Molecular mechanism for synapse-nanocolumn formation and synapse disorders

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03678
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: Fukata Masaki 生理学研究所, 分子細胞生理研究領域, 教授 (00335027)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: シナプス / 蛋白質 / 脂質 / 脳・神経 / 酵素 / 生理学 / ナノドメイン / ナノカラム

Outline of Final Research Achievements

Regulated trans-synaptic communication plays a pivotal role in synaptic transmission. Although recent studies have identified a large number of synaptic adhesion molecules, the molecular mechanism for trans-synaptic communication remains incompletely understood. In this study, we showed the crystal structure of human LGI1-ADAM22 complex, revealing a 2:2 heterotetrameric assembly through the intermolecular LGI1-LGI1 interaction. A pathogenic R474Q mutation of LGI1 is located in the LGI1-LGI1 interface and disrupts the higher-order assembly of the LGI1-ADAM22 complex in vitro and in a mouse model for familial epilepsy. These studies support the notion that the LGI1-ADAM22 complex functions as the trans-synaptic machinery for precise synaptic transmission and disruption of this linkage causes the epileptic disorder.

Free Research Field

神経科学、生化学、細胞生物学

Academic Significance and Societal Importance of the Research Achievements

てんかんの原因となる分泌蛋白質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、ADAM22がLGI1を介して神経細胞間の橋渡しをする様子を明らかにした。また、これまでに知られていたLGI1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。本研究は、神経シナプス機能の調節機構とてんかん病態の一端を明らかにしたと言える。