Structural analysis of the epilepsy-related protein complex LGI1-ADAM22-PSD-95 and its regulatory factors
Project/Area Number |
18H03983
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
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Research Institution | Kyoto 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
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Project Status |
Completed (Fiscal Year 2021)
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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)
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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.
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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。
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Report
(5 results)
Research Products
(20 results)
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[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
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Journal Title
Cell Reports
Volume: 39
Issue: 1
Pages: 110624-110624
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Cell Reports
Volume: 37
Issue: 11
Pages: 110107-110107
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
Nature Communications
Volume: 12(1)
Issue: 1
Pages: 1848-1848
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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