LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11.
The transmembrane protein ADAM22 is expressed at high levels in the brain. From its molecular structure, ADAM22 is thought to be an adhesion molecule or a receptor because it has functional disintegrin-like and cysteine-rich sequences in its ectodomain. The phenotypic analysis of ADAM22-deficient mice has indicated the important roles played by ADAM22 in proper neuronal function and peripheral nerve development, however, the precise molecular function of ADAM22 is still unknown. To understand the function of ADAM22 on a molecular basis, we identified ADAM22 binding proteins by using immunoprecipitation and mass spectrometric analysis. This analysis revealed that Leucine-rich glioma inactivated 1 (LGI1) is the most potent ADAM22 binding protein in mouse brain. By our quantitative cell-ELISA system, we demonstrated the specific binding of LGI1 with ADAM22. Furthermore, we showed that LGI4, a putative ADAM22 ligand, also bound to ADAM22. Characterization of the binding specificity of LGI1 and LGI4 suggested that ADAM22 is not a sole receptor, because ADAM11 and ADAM23 had a significant binding ability to LGI1 or LGI4. Therefore, LGI-ADAM system seems to be regulated not only by the affinity but also by the cell-type-specific expression of each protein. Our findings provide new clues to understand the functions of LGI1 and LGI4 as an ADAMs ligand.
Sagane
Koji
K
Tsukuba Research Laboratories, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibaraki 300-2635, Japan. k-sagane@hhc.eisai.co.jp
Ishihama
Yasushi
Y
Sugimoto
Hachiro
H
D051722:ADAM Proteins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002853:Chromatography, Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D013058:Mass Spectrometry; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000302:isolation & purification / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; C492120:Lgi1 protein, mouse; C485712:Lgi4 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C107204:ADAM 11 protein, mouse; D051722:ADAM Proteins; C121258:Adam22 protein, mouse; C121259:Adam23 protein, mouse