Molecular basis of the inhibition of eIF2B under stress
| Project/Area Number |
18K14644
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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 43020:Structural biochemistry-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Kashiwagi Kazuhiro 国立研究開発法人理化学研究所, 生命機能科学研究センター, 研究員 (60732980)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | クライオ電子顕微鏡 / X線結晶構造解析 / 翻訳 / 翻訳開始 / 統合的ストレス応答 / 翻訳調節 |
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| Outline of Final Research Achievements |
The structures of eIF2B complexed with the phosphorylated or unphosphorylated eIF2 were determined by cryo-electron microscopy and X-ray crystallography. The binding mode of eIF2 to eIF2B is completely different depending on the phosphorylation state of eIF2, and the stress-induced phosphorylated eIF2 binds eIF2B in a manner that is unsuitable for catalytic reaction. Furthermore, the binding of the phosphorylated eIF2 involves the rearrangement of eIF2B subunits, and a novel mechanism was proposed that ISRIB, a small molecule that alleviates eIF2B inhibition under stress, prevents this rearrangement by the phosphorylated eIF2 as an allosteric antagonist.
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| Academic Significance and Societal Importance of the Research Achievements |
細胞がストレスを検知すると、ストレスに対処するためにタンパク質合成に変化が生じる。タンパク質合成の開始に関与する因子どうしが結合した構造をストレス時と非ストレス時とで解明し、ストレスの有無によって結合様式が全く異なるものとなることを明らかにした。また、この変化を防ぐISRIBと呼ばれる薬剤はさまざまな神経疾患に対する新規治療薬としての可能性が報告されており、我々が解明した構造をもとにこの薬剤が作用する機構について提唱した。
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Report
(4 results)
Research Products
(4 results)
