Analysis of structure and formation mechanism of polyubiquitin fibrils
| Project/Area Number |
16K18503
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Structural biochemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | ポリユビキチン / アミロイド線維 / 重水素交換 / 反応中間体 / レオロジーNMR / 構造ゆらぎ / 流体力学的応力 / 線維反応中間体 / 線維重水素交換 / ユビキチン / アミロイド / NMR / 線維 / 蛋白質 / 生物物理 |
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| Outline of Final Research Achievements |
Ubiquitin is a protein with high structural stability and solubility. However, upon thermal and hydrodynamic stress, its polymerized form, a polyubiquitin chain, forms fibrillar aggregates that are associated with neurodegenerative diseases such as Alzheimer’s disease. In this study, we investigated the structure and formation mechanism of polyubiquitin fibrils at atomic resolution by using nuclear magnetic resonance. In our analysis of fibril intermediates and hydrogen-deuterium exchange experiments of fibrils, we identified important structural changes and inter-molecular interactions in the formation of polyubiquitin fibrils. Furthermore, we established a new rheological nuclear magnetic resonance to monitor fibril formation in situ and detected conformational changes of side chains in polyubiquitin chains during their fibril formation.
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| Academic Significance and Societal Importance of the Research Achievements |
長年多くの病理学者たちが抱いてきた不思議は、神経変性疾患で観察される異常タンパク質凝集体（封入体）のほとんどにユビキチンが含まれていることである。本研究は、どのようにしてポリユビキチン鎖が線維状凝集体を形成するかを原子分解能で解析したものであり、得られた研究成果は封入体の形成機構の理解、つまり神経変性疾患の発症機構の理解の一助となると考える。また、得られた構造学的情報は、熱や流体力学的応力によるマルチドメインタンパク質の構造変化や分子間相互作用を理解する上で重要な知見となり得ると考える。
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Report
(5 results)
Research Products
(34 results)
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[Journal Article] Structure of the Dnmt1 reader module complexed with a unique two-mono-ubiquitin mark on histone H3 reveals the basis for DNA methylation maintenance.2017
Author(s)
Ishiyama S, Nishiyama A, Saeki Y, Moritsugu K Morimoto D, Yamaguchi L, Arai N, Matsumura R, Kawakami T, Mishima Y, Hojo H, Shimamura S, Ishikawa F, Tajima S, Tanaka K, Ariyoshi M, Shirakawa M, Ikeguchi M, Kidera A, Suetake I, Arita K, Nakanishi M
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Journal Title
Mol Cell
Volume: 68
Issue: 2
Pages: 350-360
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Ubiquitylation-induced protein aggregation.2016
Author(s)
Morimoto, D., Walinda, E., Fukada, H, Sugase, K., Hoshino, M., Fujii, T., Namba, K., Komatsu, M., Tanaka, K., and Shirakawa, M.
Organizer
The 54th Annual Meeting of the Biophysical Society of Japan.
Place of Presentation
Tsukuba
Year and Date
2016-11-25
Related Report
Invited
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[Presentation] Highly Sensitive Rheo-NMR Spectroscopy For Proteins.2016
Author(s)
Morimoto, D., Walinda, E., Nishizawa, M., Scheler, U., Yamamoto, A., Shirakawa, M., and Sugase, K.
Organizer
The 55th Annual Meeting of the Nuclear Magnetic Resonance Society of Japan.
Place of Presentation
Hiroshima
Year and Date
2016-11-16
Related Report
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[Presentation] Elucidation of formation mechanism of ubiquitin-positive aggregates in cells.2016
Author(s)
Morimoto, D., Walinda, E., Fukada, H, Sugase, K., Kageyama, S., Hoshino, M., H., Namba, K., Komatsu, M., Tanaka, K., and Shirakawa, M.
Organizer
The 89th Annual Meeting of the Japanese Biochemical Society.
Place of Presentation
Sendai
Year and Date
2016-09-25
Related Report
Invited
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