Understanding the protein homeostasis mechanism by P5, a member of the PDI family
| Project/Area Number |
19K06520
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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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| Review Section |
Basic Section 43020:Structural biochemistry-related
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| Research Institution | Tohoku University |
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Principal Investigator |
Okumura Masaki 東北大学, 学際科学フロンティア研究所, 助教 (50635810)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | タンパク質品質管理 / ジスルフィド結合 / X線小角散乱法 / 小胞体 / NMR / 二量体化モチーフ / 酸化的フォールディング / PDI family / P5 / シャペロン / SAXS / PDI / IRE1 / oxidative folding / 溶液散乱 |
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| Outline of Research at the Start |
細胞内小器官の一つ小胞体には、厳正な蛋白質品質管理システムが存在する。近年、不良蛋白質の蓄積により誘導される小胞体ストレス応答因子の1つであるIRE1の機能制御に、PDIファミリー酵素の1つであるP5が関わっていることが報告された。しかしながら、P5は構造未知であり、機能的解析も十分に進んでいないため、同酵素による「フォールディング補助」および「小胞体ストレス応答因子の制御」の分子機構は未解明である。そこで本申請は、特に同酵素の酸化的フォールディング促進活性・シャペロン活性・小胞体ストレス応答因子の調節機構の詳細を構造生物学的、細胞生物学的手法により解明する。
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| Outline of Final Research Achievements |
P5 is a PDI family member involved in the ER quality control. We discovered that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain by SAXS and crystallographic anaylyses. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding. Disassembly of P5 to monomers compromised its ability to inactivate IRE1, one of ER stress sensor, via intermolecular disulfide bond reduction. Thus, the leucine-valine adhesive motif supports structure and function of P5. Furthermore, the enzymatic activity of P5-mediated oxidative folding is up-regulated by PDI, while the chaperone activity of P5 is stimulated by ERp72. Thus, we established molecular and mechanistic basis of P5-dependent protein quality control system in the endoplasmic reticulum.
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| Academic Significance and Societal Importance of the Research Achievements |
細胞内の小胞体には新生タンパク質に、構造を安定化するためにジスルフィド結合を導入する仕組みが存在する。このジスルフィド結合の触媒を担っているのがPDIファミリー酵素である。特にPDIファミリー酵素のひとつP5は、癌などの疾患や小胞体ストレス応答、血液凝固といった様々な生理機能と関わることが報告されていたが、全体構造が不明なため詳しいメカニズムは不明であった。本課題では全長P5がユニークな構造モチーフを介して二量体構造をとることを明らかにし本モチーフが本酵素の機能発現にとって重要であることを提示した。従って本酵素の構造機能相関研究に基づき、本成果は医学的にも重要な知見をもたらす。
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Report
(4 results)
Research Products
(53 results)
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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] Functional Interplay between P5 and PDI/ERp72 to Drive Protein Folding.2021
Author(s)
Matsusaki M, Okada R, Tanikawa Y, Kanemura S, Ito D, Lin Y, Watabe M, Yamaguchi H, Saio T, Lee YH, Inaba K, and *Okumura M.
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Journal Title
Biology
Volume: 10
Issue: 11
Pages: 1112-1112
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Ca2+ Regulates ERp57-Calnexin Complex Formation.2021
Author(s)
Tanikawa Y,# Kanemura S,# Ito D, Lin Y, Matsusaki M, Kuroki K, Yamaguchi H, Maenaka K, Lee YH, Inaba K, and *Okumura M.
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Journal Title
Molecules
Volume: 26
Issue: 10
Pages: 2853-2853
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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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: in press
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Distinct roles and actions of protein disulfide isomerase family enzymes in catalysis of co-translational 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
Pages: 102296-102296
Related Report
Peer Reviewed / Open Access
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[Journal Article] Antipsychotic olanzapine-induced misfolding of proinsulin in the ER accounts for atypical development of diabetes2020
Author(s)
Ninagawa S*, Tada S,# Okumura M,# Inoguchi K,# Kinoshita M, Kanemura S, Imami K, Umezawa H, Ishikawa T, Okada T, Mackin R, Torii S, Ishihama Y, Inaba K, Anazawa T, Nagamine T, Mori K*
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Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40)2019
Author(s)
Lin Y, Sahoo BR, Ozawa D, Kinoshita M, Kang J, Lim MH, Okumura M, Huh YH, Moon E, Jang JH, Lee HJ, Ryu KY, Ham S, Won HS, Ryu KS, Sugiki T, Bang JK, Hoe HS, Fujiwara T, Ramamoorthy A, Lee YH
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Journal Title
ACS nano
Volume: 27
Issue: 8
Pages: 8766-8783
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Dynamic assembly/disassembly of Protein Disulfide Isomerase during the catalysis of oxidative protein folding2019
Author(s)
Masaki Okumura, Kentaro Noi, Shingo Kanemura, Misaki Kinoshita, Tomohide Saio, Yuichi Inoue, Takaaki Hikima, Shuji Akiyama, Teru Ogura, Kenji Inaba
Organizer
14th ER redox club meeting, Herrsching am Ammersee, Germany
Related Report
Int'l Joint Research
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[Book] 生化学2020
Author(s)
奥村正樹、稲葉謙次
Total Pages
6
Publisher
生化学会
Related Report
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