Structural and functional analysis of mechanosensitive channel TMC proteins
Project/Area Number |
20K15754
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 43040:Biophysics-related
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Research Institution | The University of Tokyo |
Principal Investigator |
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | チャネル / 膜タンパク質 / クライオ電子顕微鏡 / 単粒子解析 |
Outline of Research at the Start |
音すなわち空気の振動によって機械刺激を受けた有毛細胞では,膜タンパク質を含むMechanotransduction (MET) channel複合体が,機械刺激を電気的シグナルへと情報を変換することで,有毛細胞から聴神経へシグナルが伝達すると考えられている。MET channel複合体のチャネル透過経路を形成するサブユニットの最有力候補がTMC1及びTMC2である。本研究では,クライオ電子顕微鏡単粒子解析によりTMC1またはTMC2の立体構造を決定し,構造情報に基づいた電気生理学解析をおこなうことで,TMC1/TMC2のイオン透過機構・機械刺激感受性チャネル開閉機構の解明を目指す。
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Outline of Final Research Achievements |
Mechanosensitive channel TMC1/TMC2 proteins interact with auxiliary subunits to form the mechanoelectrical transduction (MET) channel complex in hair cells. In this study, we aimed to elucidate the molecular mechanisms of ion permeation and mechanosensitive gating of TMC1/2 using cryo-EM single particle analysis. Expanding from the original plan, we successfully prepared complexes of TMC and CIB proteins, which are the component of the MET channel complex, and performed the structural analysis of the TMC-CIB complex.
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Academic Significance and Societal Importance of the Research Achievements |
TMCタンパク質を含む複合体解析の基盤が整ったことで、イオン透過機構のみならず、補助サブユニットによるMETチャネル複合体の活性調節機構の理解にも繋がる点で学術的意義がある。今後、補助サブユニットも含めたMETチャネル複合体の構造機能研究へと展開していく。また、METチャネル複合体は聴覚に関わることから、本研究の成果と今後の展開は難聴の病態理解を深め、構造情報に基づいた薬剤開発の可能性を提供すると期待される。
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Report
(4 results)
Research Products
(30 results)
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[Journal Article] Structure of the type V-C CRISPR-Cas effector enzyme2022
Author(s)
Kurihara Nina、Nakagawa Ryoya、Hirano Hisato、Okazaki Sae、Tomita Atsuhiro、Kobayashi Kan、Kusakizako Tsukasa、Nishizawa Tomohiro、Yamashita Keitaro、Scott David A.、Nishimasu Hiroshi、Nureki Osamu
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Journal Title
Molecular Cell
Volume: 82
Issue: 10
Pages: 1865-1877
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Cryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2.2021
Author(s)
Tomita, A., Daiho, T., Kusakizako, T., Yamashita, K., Ogasawara, S., Murata, T., Nishizawa, T. and Nureki, O.
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Journal Title
Mol. Cell
Volume: 81
Issue: 23
Pages: 4799-4809
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cryo-EM structure of the human MT1-Gi signaling complex.2021
Author(s)
Okamoto, H. H., Miyauchi, H., Inoue, A., Raimondi, F., Tsujimoto, H., Kusakizako, T., Shihoya, W., Yamashita, K., Suno, R., Nomura, N., Kobayashi, T., Iwata, S., Nishizawa, T. and Nureki, O.
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Journal Title
Nat. Struct. Mol. Biol.
Volume: 28
Issue: 8
Pages: 694-701
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] The structure of MgtE in the absence of magnesium provides new insights into channel gating.2021
Author(s)
Jin F, Sun M, Fujii T, Yamada Y, Wang J, Maturana AD, Wada M, Su S, Ma J, Takeda H, Kusakizako T, Tomita A, Nakada-Nakura Y, Liu K, Uemura T, Nomura Y, Nomura N, Ito K, Nureki O, Namba K, Iwata S, Yu Y, Hattori M.
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Journal Title
PLoS Biology
Volume: 19
Issue: 4
Pages: e3001231-e3001231
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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