Structural Insights into Modulation of Neurexin-Neuroligin Trans-synaptic Adhesion by MDGA1/Neuroligin-2 Complex

被引：50

作者：

Kim, Jung A. ^{[1
]}

Kim, Doyoun ^{[2
]}

Won, Seoung Youn ^{[3
]}

Han, Kyung Ah ^{[4
]}

Park, Dongseok ^{[4
]}

Cho, Eunju ^{[4
]}

Yun, Nayoung ^{[5
]}

An, Hyun Joo ^{[5
]}

Um, Ji Won ^{[4
]}

Kim, Eunjoon ^{[2
,6
]}

Lee, Jie-Oh ^{[3
]}

Ko, Jaewon ^{[4
]}

Kim, Ho Min ^{[2
,7
]}

机构：

[1] Korea Adv Inst Sci & Technol, Grad Sch Nanosci & Technol, Daejeon 34141, South Korea

[2] Inst for Basic Sci Korea, Ctr Synapt Brain Dysfunct, Daejeon 34141, South Korea

[3] Korea Adv Inst Sci & Technol, Dept Chem, Daejeon 34141, South Korea

[4] DGIST, Dept Brain & Cognit Sci, Daegu 42988, South Korea

[5] Chungnam Natl Univ, Grad Sch Analyt Sci & Technol, Daejeon 305764, South Korea

[6] Korea Adv Inst Sci & Technol, Dept Biol Sci, Daejeon 34141, South Korea

[7] Korea Adv Inst Sci & Technol, Grad Sch Med Sci Engn, Daejeon 34141, South Korea

来源：

NEURON | 2017年 / 94卷 / 06期

基金：

新加坡国家研究基金会;

关键词：

INHIBITORY SYNAPSE DEVELOPMENT; CRYSTAL-STRUCTURE; CELL-ADHESION; PROTEIN; MOLECULES; DISEASE; MDGAS;

D O I：

10.1016/j.neuron.2017.05.034

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1121 / +

页数：17

共 31 条

[31] Structure of Slitrk2–PTPδ complex reveals mechanisms for splicing-dependent trans-synaptic adhesion
Atsushi Yamagata
Yusuke Sato
Sakurako Goto-Ito
Takeshi Uemura
Asami Maeda
Tomoko Shiroshima
Tomoyuki Yoshida
Shuya Fukai
Scientific Reports, 5

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