한빛사 논문
Jung A Kim1, 8, Doyoun Kim2, 8, Seoung Youn Won3, Kyung Ah Han4, Dongseok Park4, Eunju Cho4, Nayoung Yun5, Hyun Joo An5, Ji Won Um4, Eunjoon Kim2, 6, Jie-Oh Lee3, 9, Jaewon Ko4, 9,*, Ho Min Kim2, 7, 9, 10,*
1 Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
2 Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Korea
3 Department of Chemistry, KAIST, Daejeon 34141, Korea
4 Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
5 Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 305-764, Korea
6 Department of Biological Sciences, KAIST, Daejeon 34141, Korea
7 Graduate School of Medical Science & Engineering, KAIST, Daejeon 34141, Korea
8 These authors contributed equally
9 Senior author
10 Lead Contact
*Corresponding author : Jaewon Ko, Ho Min Kim
Abstract
Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) bind directly to neuroligin-1 (NL1) and neuroligin-2 (NL2), thereby respectively regulating excitatory and inhibitory synapse development. However, the mechanisms by which MDGAs modulate NL activity to specify development of the two synapse types remain unclear. Here, we determined the crystal structures of human NL2/MDGA1 Ig1-3 complex, revealing their stable 2:2 arrangement with three interaction interfaces. Cell-based assays using structure-guided, site-directed MDGA1 mutants showed that all three contact patches were required for the MDGA’s negative regulation of NL2-mediated synaptogenic activity. Furthermore, MDGA1 competed with neurexins for NL2 via its Ig1 domain. The binding affinities of both MDGA1 and MDGA2 for NL1 and NL2 were similar, consistent with the structural prediction of similar binding interfaces. However, MDGA1 selectively associated with NL2, but not NL1, in vivo. These findings collectively provide structural insights into the mechanism by which MDGAs negatively modulate synapse development governed by NLs/neurexins.
Keywords : MDGA1; MDGA2; neuroligin-2; neurexin; inhibitory synapse formation; synaptic adhesion
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