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Elucidation of the mechanisms of amyloid formation by structural analyses considering the environments surrounding protein molecules

Research Project

Project/Area Number 19K07041
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
Research InstitutionCenter for Novel Science Initatives, National Institutes of Natural Sciences

Principal Investigator

Yagi Maho  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)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsアミロイド線維 / アミロイドβ / 微小重力環境 / 低温大気圧プラズマ / ガングリオシド / 核磁気共鳴 / クライオ電子顕微鏡 / 国際宇宙ステーション / 微小重力 / アミロイド
Outline of Research at the Start

タンパク質のアミロイド形成は神経変性疾患等の発症と関わっており、その分子機構を明らかにすることは薬学領域においても重要な課題である。タンパク質の分子間相互作用から線維形成に至るプロセスには、タンパク質を取り巻く様々な環境因子が複雑に関わっており、それらの寄与を考慮しない限りアミロイド形成機構の真の理解は不可能である。そこで本研究では、アルツハイマー病の発症に関わるアミロイドβをモデル分子として、対流等による溶液内ミクロ環境の揺らぎ、溶液-膜界面での空間限定の効果等を考慮した構造解析を行い、これらの環境因子がアミロイド形成に与える影響を詳細に検討して分子会合機構の実態解明に迫る。

Outline of Final Research Achievements

The effects of fluctuations in the solution microenvironment on the amyloid fibril formation were elucidated by detailed structural analysis of amyloid fibrils formed under microgravity conditions. On the other hand, to clarify the effect of spatial limitation at the solution-membrane interface on the molecular assembly of amyloid β, solid-state NMR analysis and molecular dynamics simulation were performed to determine the structure of the molecular assembly of amyloid β promoted on the ganglioside-containing membrane interface, and to identify the key amino acid residues that induce the molecular assembly. Furthermore, using high-speed atomic force microscopy, I was able to visualize the elongation of amyloid fibrils and how anti-amyloid β antibodies specifically bind to the elongation ends of amyloid fibrils and inhibit their elongation.

Academic Significance and Societal Importance of the Research Achievements

タンパク質のアミロイド形成は神経変性疾患等の発症と関わっており、その分子機構を明らかにすることは薬学領域において重要な課題である。タンパク質の分子間相互作用から線維形成に至るプロセスには、タンパク質を取り巻く様々な環境因子が複雑に関わっている。したがって、対流等による溶液内ミクロ環境の揺らぎ、溶液-膜界面での空間限定の効果等の寄与を考慮した構造解析を実施することではじめて、アミロイド形成機構の真の理解が可能となる。さらに、得られた研究成果に基づき、環境因子の影響を考慮したアミロイド標的創薬への新たな展開などが期待される。

Report

(3 results)
  • 2021 Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (14 results)

All 2021 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (5 results) (of which Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (8 results) (of which Int'l Joint Research: 4 results,  Invited: 7 results)

  • [Int'l Joint Research] University of Cambridge(英国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Cold Atmospheric Plasma Modification of Amyloid β2021

    • Author(s)
      Yagi-Utsumi Maho、Tanaka Tomohiro、Otsubo Yoko、Yamashita Akira、Yoshimura Shinji、Nishida Motohiro、Kato Koichi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 6 Pages: 3116-3116

    • DOI

      10.3390/ijms22063116

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 膜環境におけるアミロイドβの分子集合に関する構造的知見2021

    • Author(s)
      矢木真穂、加藤晃一
    • Journal Title

      膜

      Volume: 46 Pages: 2-6

    • NAID

      130007977588

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Characterization of amyloid β fibril formation under microgravity conditions2020

    • Author(s)
      Yagi-Utsumi Maho、Yanaka Saeko、Song Chihong、Satoh Tadashi、Yamazaki Chiaki、Kasahara Haruo、Shimazu Toru、Murata Kazuyoshi、Kato Koichi
    • Journal Title

      npj Microgravity

      Volume: 6 Issue: 1 Pages: 17-17

    • DOI

      10.1038/s41526-020-0107-y

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of amyloid β fibril formation under microgravity conditions2020

    • Author(s)
      Yagi-Utsumi Maho、Yanaka Saeko、Song Chihong、Satoh Tadashi、Yamazaki Chiaki、Kasahara Haruo、Shimazu Toru、Murata Kazuyoshi、Kato Koichi
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2020.03.23.004341

    • Related Report
      2019 Research-status Report
    • Open Access
  • [Journal Article] NMR Characterization of Conformational Dynamics and Molecular Assemblies of Proteins2019

    • Author(s)
      Yagi-Utsumi Maho
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 6 Pages: 867-872

    • DOI

      10.1248/bpb.b19-00115

    • NAID

      130007657695

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-06-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] ガングリオシド膜上におけるアミロイドβの構造転移2020

    • Author(s)
      矢木真穂
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 宇宙実験からアルツハイマー病の解明を目指す!2020

    • Author(s)
      矢木真穂
    • Organizer
      第30回自然科学研究機構シンポジウム「宇宙科学と生命科学の深~いつながり」
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] NMR characterization of the conformations and interactions of amyloid-β on glycolipid membrane2020

    • Author(s)
      Maho Yagi-Utsumi
    • Organizer
      7th International Postgraduate Conference on Pharmaceutical Sciences (iPOPS 2020)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Biophysical characterization of environment-dependent biomolecular assemblies2019

    • Author(s)
      Maho Yagi-Utsumi
    • Organizer
      ExCELLS visit talks
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] NMR characterization of conformational transition of amyloid-β on ganglioside membrane2019

    • Author(s)
      Maho Yagi-Utsumi, Satoru G. Itoh, Hisashi Okumura, Katsuyuki Nishimura and Koichi Kato
    • Organizer
      Frontier Bioorganization Forum 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] NMR Study of Conformational Transition of Amyloid-β on Ganglioside Membrane2019

    • Author(s)
      Maho Yagi-Utsumi and Koichi Kato
    • Organizer
      The 10th Toyota RIKEN International Worksyop on Science of Life Phenomena Woven by Water and Biomolecules
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Biophysical characterization of environment-dependent protein assemblies of physiological and pathological interest2019

    • Author(s)
      Maho Yagi-Utsumi and Koichi Kato
    • Organizer
      第57回 日本生物物理学会年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] アルツハイマー病の解明を目指したNMR構造研究2019

    • Author(s)
      矢木真穂
    • Organizer
      東京大学社会連携講座 革新分子構造解析講座:公開シンポジウム -低分子からタンパク質まで,統合分子構造解析-
    • Related Report
      2019 Research-status Report
    • Invited

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Published: 2019-04-18   Modified: 2023-01-30  

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