Insights of aspects of synaptic adhesion
Neurexins and neuroligins form trans-synaptic complexes that promote synapse development and MAM domain-containing GPI-anchored (MDGA) proteins negatively regulate this Neurexins/Neuroligins-mediated synaptic adhesion.
We determined the crystal structure of MDGA1/Neuroligin-2 complex, revealing their stable 2:2 arrangement with three interaction interfaces and a mode of competition between MDGA1 and Neurexin for Neuroligin binding.
These findings provide collective structural insights into the mechanism by which MDGAs negatively modulate synapse development governed by Neurexins/Neuroligins trans-synaptic adhesion complex.
Synapses connected by various synaptic adhesion molecules are communication spaces between neurons for transmitting information.
Among various synaptic adhesion molecules, neuroligins are arguably the most widely studied class of postsynaptic adhesion molecules, which mainly interact with presynaptic neurexins to induce excitatory or inhibitory synapse development.
Recently, the membrane-associated mucin (MAM) domain-containing GPI anchor protein 1 (MDGA1) has been characterized as a key suppressor of Neuroligin-2/Neurexin-1β-mediated inhibitory synapse development, but how it acts remains a mystery.
MDGA1 consists of six Ig-like domains, fibronectin type III repeat domain, and a MAM domain.
The crystal structure of a MDGA1/Neuroligin-2 complex reveals that they form the 2:2 hetero-tetrameric complex; only the Ig1-Ig2 domains of MDGA1 are involved in interactions with Neuroligin-2.
The structural comparison between the MDGA1/Neuroligin-2 and Neurexin-1β/Neuroligin-1 complexes intriguingly indicates that the Neuroligin-2 region binding to MDGA1 largely overlaps with that of Neurexin-1β; however the interaction interface of the MDGA1/Neuroligin-2 complex is much larger than that of the Neurexin-1β/Neuroligin-1 complex.
This explains why Neuroligin-2 binds stronger to MDGA1 than it does to Neurexin-1β, and how the favored MDGA1 binding to Neuroligin-2 sterically blocks the interaction between Neuroligin-2 and Neurexin-1β, critical for the suppression of inhibitory synapse development.
Neuroligin-2 specifically promotes the development of inhibitory synapses, whereas neuroligin-1 promotes the development of excitatory synapses.
Recently, both MDGA1 and MDGA2 have emerged as synaptic regulators for the development of excitatory or inhibitory synapses.
In vitro biochemical analysis in this research clearly demonstrates that Neuroligin-1 and Neuroligin-2 bind to both MDGA1 and MDGA2 with comparable affinity.
However, pull-down assays using detergent-solubilized mouse brain membrane fractions show the specific interaction of MDGA1 with Neuroligin-2, but not with Neuroligin-1.
This suggests that unidentified processes may dictate the selective association of MDGA1 with Neuroligin-2 in vivo.
A balance between excitatory and inhibitory synapses is crucial for healthy cognition and behavior.
Mutations in neuroligins, neurexins, and MDGAs, which can disrupt the excitatory/inhibitory balance, are associated with neuropsychiatric diseases such as autism and schizophrenia.
Therefore, these integrative investigations are an important first step both for a better understanding of Neuroligin/Neurexin synaptic adhesion pathways and MDGA-mediated regulation of synapse development as well as the development of potential new therapies for autism, schizophrenia, and epilepsy.
Kim JA et al., Neuron. 2017 Jun 21;94(6):1121-1131.
* lab webpage : http://www.kaistdmbl.org