5y2z | pdb_00005y2z
Crystal structure of human LGI1 EPTP-ADAM22 complex
Structural highlights
Disease[LGI1_HUMAN] Autosomal dominant epilepsy with auditory features. The disease is caused by mutations affecting the gene represented in this entry. Function[ADA22_HUMAN] Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1.[1] [2] [3] [LGI1_HUMAN] Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 and KCNAB1. It slows down channel inactivation by precluding channel closure mediated by the KCNAB1 subunit. Ligand for ADAM22 that positively regulates synaptic transmission mediated by AMPA-type glutamate receptors (By similarity). Plays a role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway. May play a role in the control of neuroblastoma cell survival.[4] [5] Publication Abstract from PubMedEpilepsy 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.,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 Nat Commun. 2018 Apr 18;9(1):1546. doi: 10.1038/s41467-018-03947-w. PMID:29670100[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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