Canine SOD1 harboring E40K or T18S mutations promotes protein aggregation without reducing the global structural stability
| Autor: | Hideaki Hara, Shintaro Kimura, Yuji O. Kamatari, Yukina Kuwahara, Hiroaki Kamishina, Ryo Honda, Sadatoshi Maeda, Osamu Yamato |
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| Rok vydání: | 2020 |
| Předmět: |
Veterinary Medicine
SOD1 lcsh:Medicine Protein aggregation Canine degenerative myelopathy Biochemistry SOD1 E40K mutation General Biochemistry Genetics and Molecular Biology Superoxide dismutase Aggregation 03 medical and health sciences 0302 clinical medicine medicine Amyotrophic lateral sclerosis Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology SOD1 T18S mutation General Neuroscience lcsh:R General Medicine medicine.disease Phenotype Molecular biology Enzyme chemistry Degenerative myelopathy biology.protein Protein folding ALS General Agricultural and Biological Sciences 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PeerJ, Vol 8, p e9512 (2020) PeerJ |
| ISSN: | 2167-8359 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease associated with aggregation of superoxide dismutase 1 (SOD1) protein. More than 160 mutations in human SOD1 have been identified in familial ALS and extensively characterized in previous studies. Here, we investigated the effects of T18S and E40K mutations on protein aggregation of canine SOD1. These two mutations are exclusively found in canine degenerative myelopathy (an ALS-like neurodegenerative disease in dogs), whose phenotype is unknown at the level of protein folding. Interestingly, the T18S and E40K mutations did not alter far-UV CD spectrum, enzymatic activity, or global structural stability of canine SOD1. However, thioflavin-T assay and transmission electron microscopy analysis revealed that these mutations promote formation of fibrous aggregates, in particular in the Cu2+/Zn2+-unbound state. These evidence suggested that the T18S and E40K mutations promote protein aggregation through a unique mechanism, possibly involving destabilization of the local structure, reduction of net negative charge, or production of disulfide-linked oligomers. |
| Databáze: | OpenAIRE |
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