期刊
JOURNAL OF BIOCHEMISTRY
卷 159, 期 2, 页码 247-260出版社
OXFORD UNIV PRESS
DOI: 10.1093/jb/mvv091
关键词
amyloid fibril core; ALS; mechanism; SOD1G93A mutant; structural stability
资金
- Japan Society for the Promotion of Science (JSPS) [25330027]
- X-Ray Free Electron Laser Priority Strategy Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- Wakasa Seikatsu Co. Japan
- [24113716]
- Grants-in-Aid for Scientific Research [25461315, 25440027, 25330027, 25440026] Funding Source: KAKEN
Cu, Zn-superoxide dismutase (SOD1), an enzyme implicated in the progression of familial amyotrophic lateral sclerosis (fALS), forms amyloid fibrils under certain experimental conditions. As part of our efforts to understand ALS pathogenesis, in this study we found that reduction of the intramolecular disulfide bond destabilized the tertiary structure of metal free wild-type SOD1 and greatly enhanced fibril formation in vitro. We also identified fibril core peptides that are resistant to protease digestion by using mass spectroscopy and Edman degradation analyses. Three regions dispersed throughout the sequence were detected as fibril core sequences of SOD1. Interestingly, by using three synthetic peptides that correspond to these identified regions, we determined that each region was capable of fibril formation, either alone or in a mixture containing multiple peptides. It was also revealed that by reducing the disulfide bond and causing a decrease in the structural stability, the amyloid fibril formation of a familial mutant SOD1 G93A was accelerated even under physiological conditions. These results demonstrate that by destabilizing the structure of SOD1 by removing metal ions and breaking the intramolecular disulfide bridge, multiple fibril-forming core regions are exposed, which then interact with each another and form amyloid fibrils under physiological conditions.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据