Novel mechanisms of protein quality control mediated by the cooperation of ERp44 and zinc ions in the early secretory pathway
Project/Area Number |
18H03978
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
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Research Institution | Tohoku University |
Principal Investigator |
Inaba Kenji 東北大学, 多元物質科学研究所, 教授 (10423039)
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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 |
¥44,850,000 (Direct Cost: ¥34,500,000、Indirect Cost: ¥10,350,000)
Fiscal Year 2020: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
Fiscal Year 2019: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
Fiscal Year 2018: ¥22,230,000 (Direct Cost: ¥17,100,000、Indirect Cost: ¥5,130,000)
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Keywords | タンパク質品質管理 / 亜鉛イオン / 亜鉛輸送体 / ERp44 / 小胞体 / ゴルジ体 / X線結晶構造解析 / 細胞イメージング / 亜鉛トランスポーター / クライオ電子顕微鏡 / タンパク質品管理 / 蛋白質品質管理 / 亜鉛 |
Outline of Final Research Achievements |
ERp44 is a PDI family member that plays an important role in protein quality control in the early secretory pathway. We recently discovered that zinc ions (Zn2+) regulate structure, affinity for client proteins and intracellular localization of ERp44, leading to its maximal client retention activity. We also developed an organelle-targettable Zn2+ fluorescent probe in collaboration with Prof. Shin Mizukami's group, and succeeded in quantification of labile Zn2+ concentration in the Golgi with the probe. By Zn2+ imaging under the conditions of systematic Zn2+ transporter (ZnT) knockdowns, we revealed that ZnT7 serves as a ZnT that primarily regulates intracellular localization and function of ERp44. Thus, we established molecular and mechanistic basis of the ZnT-mediated Zn2+ homeostasis and ERp44-dependent protein quality control in the early secretory pathway.
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Academic Significance and Societal Importance of the Research Achievements |
細胞のタンパク質品質管理機構の異常は、アルツハイマー病などの神経変性疾患や糖尿病を引き起こすことが数多く報告されている。また亜鉛イオンの恒常性維持の破綻が、発育障害、免疫低下、皮膚病等のいわゆる亜鉛欠乏症を引き起こすことも広く知られる。本研究において我々は、小胞体とゴルジ体における、亜鉛イオンとpHによって制御される全く新しいタンパク質品質管理機構を解明した。さらに細胞内小器官の遊離亜鉛イオン濃度を定量することにも成功し、細胞の亜鉛恒常性維持機構に関する重要な知見を得た。本研究成果は上記の疾患の原因解明・創薬につながり、基礎細胞生物学のみならず、医学的にも非常に重要なものである。
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Report
(4 results)
Research Products
(92 results)
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[Journal Article] Distinct roles and actions of protein disulfide isomerase family enzymes in catalysis of nascent-chain disulfide bond formation2021
Author(s)
Hirayama, C., Machida, K., Noi, K., Murakawa, T., Okumura, M., Ogura, T., Imataka, H., and Inaba, K.*
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Journal Title
iScience
Volume: 4
Issue: 4
Pages: 102296-102296
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A unique leucine-valine adhesive motif supports structure and function of protein disulfide isomerase P5 via dimerization2021
Author(s)
Okumura M, Kanemura S., Matsusaki M., Kinoshita M., Saio T., Ito D., Hirayama C., Kumeta H., Watabe M., Amagai Y., Lee Y. H., Akiyama S. and Inaba K.
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Journal Title
Structure
Volume: 29
Issue: 12
Pages: 1-14
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail2020
Author(s)
Zhang. Y., Inoue, M., Tsutsumi, A., Watanabe, S., Nishizawa, T., Nagata, K., Kikkawa, M. and Inaba, K.*
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Journal Title
Science Advances
Volume: 6
Issue: 33
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Structural basis of sarco/endoplasmic reticulum Ca2+-ATPase 2b regulation via transmembrane helix interplay2019
Author(s)
Michio Inoue, Nanami Sakuta, Satoshi Watanabe, Yuxia Zhang, Kunihito Yoshikaie, Yoshiki Tanaka, Ryo Ushioda, Yukinari Kato, Junichi Takagi, Tomoya Tsukazaki, Kazuhiro Nagata, Kenji Inaba
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Journal Title
Cell Reports
Volume: 27
Issue: 4
Pages: 1221-1230
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Structural basis of zinc-dependent protein quality control in the early secretory pathway2019
Author(s)
Watanabe, S., Amagai, Y., Sannino, S., Yamada, M., Sitia, R. and Inaba, K.
Organizer
Cell Biology of Metals, Gordon Research Conference
Related Report
Int'l Joint Research / Invited
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[Presentation] Visualization of zinc in the ER and Golgi2019
Author(s)
Amagai, Y., Yamada, M., Watanabe, T., Kowada, T., Naramoto, S., Watanabe, S., Kyozuka, J., Sitia, R., Mizukami, S. and Inaba, K.
Organizer
The 14th ER & Redox Club Meeting
Related Report
Int'l Joint Research
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[Presentation] ERp44 acquires Zinc ions at the ER-Golgi intermediate compartment via ZnT72019
Author(s)
Amagai, Y., Yamada, M., Watanabe, T., Kowada, T., Naramoto, S., Watanabe, S., Kyozuka, J., Sitia, S., Mizukami, S. and Inaba, K.
Organizer
The 6th Meeting of International Society for Zinc Biology
Related Report
Int'l Joint Research
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[Presentation] Structural basis of Sarco/Endoplasmic Reticulum Ca2+-ATPase 2b regulation via transmembrane helix interplay2019
Author(s)
Zhang, Y., Inoue, M., Watanabe, S., Tsutsumi, A., Nishizawa, T., Kikkawa, M., Nagata, K. and Inaba, K.
Organizer
第42回日本分子生物学会年会
Related Report
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[Presentation] Structural basis of zinc-dependent ERp44 regulation for protein quality control in the early secretory pathway2018
Author(s)
Watanabe, S., Amagai, Y., Sannino, S., Harayama, M., Masui, S., Yamada, M., Sitia, R. and Inaba, K.
Organizer
International Meeting “Proteins: from the cradle to the grave
Related Report
Int'l Joint Research
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[Book] 実験医学2020
Author(s)
天貝佑太、渡部聡、稲葉謙次
Total Pages
8
Publisher
羊土社
Related Report
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[Book] 実験医学2020
Author(s)
天貝 佑太、渡部 聡、稲葉 謙次
Total Pages
8
Publisher
羊土社
Related Report
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[Book] 月刊『細胞』2019
Author(s)
奥村 正樹、稲葉 謙次
Total Pages
6
Publisher
ニューサイエンス社
Related Report
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