[대학원 생명과학과 세미나 안내] 

연사 : 김호민 교수(KAIST 의과학대학원)

연제 : 3D-structural aspects of synaptic adhesion complex

일시 : 2017년 12월 1일 (금) 오후 5시 

장소 : 하나과학관 A동 B131호

초청교수 : 송현규 교수

Abstract

Synaptic adhesion molecules orchestrate synaptogenesis. Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) bind directly to neuroligin-1 (NL1) and neuroligin-2 (NL2), thereby regulating the development of excitatory and inhibitory synapses, respectively. 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 negative regulation of NL2-mediated synaptogenic activity by MDGA1. 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. These findings collectively provide structural insights into the mechanism by which MDGAs negatively modulate synapse development governed by NLs/neurexins. Another type of synaptic adhesion protein, leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs), regulate synapse development by interacting with postsynaptic adhesion partner including NGL-3, TrkC, IL-1RAcP, IL1RAPL1 and Slitrks. Here, we show that LAR-RPTP binding to postsynaptic ligands (e.g., Slitrks, IL1RAPL1, and IL-1RAcP) induces a reciprocal higher-order clustering of trans-synaptic adhesion complexes. Subsequent crystallographic and structure-guided functional analyses reveal that lateral interactions between adjacent trans-synaptic adhesion complexes (LAR-RPTP/Slitrk and LAR-RPTP/IL1RAPL) observed in crystal lattices are critical for their high-order clustering and synaptogenic activity. Although LAR-RPTP clustering can be induced by either HS or postsynaptic adhesion ligands, the dominant binding of HS to LAR-RPTP can dismantle pre-established LAR-RPTP-mediated trans-synaptic adhesion complexes. Thus, we propose that HS and postsynaptic adhesion ligands compete with one another to modulate LAR-RPTP clustering and modulate synaptogenesis through a complex synapse-organizing protein network.