期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 7, 页码 4970-4980出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.414235
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [24111542, 23111006, 24657093]
- Research Committee of CNS Degenerative Diseases from the Ministry of Health, Labor, and Welfare of Japan
- CREST, Japan Science and Technology Agency
- Japan ALS association
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Grants-in-Aid for Scientific Research [24111542, 24657093] Funding Source: KAKEN
Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) are a cause of a familial form of amyotrophic lateral sclerosis. Wild-type SOD1 forms a highly conserved intra-molecular disulfide bond, whereas pathological SOD1 proteins are crosslinked via intermolecular disulfide bonds and form insoluble oligomers. A thiol-disulfide status in SOD1 will thus play a regulatory role in determining its folding/misfolding pathways; however, it remains unknown how pathogenic mutations in SOD1 affect the thiol-disulfide status to facilitate the protein misfolding. Here, we show that the structural destabilization of SOD1 scrambles a disulfide bond among four Cys residues in an SOD1 molecule. The disulfide scrambling produces SOD1 monomers with distinct electrophoretic mobility and also reproduces the formation of disulfide-linked oligomers. We have also found that the familial form of amyotrophic lateral sclerosis-causing mutations facilitate the disulfide scrambling in SOD1. Based upon our results, therefore, scrambling of the conserved disulfide bond will be a key event to cause the pathological changes in disease-associated mutant SOD1 proteins.
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