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

Neuron types in brain are defined by gene activity shaping their communication patterns

September 21, 2017
In a major step forward in research, scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Cell a discovery about the molecular-genetic basis of neuronal cell types. Neurons are the basic building blocks that ...

Gene immunotherapy protects against multiple sclerosis in mice

September 21, 2017
A potent and long-lasting gene immunotherapy approach prevents and reverses symptoms of multiple sclerosis in mice, according to a study published September 21st in the journal Molecular Therapy. Multiple sclerosis is an ...

Your neurons register familiar faces, whether you notice them or not

September 21, 2017
When people see an image of a person they recognize—the famous tennis player Roger Federer or actress Halle Berry, for instance—particular cells light up in the brain. Now, researchers reporting in Current Biology on ...

Touching helps build the sexual brain

September 21, 2017
Hormones or sexual experience? Which of these is crucial for the onset of puberty? It seems that when rats are touched on their genitals, their brain changes and puberty accelerates. In a new study publishing September 21 ...

Highly precise wiring in the cerebral cortex

September 21, 2017
Our brains house extremely complex neuronal circuits whose detailed structures are still largely unknown. This is especially true for the cerebral cortex of mammals, where, among other things, vision, thoughts or spatial ...

Faulty cell signaling derails cerebral cortex development, could it lead to autism?

September 20, 2017
As the embryonic brain develops, an incredibly complex cascade of cellular events occur, starting with progenitors - the originating cells that generate neurons and spur proper cortex development. If this cascade malfunctions ...

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.