期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 29, 页码 22221-22231出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.113597
关键词
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资金
- Scientific Research on Priority Areas [17025044]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20770130, 21390274]
- Health and Labour Science Research
- Grants-in-Aid for Scientific Research [17025044, 20770130, 21390274] Funding Source: KAKEN
More than 100 different mutations in Cu, Zn-superoxide dismutase (SOD1) are linked to a familial form of amyotrophic lateral sclerosis (fALS). Pathogenic mutations facilitate fibrillar aggregation of SOD1, upon which significant structural changes of SOD1 have been assumed; in general, however, a structure of protein aggregate remains obscure. Here, we have identified a protease-resistant core in wild-type as well as fALS-causing mutant SOD1 aggregates. Three different regions within an SOD1 sequence are found as building blocks for the formation of an aggregate core, and fALS-causing mutations modulate interactions among these three regions to form a distinct core, namely SOD1 aggregates exhibit mutation-dependent structural polymorphism, which further regulates biochemical properties of aggregates such as solubility. Based upon these results, we propose a new pathomechanism of fALS in which mutation-dependent structural polymorphism of SOD1 aggregates can affect disease phenotypes.
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