| 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 PubMed
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.,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
- ↑ Zhu P, Sun Y, Xu R, Sang Y, Zhao J, Liu G, Cai L, Li C, Zhao S. The interaction between ADAM 22 and 14-3-3zeta: regulation of cell adhesion and spreading. Biochem Biophys Res Commun. 2003 Feb 21;301(4):991-9. PMID:12589811
- ↑ Zhu P, Sang Y, Xu H, Zhao J, Xu R, Sun Y, Xu T, Wang X, Chen L, Feng H, Li C, Zhao S. ADAM22 plays an important role in cell adhesion and spreading with the assistance of 14-3-3. Biochem Biophys Res Commun. 2005 Jun 17;331(4):938-46. PMID:15882968 doi:http://dx.doi.org/10.1016/j.bbrc.2005.03.229
- ↑ D'Abaco GM, Ng K, Paradiso L, Godde NJ, Kaye A, Novak U. ADAM22, expressed in normal brain but not in high-grade gliomas, inhibits cellular proliferation via the disintegrin domain. Neurosurgery. 2006 Jan;58(1):179-86; discussion 179-86. PMID:16385342
- ↑ Kunapuli P, Kasyapa CS, Hawthorn L, Cowell JK. LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway. J Biol Chem. 2004 May 28;279(22):23151-7. doi: 10.1074/jbc.M314192200. Epub 2004 , Mar 26. PMID:15047712 doi:http://dx.doi.org/10.1074/jbc.M314192200
- ↑ Gabellini N, Masola V, Quartesan S, Oselladore B, Nobile C, Michelucci R, Curtarello M, Parolin C, Palu G. Increased expression of LGI1 gene triggers growth inhibition and apoptosis of neuroblastoma cells. J Cell Physiol. 2006 Jun;207(3):711-21. doi: 10.1002/jcp.20627. PMID:16518856 doi:http://dx.doi.org/10.1002/jcp.20627
- ↑ 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. 2018 Apr 18;9(1):1546. doi: 10.1038/s41467-018-03947-w. PMID:29670100 doi:http://dx.doi.org/10.1038/s41467-018-03947-w
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