| First Author | Yamagata A | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 1546 |
| PubMed ID | 29670100 | Mgi Jnum | J:265744 |
| Mgi Id | MGI:6158091 | Doi | 10.1038/s41467-018-03947-w |
| Citation | Yamagata A, et al. (2018) Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22. Nat Commun 9(1):1546 |
| abstractText | 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. |
