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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.

Structural basis of epilepsy-related ligand–receptor complex LGI1–ADAM22