaris)E40K/M117L variant of Cu/Zn-superoxide dismutase from dog (Canis familiaris)

Structural highlights

7wx1 is a 2 chain structure with sequence from Canis lupus familiaris. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.65Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SODC_CANLF Destroys radicals which are normally produced within the cells and which are toxic to biological systems.

Publication Abstract from PubMed

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(E40K). 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(E40K). Furthermore, crystal structural analysis of canine SOD1 proteins revealed that M117L increased the packing within the hydrophobic core of the beta-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 beta-barrel structure induces E40K-dependent species-specific aggregation in canine SOD1.

Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy-linked E40K mutation.,Hashimoto K, Watanabe S, Akutsu M, Muraki N, Kamishina H, Furukawa Y, Yamanaka K J Biol Chem. 2023 Jun;299(6):104798. doi: 10.1016/j.jbc.2023.104798. Epub 2023 , May 6. PMID:37156398^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. 2023 Jun;299(6):104798. PMID:37156398 doi:10.1016/j.jbc.2023.104798

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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. 2023 Jun;299(6):104798. PMID:37156398 doi:10.1016/j.jbc.2023.104798

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