How MDGAs Negatively Modulate Synapse Development

The control mechanisms of synapse formation have been identified in a first time study of the three-dimensional structure of proteins that regulate neuronal cell connections. The work was conducted by Professor Ko Jae-won at Korea Advanced Institute of Science and Technology (KAIST).

The brain is made up of innumerable neurons. Neurotransmitters are secreted and absorbed at the synapse, the junction of the two neurons; the signals are transmitted and the brain functions properly.

As the brain develops, efficient neurotransmission relies on a balance of excitatory synapses and inhibitory synapses created between the neurons. Excitatory synapses release neurotransmitters that excite neurons and synaptic inhibitors release neurotransmitters to inhibit nerve cell excitability.

When the balance of the two synapses is broken, it is known that mental disorders such as autism, bipolar disorder and obsessive-compulsive disorder occur.

Neuroligin And Neurexin Proteins

In 2013, Professor Thomas C. Sudhof of Stanford University discovered the neuroligin and neurexin proteins, important synaptic adhesion proteins that are important factors in synapse development and function maintenance. However, specific mechanisms have yet to be identified.

Moreover, it is also known that the mucin domain-containing glycosylphosphatidylinositol anchor 1 (MDGA1) protein binds neuroligin-2 at the inhibitory synapses and interferes with the interaction of neuroligin and neurexin and stops inhibitory synapse development, but its mechanism is also unclear.

Neurexins at the presynapse

Neurexins (orange) at the presynapse and Neuroligin at the postsynapse mediate synaptic development by binding two neurons through interactions.
In inhibitory synapses, the regulatory protein MDGA1 produces a Neuroligin-2 (NL2) / MDGA1 complex based on strong binding power to Neuroligin-2 / Neurexin and effectively inhibits the development of inhibitory synapse by selectively interferes with binding of Neuroligin-2/Neurexin.
Credit: DGIST

The research teams used protein crystallography to crystallize neuroligin-2 and MDGA1 protein complexes that are involved in inhibitory synapse development and observed the three-dimensional structure. The researchers have identified for the first time that the MDGA1 protein at the post-synapse interferes with the binding between neuroligin-2 and neurexin and prevents inhibitory synapse formation.

Based on the three-dimensional molecular structure, the researchers created mutations of core amino acids that play a pivotal role in the binding of neuroligin-2 and MDGA1.

Critical Functional Region

Through the neuron culture experiment, they verified that the protein interaction site is a critical functional region for the negative regulation of the synapse development process.

Neuroligin-2 /MDGA1 and Neuroligin-1 / Neurxin1ß binding sites

Neuroligin-2 /MDGA1 and Neuroligin-1 / Neurxin1ß binding sites partially overlap and researchers proposed a binding competition model between MDGA1 and Neurexin1ß in this part.
Credit: DGIST

In addition, the study has proved that MDGA1 can effectively control inhibitory synapse formation as the binding ability of MDGA1 is superior to neurexin while MDGA1 and neurexin can both competitively bind with neuroligin-2.

“We have found the mechanism of molecular regulation of MDGA1 protein, which is necessary for the balanced operation of excitatory and inhibitory synapses. We will continue working to identify the mechanisms of brain diseases caused by dysfunction of synaptic proteins and conduct researches to develop therapeutic drugs,”

said Professor Jaewon Ko of Daegu Gyeongbuk Institute of Science and Technology’s Department of Brain and Cognitive Sciences.

Kim, Jung A et al.
Structural Insights into Modulation of Neurexin-Neuroligin Trans-synaptic Adhesion by MDGA1/Neuroligin-2 Complex
Neuron, Volume 94 , Issue 6 , 1121 – 1131.e6

Top Image: Molecular Structure of Synapse Regulatory Protein binding Neuroligin-2 and MDGA1. Credit: Daegu Gyeongbuk Institute of Science and Technology (DGIST)