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

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, Masaki Fukata () and Shuya Fukai ()
Additional contact information
Atsushi Yamagata: The University of Tokyo
Yuri Miyazaki: National Institutes of Natural Sciences
Norihiko Yokoi: National Institutes of Natural Sciences
Hideki Shigematsu: Tsurumi-ku
Yusuke Sato: The University of Tokyo
Sakurako Goto-Ito: The University of Tokyo
Asami Maeda: 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)
Mikako Shirouzu: Tsurumi-ku
Yuko Fukata: National Institutes of Natural Sciences
Masaki Fukata: National Institutes of Natural Sciences
Shuya Fukai: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-03947-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03947-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-03947-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().