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

Author

Listed:
  • Atsushi Yamagata

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

  • Yuri Miyazaki

    (National Institutes of Natural Sciences
    SOKENDAI (The Graduate University for Advanced Studies))

  • Norihiko Yokoi

    (National Institutes of Natural Sciences
    SOKENDAI (The Graduate University for Advanced Studies))

  • Hideki Shigematsu

    (Tsurumi-ku)

  • Yusuke Sato

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

  • Sakurako Goto-Ito

    (The University of Tokyo
    The University of Tokyo)

  • Asami Maeda

    (The University of Tokyo
    The University of Tokyo)

  • Teppei Goto

    (National Institutes of Natural Sciences)

  • Makoto Sanbo

    (National Institutes of Natural Sciences)

  • Masumi Hirabayashi

    (SOKENDAI (The Graduate University for Advanced Studies)
    National Institutes of Natural Sciences)

  • Mikako Shirouzu

    (Tsurumi-ku)

  • Yuko Fukata

    (National Institutes of Natural Sciences
    SOKENDAI (The Graduate University for Advanced Studies))

  • Masaki Fukata

    (National Institutes of Natural Sciences
    SOKENDAI (The Graduate University for Advanced Studies))

  • Shuya Fukai

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

Abstract

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.

Suggested Citation

  • Atsushi Yamagata & Yuri Miyazaki & Norihiko Yokoi & Hideki Shigematsu & Yusuke Sato & Sakurako Goto-Ito & Asami Maeda & Teppei Goto & Makoto Sanbo & Masumi Hirabayashi & Mikako Shirouzu & Yuko Fukata , 2018. "Structural basis of epilepsy-related ligand–receptor complex LGI1–ADAM22," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03947-w
    DOI: 10.1038/s41467-018-03947-w
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