Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-03947-w
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Funding
- Japan Agency for Medical Research and Development (AMED)
- JSPS/MEXT KAKENHI [16H04749, 17J07958, 17K14969, 17H05897, 15H04279, 17H03678, 17H05709, 27-7]
- Japan Epilepsy Research Foundation
- Kato Memorial Bioscience Foundation
- Takeda Science Foundation
- Hori Sciences and Arts Foundation
- JST CREST [JPMJCR12M5]
- Grants-in-Aid for Scientific Research [17H05709, 17H03678, 16H04749, 17J07958, 15H04279, 17H05897, 17K14969] Funding Source: KAKEN
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Epilepsy is a common brain disorder throughout history. Epilepsy-related ligand-receptor complex, LGI1-ADAM22, regulates synaptic transmission and has emerged as a determinant of brain excitability, as their mutations and acquired LGI1 autoantibodies cause epileptic disorders in human. Here, we report the crystal structure of human LGI1-ADAM22 complex, revealing a 2:2 heterotetrameric assembly. The hydrophobic pocket of the C-terminal epitempin- repeat (EPTP) domain of LGI1 binds to the metalloprotease-like domain of ADAM22. The N-terminal leucine-rich repeat and EPTP domains of LGI1 mediate the intermolecular LGI1-LGI1 interaction. A pathogenic R474Q mutation of LGI1, which does not exceptionally affect either the secretion or the ADAM22 binding, 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.
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