The brain controls all functions in the body and interprets information from the outside world with intelligence, creativity, emotion, and memory all governed by the central nervous system. The central nervous system is made up of glial cells and neurons, additionally, the latter comes in many sizes and shapes, all consisting of a cell body, dendrites, and an axon. Neurons convey information through electrical and chemical signals via a synapse in a process called neurotransmission, without this crucial action the brain, and by extension, the body would not function. Now, a study led by researchers at GIST identifies the control mechanisms of synapse formation. The team states they have also provided the previously unknown three-dimensional structure of proteins regulating neuronal synapses. The study is published in the journal Neuron.
Previous studies show that 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 the development of the two synapse types remain unclear. The current study provides structural insights into the mechanism MDGAs use to negatively modulate synapse development governed by NLs.
The current study utilizes protein crystallography to crystallize NL2 and MDGA1 protein complexes involved in inhibitory synapse development, and observe the three-dimensional structure. Results show MDGA1 protein at the post-synapse interferes with the binding between NL2 & Neurexin, stopping inhibitory synapse formation.
Data findings show the protein interaction site is a critical functional region for the negative regulation of the synapse development process. Results show 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 NL2.
The team surmises they have identified the mechanism of the molecular regulation of MDGA1 protein necessary for the balanced operation of excitatory and inhibitory synapses. For the future, the researchers state they will continue to investigate the mechanisms of brain diseases caused by dysfunction of synaptic proteins to develop therapeutic drugs.
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