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Structural analysis of the epilepsy-related protein complex LGI1-ADAM22-PSD-95 and its regulatory factors

Research Project

Project/Area Number 18H03983
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
Research InstitutionKyoto University (2020-2021)
The University of Tokyo (2018-2019)

Principal Investigator

Fukai Shuya  京都大学, 理学研究科, 教授 (10361792)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥43,810,000 (Direct Cost: ¥33,700,000、Indirect Cost: ¥10,110,000)
Fiscal Year 2021: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2020: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2019: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
Fiscal Year 2018: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
Keywords構造生物学 / 分子間相互作用 / 膜受容体 / てんかん / 足場タンパク質 / パルミトイル化 / シナプス / パルミトリル化
Outline of Final Research Achievements

In this study, we analyzed the three-dimensional structure of the epilepsy-associated protein complex LGI1-ADAM22-PSD-95 to understand the mechanism of signal transduction through the membrane and pathogenesis. We revealed the details of the interaction mode between LGI1 and ADAM22 by the integrated structure analysis combining X-ray crystallography, X-ray small-angle scattering analysis, and cryo-electron microscopy. Furthermore, we showed that a mutation in LGI1 whose pathogenic mechanism was unknown causes abnormalities in the formation of higher-order assembly of LGI1-ADAM22, using a mouse model. In addition, we contributed to the elucidation of the molecular mechanism underlying the molecular condensation of PSD-95 induced by LGI1-ADAM22 and the regulation of the amount of ADAM22 by 14-3-3 protein.

Academic Significance and Societal Importance of the Research Achievements

てんかんの原因となる分子LGI1とその受容体であるADAM22が結合した状態の立体構造を決定することで、LGI1を介してADAM22ファミリーのタンパク質が神経細胞間の橋渡しをする様子を明らかにし、これまでに知られていたLGI1の変異の中で発症の仕組みが不明であった変異に関して、新たな発症の仕組みを明らかにした。また、神経細胞間の信号伝達に必要な細胞内タンパク質PSD-95の集合状態をADAM22が制御する仕組みや14-3-3タンパク質がADAM22の量を調節する仕組みの理解にも貢献した。これらは、てんかん病態とそれに関連する神経活動の分子機構に関わる今後の研究に役立つ知見になると期待される。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (20 results)

All 2022 2021 2020 2019 2018 Other

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 9 results) Presentation (3 results) (of which Invited: 3 results) Book (1 results) Remarks (5 results)

  • [Journal Article] Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins2022

    • Author(s)
      Uemura T, Suzuki-Kouyama E, Kawase S, Kurihara T, Yasumura M, Yoshida T, Fukai S, Yamazaki M, Fei P, Abe M, Watanabe M, Sakimura K, Mishina M, Tabuchi K
    • Journal Title

      Cell Reports

      Volume: 39 Issue: 1 Pages: 110624-110624

    • DOI

      10.1016/j.celrep.2022.110624

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice2021

    • Author(s)
      Norihiko Yokoi, Yuko Fukata, Kei Okatsu, Atsushi Yamagata, Yan Liu , Makoto Sanbo, Yuri Miyazaki, Teppei Goto, Manabu Abe , Hidetoshi Kassai, Kenji Sakimura, Dies Meijer, Masumi Hirabayashi, Shuya Fukai, Masaki Fukata
    • Journal Title

      Cell Reports

      Volume: 37 Issue: 11 Pages: 110107-110107

    • DOI

      10.1016/j.celrep.2021.110107

    • NAID

      120007177780

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice2021

    • Author(s)
      Yoshida T, Yamagata A, Imai A, Kim J, Izumi H, Nakashima S, Shiroshima T, Maeda A, Iwasawa-Okamoto S, Azechi K, Osaka F, Saitoh T, Maenaka K, Shimada T, Fukata Y, Fukata M, Matsumoto J, Nishijo H, Takao K, Tanaka S, Okabe S, Tabuchi K, Uemura T, Mishina M, Mori H & Fukai S
    • Journal Title

      Nature Communications

      Volume: 12(1) Issue: 1 Pages: 1848-1848

    • DOI

      10.1038/s41467-021-22059-6

    • NAID

      120006996978

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention2021

    • Author(s)
      Fukata Yuko、Chen Xiumin、Chiken Satomi、Hirano Yoko、Yamagata Atsushi、Inahashi Hiroki、Sanbo Makoto、Sano Hiromi、Goto Teppei、Hirabayashi Masumi、Kornau Hans-Christian、Pruss Harald、Nambu Atsushi、Fukai Shuya、Nicoll Roger A.、Fukata Masaki
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 3 Pages: 1-12

    • DOI

      10.1073/pnas.2022580118

    • NAID

      120006976050

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Frontiers in structural biology of synaptic adhesion molecules2020

    • Author(s)
      深井 周也
    • Journal Title

      生化学

      Volume: 92 Issue: 2 Pages: 166-178

    • DOI

      10.14952/SEIKAGAKU.2020.920166

    • NAID

      40022245228

    • ISSN
      0037-1017
    • Year and Date
      2020-04-25
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Roles of type IIa receptor protein tyrosine phosphatases as synaptic organizers2020

    • Author(s)
      Shuya Fukai, Tomoyuki Yoshida
    • Journal Title

      FEBS Journal

      Volume: - Issue: 24 Pages: 6913-6926

    • DOI

      10.1111/febs.15666

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM222020

    • Author(s)
      Atsushi Yamagata & Shuya Fukai
    • Journal Title

      Cellular and Molecular Life Sciences

      Volume: 77 Issue: 2 Pages: 267-274

    • DOI

      10.1007/s00018-019-03269-0

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α2020

    • Author(s)
      Wakita Maiko、Yamagata Atsushi、Shiroshima Tomoko、Izumi Hironori、Maeda Asami、Sendo Mizuki、Imai Ayako、Kubota Keiko、Goto-Ito Sakurako、Sato Yusuke、Mori Hisashi、Yoshida Tomoyuki、Fukai Shuya
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 649-649

    • DOI

      10.1038/s41467-020-14516-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural basis of guanine nucleotide exchange for Rab11 by SH3BP52019

    • Author(s)
      Goto-Ito Sakurako、Morooka Nobukatsu、Yamagata Atsushi、Sato Yusuke、Sato Ken、Fukai Shuya
    • Journal Title

      Life Science Alliance

      Volume: 2 Issue: 2 Pages: e201900297-e201900297

    • DOI

      10.26508/lsa.201900297

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural insights into leucine-rich repeat-containing synaptic cleft molecules2019

    • Author(s)
      Yamagata, A., Fukai, S.
    • Journal Title

      Current Opinion in Structural Biology

      Volume: 54 Pages: 68-77

    • DOI

      10.1016/j.sbi.2019.01.001

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM222018

    • Author(s)
      Yamagata Atsushi、Miyazaki Yuri、Yokoi Norihiko、Shigematsu Hideki、Sato Yusuke、Goto-Ito Sakurako、Maeda Asami、Goto Teppei、Sanbo Makoto、Hirabayashi Masumi、Shirouzu Mikako、Fukata Yuko、Fukata Masaki、Fukai Shuya
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 1546-1546

    • DOI

      10.1038/s41467-018-03947-w

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 受容体タンパク質チロシン脱リン酸化酵素 PTP δによるシナプス分化誘導 の構造基盤2021

    • Author(s)
      深井 周也
    • Organizer
      2021年度 生理研研究会 機能的神経回路の構築と動作を支える分子細胞基盤
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] シナプスオーガナイザーの選択的相互作用の構造基盤2019

    • Author(s)
      深井 周也
    • Organizer
      第19回日本蛋白質科学会年会 第71回日本細胞生物学会大会 合同年次大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Structural insights into transsynaptic molecular interactions for synapse formation and function2019

    • Author(s)
      深井 周也
    • Organizer
      The 5th Symposium of Neuroscience Network in Kobe
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Book] イメージング時代の構造生命科学2020

    • Author(s)
      田中 啓二、若槻 壮市
    • Total Pages
      248
    • Publisher
      羊土社
    • ISBN
      9784758103855
    • Related Report
      2020 Annual Research Report
  • [Remarks] 社会性の発達を調節する新たな機構を発見

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2021-03-26-1

    • Related Report
      2020 Annual Research Report
  • [Remarks] 神経シナプス間の軸調整を担う分子群を発見 ―新たなてんかん病態を解明―

    • URL

      https://www.nips.ac.jp/release/2021/01/post_426.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] 神経細胞間の信号伝達を担う接着構造を形成する仕組みの解明

    • URL

      https://www.u-tokyo.ac.jp/focus/ja/press/z0207_00023.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] てんかんの原因タンパク質が神経細胞間の橋渡しをする仕組みを解明

    • URL

      http://www.iam.u-tokyo.ac.jp/press_release/180418/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 神経発達障害に関連する細胞接着分子がカルシウムイオンを介して神経細胞同士を適切につなぐ仕組みの解明

    • URL

      http://www.iam.u-tokyo.ac.jp/press_release/180927/

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2023-01-30  

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