5Y31

Crystal structure of human LGI1-ADAM22 complex

Summary for 5Y31

• Entry DOI: 10.2210/pdb5y31/pdb
• Descriptor: Disintegrin and metalloproteinase domain-containing protein 22, Leucine-rich glioma-inactivated protein 1, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: epilepsy, synapse, adam, eptp, wd40, cell adhesion
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 237280.73

Authors

Yamagata, A.,Fukai, S. (deposition date: 2017-07-27, release date: 2018-05-02, Last modification date: 2024-10-23)

Primary citation

Yamagata, A.,Miyazaki, Y.,Yokoi, N.,Shigematsu, H.,Sato, Y.,Goto-Ito, S.,Maeda, A.,Goto, T.,Sanbo, M.,Hirabayashi, M.,Shirouzu, M.,Fukata, Y.,Fukata, M.,Fukai, S.
Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22.
Nat Commun, 9:1546-1546, 2018

PubMed 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.

PubMed: 29670100
DOI: 10.1038/s41467-018-03947-w

Experimental method

X-RAY DIFFRACTION (7.125 Å)