Characterization of intramembrane proteases by the yeast resonctitution system
| Project/Area Number |
16K07290
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
Eugene Futai 東北大学, 農学研究科, 准教授 (90447459)
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| Research Collaborator |
Shintani Takahiro
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 酵素 / 脳神経疾患 / 神経科学 / 応用微生物 / バイオテクノロジー / 膜内切断プロテアーゼ / 認知症 / 酵母 / 脳・神経 |
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| Outline of Final Research Achievements |
γ-secretase generates amyloid β peptide (Aβ) from amyloid precursor protein (APP) through multi step cleavage, such as endoproteolysis and trimming. In the study, we reconstituted human γ-secretase complex and APP in yeast and identified activating mutations in the catalytic subunit of γ-secretase presenilin 1 (PS1), and the regulatory subunit Aph1aL. We introduced these mutants in yeast and mammalian cells and found that the mutations increase the stepwise cleavage activity (cleavage and trimming), and in particular, decrease long-chain Aβ42 by raising trimming. We also clarified the conformational changes of each subunit with activation. It has become an important finding in the development of antidementia drugs that reduce the production of highly toxic Aβ42 involved in the onset of dementia.
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| Academic Significance and Societal Importance of the Research Achievements |
膜内切断プロテアーゼは、疎水的な膜内で加水分解を行う特殊なタンパク分解酵素で、どのようにして反応を遂行するのか、そのメカニズムが分かっていない。γセクレターゼ複合体は、アルツハイマー病の原因となる脳内アミロイドを作り出す、認知症治療において重要なターゲット分子です。本研究では、モデル生物である出芽酵母を使った独創的な解析手法をとり入れ、γセクレターゼ複合体とそのモデルとなる単量体膜内切断プロテアーゼによる分解機構を解析しました。私達の研究成果は、膜内タンパク分解機構を解明する重要な知見であり、γセクレターゼ複合体の活性調節機構を解明することにより認知症治療薬の開発への戦略を提案します。
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Report
(4 results)
Research Products
(11 results)
