Elucidation of the proteasome formation mechanisms through multilateral structural biology approach toward drug discovery
| Project/Area Number |
15H02491
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Nagoya City University |
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Principal Investigator |
Kato Koichi 名古屋市立大学, 大学院薬学研究科, 教授 (20211849)
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| Co-Investigator(Kenkyū-buntansha) |
矢木 真穂 大学共同利用機関法人自然科学研究機構(新分野創成センター、アストロバイオロジーセンター、生命創成探究, 生命創成探究センター, 助教 (40608999)
山口 拓実 北陸先端科学技術大学院大学, 先端科学技術研究科, 准教授 (60522430)
矢木 宏和 名古屋市立大学, 大学院薬学研究科, 講師 (70565423)
佐藤 匡史 名古屋市立大学, 大学院薬学研究科, 准教授 (80532100)
谷中 冴子 分子科学研究所, 生命・錯体分子科学研究領域, 助教 (80722777)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥44,980,000 (Direct Cost: ¥34,600,000、Indirect Cost: ¥10,380,000)
Fiscal Year 2018: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2017: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
Fiscal Year 2016: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
Fiscal Year 2015: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
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| Keywords | プロテアソーム / アッセンブリーシャペロン |
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| Outline of Final Research Achievements |
The proteasome, a major proteolytic machine comprising approximately 70 subunits, is one of the largest and most complicated biological supramolecular complexes. Assembly of these subunits is not an autonomous process but is assisted by a series of proteasome assembly chaperones. In this study, we focused on the α-ring, which is a core component of the proteasome. By using a multilateral structural biology approach combining various biophysical techniques, we successfully constructed precise three-dimensional models of the human α-ring intermediate complexes mediated by the assembly chaperones. These findings provide an important basis for the rational inhibitor design targeting the proteasome assembly system.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で得られた構造情報は、プロテアソームアッセンブリー系を標的としてその機能を阻害する分子の設計に重要な指針を与える。具体的には、プロテアソーム新生が活発ながん細胞に選択的に作用する医薬品の開発に資することができる。本研究は、プロテアソーム形成過程を標的とする新たな創薬の可能性を切り拓くものであり、その社会的波及効果は極めて大きい。また、本研究を通じて確立された研究戦略はリボソームやウィルスなど、様々な生体超分子の構造研究に応用可能であり、それらを標的とする創薬にも新たな着想をもたらすものと期待される。
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Report
(5 results)
Research Products
(47 results)
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[Journal Article] Mutational and Combinatorial Control of Self-Assembling and Disassembling of Human Proteasome α Subunits2019
Author(s)
Taichiro Sekiguchi, Tadashi Satoh, Eiji Kurimoto, Chihong Song, Toshiya Kozai, Hiroki Watanabe, Kentaro Ishii, Hirokazu Yagi, Saeko Yanaka, Susumu Uchiyama, Takayuki Uchihashi, Kazuyoshi Murata and Koichi Kato
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Journal Title
Int. J. Mol. Sci.
Volume: 20
Issue: 9
Pages: 2308-2308
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Conversion of functionally undefined homopentameric protein PbaA into a proteasome activator by mutational modification of its C-terminal segment conformation2018
Author(s)
M. Yagi-Utsumi, A. Sikdar, T. Kozai, R. Inoue, M. Sugiyama, T. Uchihashi, H. Yagi, T. Satoh, and K. Kato
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Journal Title
Protein Engineering, Design, and Selection
Volume: 31
Issue: 1
Pages: 29-36
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Two-step process for disassembly mechanism of proteasome α7 homo-tetradecamer by α6 revealed by high-speed atomic force microscopy2017
Author(s)
Kozai, T., Sekiguchi, T., Satoh, T., Yagi, H., Kato, K., Uchihashi, T.
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Journal Title
Scientific Reports
Volume: 7(1)
Issue: 1
Pages: 15373-15373
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Multiple structural architectures of archaeal homolog of proteasome assembly chaperone, PbaA2017
Author(s)
Arunima Sikdar, Chihong Song, Toshiya Kozai, Kentaro Ishii, Susumu Uchiyama, Takayuki Uchihashi, Kazuyoshi Murata, Tadashi Satoh, Maho Yagi-Utsumi, and Koichi Kato
Organizer
2016年度生物物理学会中部支部講演会
Place of Presentation
名古屋大学東山キャンパスES総合館1階ESホール（愛知県名古屋市）
Year and Date
2017-03-06
Related Report
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[Presentation] 高速AFMによる20Sプロテアソーム関連タンパク質の動態観察2016
Author(s)
Toshiya Kozai, Tadashi Satoh, Arunima Sikdar, Hirokazu Yagi, Maho Yagi-Utsumi, Takayuki Uchihashi , Toshio Ando , and Koichi Kato
Organizer
第54回日本生物物理学会年会
Place of Presentation
つくば国際会議場（茨城県つくば市）
Year and Date
2016-11-27
Related Report
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[Presentation] High pressure NMR reveals a fluctuating ubiquitin structure2016
Author(s)
Ryo Kitahara, Soichiro Kitazawa, Takuro Wakamoto, Teppei Ikeya, Tomoshi Kameda, Maho Yagi-Utsumi, Koichi Kato, Christian Roumestand, Nicola J. Baxter, and Mike P. Williamson
Organizer
The 42nd Naito Conference
Place of Presentation
シャトレーゼ・ガトーキングダムサッポロ（北海道札幌市）
Year and Date
2016-10-05
Related Report
Int'l Joint Research
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[Presentation] NMR snapshots of a fluctuating ubiquitin structure2016
Author(s)
Soichiro Kitazawa, Takuro Wakamoto, Teppei Ikeya, Tomoshi Kameda, Maho Yagi-Utsumi, Koichi Kato, Christian Roumestand, Nicola J. Baxter, Mike P. Williamson, and Ryo Kitahara
Organizer
EUROMAR2016
Place of Presentation
Aarhus、Denmark
Year and Date
2016-07-06
Related Report
Int'l Joint Research
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[Presentation] Structural insights into molecular assembly in the proteasomal systems2016
Author(s)
Tadashi Satoh, Arunima Sikdar, Kazuyoshi Murata, Toshiya Kozai, Kentaro Ishii, Masanori Noda, Hiroki Kawamura, Hirokazu Yagi, Maho Yagi-Utsumi, Susumu Uchiyama, Takayuki Uchihashi, and Koichi Kato
Organizer
The 7th alan-Taiwan Joint Meeting on Neutron and X-ray Scattering
Place of Presentation
京都大学 原子炉実験所
Year and Date
2016-03-12
Related Report
Invited
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