Structural insights into the modulation of synaptic adhesion by MDGA for synaptogenesis

July 11, 2017
Model of MDGA1 action on Neuroligin-2-mediated inhibitory synapse organization. Neuroligins' postsynaptic membrane tran-synaptically interact with presynaptic Neurexins for synaptic development. MDGA1 (Red, Yellow and Blue) suppresses the development of inhibitory synapses by blocking the physical access of Neuroligin-2 (Cyan) to presynaptic neurexin1-β(Orange). Credit: KAIST

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.

In a recent issue of Neuron, published on June 21, 2017, a research team led by Professor Ho Min Kim at the Graduate School of Medical Science and Engineering of KAIST reported the three-dimensional structure of MDGA1/Neuroligin-2 complex and mechanistic insights into how MDGAs negatively modulate synapse development governed by Neurexins/Neuroligins trans-synaptic adhesion complex.

MDGA1 consists of six Ig-like domains, the fibronectin type III repeat domain, and the MAM . The crystal structure of MDGA1/Neuroligin-2 complex reveals that they form the 2:2 heterotetrameric complex and 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, but 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 more strongly to MDGA1 than Neurexin-1β, and how the favored MDGA1 binding to Neuroligin-2 sterically blocks the interaction between Neuroligin-2 and Neurexin-1β, which is critical for the suppression of inhibitory synapse development.

"Although we found that MDGA Ig domains (Ig 1 and Ig 2) are sufficient to form a complex with NL2, other extracellular domains, including Ig 3-6, FN III, and MAM domains, may also contribute to stable cis-interactions between MDGA1 and Neuroligin-2 by providing conformational flexibility. Therefore, further structural analysis of full-length MDGA will be required," Professor Kim said.

Neuroligin-2 specifically promotes the development of inhibitory synapses, whereas neuroligin-1 promotes the development of . Recently, besides MDGA1, MDGA2 has emerged as a synaptic regulator 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," explained Professor Jaewon Ko at the Daegu Gyeongbuk Institute of Science and Technology (DGIST).

A balance between excitatory and is crucial to 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. Jung A Kim at KAIST, first author of the study, said, "Our discovery from 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."

Explore further: Protein family linked to autism suppresses the development of inhibitory synapses

More information: Jung A Kim et al, Structural Insights into Modulation of Neurexin-Neuroligin Trans -synaptic Adhesion by MDGA1/Neuroligin-2 Complex, Neuron (2017). DOI: 10.1016/j.neuron.2017.05.034

Related Stories

Protein family linked to autism suppresses the development of inhibitory synapses

January 28, 2013
Synapse development is promoted by a variety of cell adhesion molecules that connect neurons and organize synaptic proteins. Many of these adhesion molecules are linked to neurodevelopmental disorders; mutations in neuroligin ...

Trio of autism-linked molecules orchestrate neuron connections

January 14, 2016
New research from Duke University reveals how three proteins work in concert to wire up a specific area of the developing brain that is responsible for processing sensory information.

Molecule may help maintain brain's synaptic balance

June 13, 2017
Many neurological diseases are malfunctions of synapses, or the points of contact between neurons that allow senses and other information to pass from finger to brain. In the brain, there is a careful balance between the ...

Recommended for you

Cognitive cross-training enhances learning, study finds

July 25, 2017
Just as athletes cross-train to improve physical skills, those wanting to enhance cognitive skills can benefit from multiple ways of exercising the brain, according to a comprehensive new study from University of Illinois ...

Lutein may counter cognitive aging, study finds

July 25, 2017
Spinach and kale are favorites of those looking to stay physically fit, but they also could keep consumers cognitively fit, according to a new study from University of Illinois researchers.

Zebrafish study reveals clues to healing spinal cord injuries

July 25, 2017
Fresh insights into how zebrafish repair their nerve connections could hold clues to new therapies for people with spinal cord injuries.

Brain stimulation may improve cognitive performance in people with schizophrenia

July 24, 2017
Brain stimulation could be used to treat cognitive deficits frequently associated with schizophrenia, according to a new study from King's College London.

New map may lead to drug development for complex brain disorders, researcher says

July 24, 2017
Just as parents are not the root of all their children's problems, a single gene mutation can't be blamed for complex brain disorders like autism, according to a Keck School of Medicine of USC neuroscientist.

Bird songs provide insight into how developing brain forms memories

July 24, 2017
Researchers at the University of Chicago have demonstrated, for the first time, that a key protein complex in the brain is linked to the ability of young animals to learn behavioral patterns from adults.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.