Structural basis of the novel mechanism to regulate the synapse formation

• Project/Area Number: 19H03162
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Yamagata Atsushi 国立研究開発法人理化学研究所, 生命機能科学研究センター, 上級研究員 (20463903)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
• Keywords: シナプス / 結晶構造解析 / クライオ電子顕微鏡 / タンパク質複合体 / ホスファターゼ / SAMドメイン

Outline of Research at the Start

シナプス形成の新たな分子機構として注目されている３つのタンパク質複合体、1. RPTPの細胞内ホスファターゼドメインとリプリンαとの複合体、2. ニューレキシンとSorCSとの複合体、3. LRRTMと糖鎖との複合体について、結晶構造解析またはクライオ電子顕微鏡を用いた構造生物学的解析を行う。さらに得られた構造情報を元に、機能解析を行い、これらのタンパク質複合体によるシナプス形成のメカニズムを構造と機能の両面から明らかにする。

Outline of Final Research Achievements

We determined the crystal structure of IIaRPTP, a neuronal cell adhesion protein that governs the synapse formation, and the synaptic scaffold protein, Liprin-α. The structure reveals the specific interaction between them. The structure-based mutational analyses demonstrated that their specific interaction is essential for synapse formation. In addition, we identified the interaction between PTPRD and NLGN3, as a novel trans-synaptic complex to regulate the synapse formation. We solved the crystal structure of the complex between IIaRPTP and Neuroligan 3(NL3). Moreover, the behavioral testing using the knock-in mice revealed that the specific interaction between IIaRPTP and NL3 plays an important role for the development of sociality.

Academic Significance and Societal Importance of the Research Achievements

脳は1000億以上もの神経細胞が集まっており、それぞれの神経細胞間はシナプスによって接合されている。シナプス形成の異常は、統合失調症や自閉症、難治性てんかんといった神経発達障害の原因となることが知られている。本研究はこれまで解析されていないタンパク質分子複合体であるIIaRPTP-Liprin-α複合体とIIaRPTP-NL3複合体について立体構造を明らかにし、さらに複合体形成の破綻がもたらすシナプス形成不全や高次脳機能（社会性など）の異常との関わりを明らかにした。一連の研究はシナプス形成異常がもたらす神経発達障害のメカニズムの解明につながるものであり、将来の創薬の基盤となることが期待される。

Research Products

• [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cryo-EM structure of the photosynthetic RC-LH1-PufX supercomplex at 2.8 Å resolution (2021)
  • Author(s): Laura Bracun, Atsushi Yamagata, Bern M. Christianson, Tohru Terada, Daniel P. Canniffe, Mikako Shirouzu, Lu-Ning Liu
  • Journal Title: Science Advances Volume: 7 Issue: 25
  • DOI: 10.1126/sciadv.abf8864
  • Peer Reviewed / Open Access
• [Journal Article] 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus (2020)
  • Author(s): Shirakawa Ryutaro、Goto‐Ito Sakurako、Goto Kota、Wakayama Shonosuke、Kubo Haremaru、Sakata Natsumi、Trinh Duc Anh、Yamagata Atsushi、Sato Yusuke、Masumoto Hiroshi、Cheng Jinglei、Fujimoto Toyoshi、Fukai Shuya、Horiuchi Hisanori
  • Journal Title: The EMBO Journal Volume: 39 Issue: 8
  • DOI: 10.15252/embj.2019104120
  • Peer Reviewed
• [Journal Article] Structural insights into ubiquitin recognition and Ufd1 interaction of Npl4 (2019)
  • Author(s): Sato Yusuke、Tsuchiya Hikaru、Yamagata Atsushi、Okatsu Kei、Tanaka Keiji、Saeki Yasushi、Fukai Shuya
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 5708-5708
  • DOI: 10.1038/s41467-019-13697-y
  • Peer Reviewed / Open Access
• [Presentation] 抗てんかんLGI1-ADAM22複合体を安定化する14-3-3-ADAM22相互作用 (2022)
  • Author(s): 横井紀彦、深田優子、尾勝圭、山形敦史、劉岩、三宝誠、宮崎裕理、後藤哲平、平林真澄、深井周也、深田正紀
  • Organizer: Neuro2022
• [Presentation] Structural insights into the selective interaciton between type IIa protein tyrosine phosphatase and the neuronal scaffolding protein, Liprin-alpha. (2021)
  • Author(s): 山形敦史
  • Organizer: BDR Symposium 2021
• [Presentation] Structural insights into the synapse formation by typeII protein tyrosine phosphatase (2020)
  • Author(s): 山形敦史
  • Organizer: 日本神経科学学会
• [Presentation] Selective interaction between RPTP pseudo phosphatase domain and the neuronal scaffold protein, Liprin-alpha (2020)
  • Author(s): 山形敦史
  • Organizer: International Conference on Protein Phosphatases
• [Presentation] IIa型受容体ホスファターゼとシナプスオーガナイザーとのシナプスを跨ぐ複合体の構造基盤 (2019)
  • Author(s): 山形敦史
  • Organizer: 日本神経科学学会
• [Presentation] IIa 型受容体型チロシンホスファターゼによるシナプス形成の構造基盤 (2019)
  • Author(s): 山形敦史
  • Organizer: 日本生化学会