New powerful collaborative work with IRCM team

New powerful collaborative work with IRCM team

Designer Molecules of the Synaptic Organizer MDGA1 Reveal 3D Conformational Control of Biological Function

From left to right: Nicolas Chofflet and Hideto Takahashi.

The Montreal Clinical Research Institute (IRCM) is pleased to highlight the publication in the Journal of Biological Chemistry of substantial work shedding light on how changes in 3D structures of neuronal cell adhesion molecules are involved in the regulation of brain wiring and synaptic connectivity. 

Under the title Designer Molecules of the Synaptic Organizer MDGA1 Reveal 3D Conformational Control of Biological Function, this research, led by IRCM’s Nicolas Chofflet, under Hideto Takahashi’s supervision, Hubert Lee, from the University of Texas Medical Branch (UTMB), and Jianfang Liu from Lawrence Berkely National Laboratory (LBNL) is a perfect example of the strength of collaborative and multidisciplinary work between laboratories of different expertise tackling a common problematic through different and complementary approaches.

About this work
Synaptic inhibition in the central nervous system is crucial for regulating neuronal activity and networks, and its dysregulation is thought to be linked with many neurodevelopmental and neurodegenerative diseases such as autism, epilepsy, and Huntington’s disease. MDGA1 are crucial molecules to control the development of GABA-releasing inhibitory synapses, through regulation of protein-protein interactions at neuronal synapses. Notably, they disrupt transsynaptic protein complexes made by neurexin and neuroligin proteins, two major synaptic cell adhesion molecules. Because of their central roles in synapse development, neurexins, neuroligins and MDGA1 are genetically linked to several neurodevelopmental and neuropsychiatric disorders such as autism and schizophrenia. This research reveals fundamental insights into the structure-function relationships governing MDGA1 actions by generating and a series of MDGA1 conformational mutated molecules. Given the genetic linkage of MDGA1 to several neurological disorders, these mutants may also serve as important tools to test whether manipulating MDGA1 can be used to selectively regulate inhibitory synapse development to ameliorate disrupted neural circuits such as those seen in neuropsychiatric disorders.

Key findings
While previous studies have revealed that MDGA1 molecules adopt a compact triangular structure, through UTMB’s Dr. Rudenko and LBNL’s Dr. Ren’s work, this research was able to show that they can adopt a compact/closed or elongated/open form, at least in vitro. 

This research also successfully engineered mutations in MDGA1 that leads the molecules in either constitutively compact or constitutively elongated shapes. 

The work then assessed whether MDGA1 conformational mutants would have altered ability to interact with neuroligin, its known binding partner. Through an array of cell-free and cell-based experiments, the teams demonstrated that MDGA1 conformation/structure is crucial for its capacity to interact with neuroligin. 

Finally, Dr. Takahashi’s laboratory was able to show that MDGA1 conformation is crucial to regulate neurexin-neuroligin transsynaptic complex. As a consequence, changes in MDGA1 conformation would lead to altered ability in controlling inhibitory synapses development.

Thanks to
The IRCM wants to thank the Canadian Institutes of Health as well as the Natural Science and Engineering Research Council and the Fonds de la Recherche du Québec.

Link to this study:
Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function - ScienceDirect

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