期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 8, 页码 4144-4155出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.683763
关键词
amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); protein aggregation; protein folding; protein misfolding; superoxide dismutase (SOD)
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [25291028, 15H01566]
- Cooperative Research in Joint Studies at Institute for Molecular Science, Japan
- Grants-in-Aid for Scientific Research [15K14480, 15H01566] Funding Source: KAKEN
Misfolding of Cu,Zn-superoxide dismutase (SOD1) is a pathological change in the familial form of amyotrophic lateral sclerosis caused by mutations in the SOD1 gene. SOD1 is an enzyme that matures through the binding of copper and zinc ions and the formation of an intramolecular disulfide bond. Pathogenic mutations are proposed to retard the post-translational maturation, decrease the structural stability, and hence trigger the misfolding of SOD1 proteins. Despite this, a misfolded and potentially pathogenic conformation of immature SOD1 remains obscure. Here, we show significant and distinct conformational changes of apoSOD1 that occur only upon reduction of the intramolecular disulfide bond in solution. In particular, loop regions in SOD1 lose their restraint and become significantly disordered upon dissociation of metal ions and reduction of the disulfide bond. Such drastic changes in the solution structure of SOD1 may trigger misfolding and fibrillar aggregation observed as pathological changes in the familial form of amyotrophic lateral sclerosis.
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