Molecular mechanisms of synaptic proteins

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December 2023

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Synaptic adhesion molecules (SAMs) are critical for regulating synapse development and synaptic plasticity. Many studies have linked their putative roles in neuropsychiatric and neurodevelopmental diseases, such as schizophrenia and autism spectrum disorder. Here, the structure-function relationships of a select group of synaptic organizers were explored for MDGA1 (MAM domain-containing glycosylphosphatidylinositol (GPI) anchor 1. In the following chapters, the SAMs neurexins (NRXNs), neuroligins (NLGNs), MDGAs, and immunoglobin superfamily 21 (IgSF21) are introduced. In our studies, we characterize how the structure-function relationships of SAMs and their interactions within the synaptic cleft could be regulated. We demonstrate the critical structural features of MDGA1 that impact the distribution of its three-dimensional conformations. We show that altering this distribution leads to unique functional consequences, including altered binding to NLGN2 ex vivo but not in vitro. We examine several missense mutations localized to strategic places within the MDGA1 protein structure that would be expected to destabilize the domain interfaces and possibly alter biological function. These results demonstrated that the entire 3D conformation of the MDGA1 ectodomain is critical for its function. The SAM, IgSF21, promotes the formation of inhibitory synapses and is known to bind specifically to NRXN2α (Tanabe et al., 2017). Delineating the IgSF21 3D structure and the IgSF21: NRXN2α interaction mechanism at a molecular level will further advance our understanding of the SAM interactome. We describe our valiant efforts to set up an over-expression system for IgSF21. Our work supports the idea that SAMs are not static adhesion molecules. The trans-synaptic bridges they form (via their interactions) are subject to different regulation mechanisms, some of which leverage key structural motifs.

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