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Elucidation of the proteasome formation mechanisms through multilateral structural biology approach toward drug discovery

Research Project

Project/Area Number 15H02491
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionNagoya City University

Principal Investigator

Kato Koichi  名古屋市立大学, 大学院薬学研究科, 教授 (20211849)

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)
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
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)
Keywordsプロテアソーム / アッセンブリーシャペロン
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.

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。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (47 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (2 results) Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (35 results) (of which Int'l Joint Research: 9 results,  Invited: 9 results)

  • [Int'l Joint Research] ウプスラ大学(スウェーデン)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] バーゼル大学(スイス)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Molecular and Structural Basis of the Proteasome α Subunit Assembly Mechanism Mediated by the Proteasome-Assembling Chaperone PAC3-PAC4 Heterodimer2019

    • Author(s)
      Tadashi Satoh, Maho Yagi-Utsumi, Kenta Okamoto, Eiji Kurimoto, Keiji Tanaka and Koichi Kato
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 20 Issue: 9 Pages: 2231-2231

    • DOI

      10.3390/ijms20092231

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 20 Issue: 9 Pages: 2308-2308

    • DOI

      10.3390/ijms20092308

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
    • Journal Title

      Protein Engineering, Design, and Selection

      Volume: 31 Issue: 1 Pages: 29-36

    • DOI

      10.1093/protein/gzx066

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural insights on the dynamics of proteasome formation2018

    • Author(s)
      Kato Koichi、Satoh Tadashi
    • Journal Title

      Biophysical Reviews

      Volume: 10 Issue: 2 Pages: 597-604

    • DOI

      10.1007/s12551-017-0381-4

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 集合シャペロンを介したプロテアソーム形成機構2018

    • Author(s)
      佐藤匡史,加藤晃一
    • Journal Title

      医学のあゆみ

      Volume: 276 Pages: 949-953

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [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.
    • Journal Title

      Scientific Reports

      Volume: 7(1) Issue: 1 Pages: 15373-15373

    • DOI

      10.1038/s41598-017-15708-8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crystal structure of human proteasome assembly chaperone PAC4 involved in proteasome formation2017

    • Author(s)
      Eiji Kurimoro, Tadashi Satoh, Yuri Ito, Eri Ishihara, Kenta Okamoto, Maho Yagi-Utsumi, Keiji Tanaka, and Koichi Kato
    • Journal Title

      Protein Sci.

      Volume: 26 Issue: 5 Pages: 1080-1085

    • DOI

      10.1002/pro.3153

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Disassembly of the self-assembled, double-ring structure of proteasome α7 homo-tetradecamer by α62015

    • Author(s)
      K. Ishii, M. Noda, H. Yagi, R. Thammaporn, S. Seetaha, T. Satoh, K. Kato and S. Uchiyama
    • Journal Title

      Sci. Rep.

      Volume: 5 Issue: 1 Pages: 18167-18167

    • DOI

      10.1038/srep18167

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 離合集散が織りなす生命分子機能の研究フロンティア2015

    • Author(s)
      加藤晃一, 稲垣直之
    • Journal Title

      実験医学

      Volume: 33 Pages: 1316-1320

    • Related Report
      2015 Annual Research Report
  • [Journal Article] 生命分子の自己組織化のダイナミクス2015

    • Author(s)
      加藤晃一, 佐藤匡史
    • Journal Title

      化学工業

      Volume: 66 Pages: 32-37

    • Related Report
      2015 Annual Research Report
  • [Presentation] Mechanistic insights on the dynamics of proteasome formation2019

    • Author(s)
      Koichi Kato and Tadashi Sato
    • Organizer
      2019 EWU-NCU joint symposium
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] プロテアソームαサブユニットの自己組織化2019

    • Author(s)
      佐藤匡史,関口太一郎,石井健太郎,Chihong Song,小財稔矢,渡辺大輝,矢木宏和,矢木真穂,谷中冴子,栗本英治,内橋貴之,村田和義,内山 進,加藤晃一
    • Organizer
      平成30年度 日本生物物理学会中部支部講演会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Characterization of the “scrap-and-build” process in the proteasome α ring formation2018

    • Author(s)
      Taichiro Sekiguchi, Tadashi Satoh, Kentaro Ishii, Hirokazu Yagi, Koichi Kato
    • Organizer
      第56回 日本生物物理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Characterization of the “scrap-and-build” process in the proteasome α ring formation2018

    • Author(s)
      Taichiro Sekiguchi, Tadashi Satoh, Kentaro Ishii1, Hirokazu Yagi, and Koichi Kato
    • Organizer
      1st ExCELLS Symposium
    • Related Report
      2018 Annual Research Report
  • [Presentation] 構造に基づいたプロテアソームのサブユニット集合メカニズムの理解2018

    • Author(s)
      関口太一朗,河村裕樹,栗本英治,矢木宏和,佐藤匡史,加藤晃一
    • Organizer
      第5回 将来を見据えた生体分子の構造・機能解析から分子設計に関する研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 超分子質量分析によるプロテアソーム構成サブユニットの相互作用解析2018

    • Author(s)
      石井健太郎,関口太一朗,矢木宏和,佐藤匡史,内山 進,加藤晃一
    • Organizer
      平成29年度中部支部講演会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 高速AFMを用いたプロテアソームα7サブユニット14量体のα6による解体機構の解明2017

    • Author(s)
      小財稔矢,佐藤匡史,矢木宏和,内橋貴之,加藤晃一
    • 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
      2016 Annual Research Report
  • [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
      2016 Annual Research Report
  • [Presentation] Electron microscopy studies of ER glycoprotein folding sensor enzyme and archaeal homolog of proteasome assembly chaperone2017

    • Author(s)
      Tadashi Satoh, Chihong Song, Arunima Sikar, Maho Yagi-Utsumi, Kazuyoshi Murata, and Koichi Kato
    • Organizer
      The 1st ABiS Symposium “Towards the Future of Advanced Bioimaging for Life Sciences”
    • Place of Presentation
      岡崎コンファレンスセンター(愛知県岡崎市)
    • Year and Date
      2017-02-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] Multiple structural architectures of archaeal homolog of proteasome-assembly chaperone Structural insights into the molecular mechanisms of circadian clock protein complexes2017

    • Author(s)
      Arunima Sikdar, Tadashi Satoh, Maho Yagi-Utsumi, and Koichi Kato
    • Organizer
      The 9th Korea-Japan Seminars on Biomolecular Sciences: Experiments and Simulations
    • Place of Presentation
      北陸先端科学技術大学院大学 金沢駅前オフィス(石川県金沢市)
    • Year and Date
      2017-02-04
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Structural insights into dynamic orchestration of biomolecular systems2017

    • Author(s)
      Koichi Kato
    • Organizer
      Frontier Bioorganization Forum 2017: Dynamical ordering and integrated functions of biomolecular systems
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Versatile structural architectures of archaeal homolog of proteasome assembly chaperone2017

    • Author(s)
      Maho Yagi-Utsumi, Arunima Sikdar, Tadashi Satoh and Koichi Kato
    • Organizer
      Frontier Bioorganization Forum 2017: Dynamical ordering and integrated functions of biomolecular systems
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] α7サブユニットを起点としたαリング形成中間体の同定と構造解析2017

    • Author(s)
      関口太一朗,河村裕樹,石井健太郎,Chihong Song,村田和義,栗本英治,内山 進,矢木宏和,佐藤匡史,加藤晃一
    • Organizer
      第81回 日本生化学会中部支部例会・シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Presentation] 生体分子の集合離散が織りなす細胞機能研究の最前線2017

    • Author(s)
      加藤晃一
    • Organizer
      第69回 日本細胞生物学会大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 超分子質量分析による蛋白質複合体の形成過程の解明2017

    • Author(s)
      石井健太郎,杉山正明,加藤晃一,内山 進
    • Organizer
      第17回 日本蛋白質科学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] プロテアソームアッセンブリーシャペロンの古細菌ホモログPbaAの高次構造多型2017

    • Author(s)
      矢木-内海真穂,Arunima Sikdar,佐藤匡史,加藤晃一
    • Organizer
      第17回 日本蛋白質科学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] プロテアソーム分子集合の構造生物学2017

    • Author(s)
      加藤晃一
    • Organizer
      大阪大学蛋白質研究所セミナー・SPring-8先端利用技術ワークショップ SPring-8における蛋白質構造生物学研究の現状と将来
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 高速 AFM 観察で明らかにされた α7 ホモ 14 量体の α6 による解体過程2017

    • Author(s)
      小財稔矢,佐藤匡史,矢木宏和,内橋貴之,加藤晃一
    • Organizer
      第55回 日本生物物理学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Dynamic ordering of biomolecular systems coupled with creation of integrated functions2017

    • Author(s)
      Koichi Kato
    • Organizer
      The NANOTEC-IMS Joint Research Meeting
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Dynamic ordering of biomolecular systems coupled with creation of integrated functions2017

    • Author(s)
      Koichi Kato
    • Organizer
      CU-IMS collaborative seminar
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 試験管内再構成系を利用したプロテアソームアッセンブリー機構の解析2017

    • Author(s)
      河村裕樹,関口太一朗,栗本英治,矢木宏和,佐藤匡史,加藤晃一
    • Organizer
      日本病院薬剤師東海ブロック・日本薬学会東海支部 合同学術大会2017
    • Related Report
      2017 Annual Research Report
  • [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
      2016 Annual Research Report
  • [Presentation] Structural insights into proteasome orchestration mechanisms2016

    • Author(s)
      Koichi Kato
    • Organizer
      The 9th Korea-Japan Seminars on Biomolecular Sciences: Experiments and Simulations
    • Place of Presentation
      Gyeongju、Korea
    • Year and Date
      2016-11-14
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Structural basis for dynamic orchestration of proteasomes2016

    • Author(s)
      Koichi Kato
    • 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
      2016-10-06
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [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
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Structure and Dynamics of the Locally Disordered State of Ubiquitin Studied by High Pressure NMR Spectroscopy2016

    • Author(s)
      Takuro Wakamoto, Soichiro Kitazawa, Teppei Ikeya, Tomoshi Kameda, Maho Yagi-Utsumi, Koichi Kato, Christian Roumestand, Nicola J. Baxter, P. Mike Williamson, and Ryo Kitahara
    • Organizer
      The 17th International Conference on Magnetic Resonance in Biological Systems
    • Place of Presentation
      京都国際会議場(京都府京都市)
    • Year and Date
      2016-08-25
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [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
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mechanism of Lysine 48-linked Multiple Ubiquitin Chain Synthesis by a HECT Ubiquitin Ligase2016

    • Author(s)
      Yuji Masuda, Yasushi Saeki, Saeko Yanaka, Hidehiko Kawai, Iwao Kukimoto, Koichi Kato, Keiji Tanaka and Chikahide Masutani
    • Organizer
      FASEB Science Research Conference (Ubiquitin & Cellular Regulation)
    • Place of Presentation
      Montana、U.S.A.
    • Year and Date
      2016-06-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [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
      2015 Annual Research Report
    • Invited
  • [Presentation] Structural insights into molecular assembly of an archaeal homolog of proteasome assembly chaperone and its partner protein2016

    • Author(s)
      Arunima Sikdar, Chihong Song, Toshiya Kozai, Kentaro Ishii, Maho Yagi-Utsumi, Susumu Uchiyama, Takayuki Uchihashi, Kazuyoshi Murata, Tadashi Satoh, and Koichi Kato
    • Organizer
      平成27年度 日本生物物理学会 中部支部講演会
    • Place of Presentation
      岡崎コンファレンスセンター(岡崎)
    • Year and Date
      2016-02-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] 高速 AFM による 20S プロテアソーム関連タンパク質のダイナミクス観察2016

    • Author(s)
      小財稔矢,佐藤匡史,Arunima Sikdar,矢木宏和,矢木-内海真穂,内橋貴之,安藤敏夫,加藤晃一
    • Organizer
      平成27年度 日本生物物理学会 中部支部講演会
    • Place of Presentation
      岡崎コンファレンスセンター(岡崎)
    • Year and Date
      2016-02-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] Structural insights into working mechanism of PbaA, an archaealhomolog of proteasome assembly chaperone2015

    • Author(s)
      Arunima Sikdar, Tadashi Satoh, Kentaro Kumoi, Kentaro Ishii, Maho Yagi-Utsumi, and Koichi Kato
    • Organizer
      Okazaki Institute for Integrative Bioscience Retreat 2015
    • Place of Presentation
      岡崎統合バイオサイエンスセンター(岡崎)
    • Year and Date
      2015-12-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] Disassembly of the self-assembled, double-ring structure of proteasome α7 homo-tetradecamer by α62015

    • Author(s)
      Kentaro Ishii, Masanori Noda, Hirokazu Yagi, Ratsupa Thammaporn, Supaporn Seetaha, Tadashi Satoh, Koichi Kato, and Susumu Uchiyama
    • Organizer
      Okazaki Institute for Integrative Bioscience Retreat 2015
    • Place of Presentation
      岡崎統合バイオサイエンスセンター(岡崎)
    • Year and Date
      2015-12-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] ESI-MSによるプロテアソームサブユニット複合体の化学量論の解析2015

    • Author(s)
      石井健太郎,矢木宏和,加藤晃一,内山 進
    • Organizer
      第42回BMSコンファレンス
    • Place of Presentation
      岐阜グランドホテル(岐阜)
    • Year and Date
      2015-07-07
    • Related Report
      2015 Annual Research Report
  • [Presentation] Native MSによるプロテアソームα7サブユニットの自己会合状態の解析2015

    • Author(s)
      石井健太郎,矢木宏和,加藤晃一,内山 進
    • Organizer
      第63回質量分析総合討論会
    • Place of Presentation
      つくば国際会議場エポカルつくば(つくば)
    • Year and Date
      2015-06-17
    • Related Report
      2015 Annual Research Report

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Published: 2015-04-16   Modified: 2020-03-30  

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