2021 Fiscal Year Final Research Report
Molecular mechanism of disulfide-bonded active oligomerization by an endoplasmic stress sensor IRE1
| Project/Area Number |
20K15969
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
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| Research Institution | The University of Tokushima |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Keywords | ジスルフィド結合 / 小胞体 / IRE1 / PDIファミリー / 小胞体ストレス応答 / ミスフォールドタンパク質 / インスリン |
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| Outline of Final Research Achievements |
The endoplasmic reticulum (ER) stress response is a cellular defense system that senses the accumulation of cytotoxic misfolded proteins and promotes their removal. IRE1, a major mammalian stress sensor, has been studied intensively, but the molecular mechanisms underlying its activation remain largely unresolved. In this study, I worked to elucidate the structural dynamics of active oligomers formed by IRE1 and clarified the effects of the amount of regulatory factors such as IRE1 concentration, intermolecular disulfide bonds, and misfolded proteins on its dynamics.
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| Free Research Field |
生化学
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| Academic Significance and Societal Importance of the Research Achievements |
小胞体ストレス応答制御の破綻や過剰な活性化が、神経変性疾患、Ⅱ型糖尿病、癌などの様々な疾患と結びついているため、制御の分子機構解明は急務だが、IRE1によるUPR経路の初期に起きるイベントの分子機構が未解明なことが創薬等の障害になっていた。本研究の成果からこれまで不明だったIRE1活性化機構の一端が解明され、その制御に分子間ジスルフィド結合が重要なことが示された。今後IRE1の分子間ジスルフィド結合をターゲットとし、UPR制御に働く、新たな創薬基盤の確立が期待される。
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