Dissecting the binding mechanisms of synaptic membrane adhesion complexes using a micropattern based cellular model

Piette, N.; Strale, P.-O.; Lagardere, M.; Saphy, C.; Reissner, C.; Munier, M.; Missler, M.; Chamma, I.; Sainlos, M.; Thoumine, o.; Studer, V.

doi:10.1101/2024.03.17.584836

bioRxiv · 10.1101/2024.03.17.584836

Dissecting the binding mechanisms of synaptic membrane adhesion complexes using a micropattern based cellular model

Piette, N.·Strale, P.-O.·Lagardere, M.·Saphy, C.·Reissner, C.·Munier, M.·Missler, M.·Chamma, I.·Sainlos, M.·Thoumine, o.·Studer, V.

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Abstract

The formation of adhesive cell-cell contacts is based on the intrinsic binding properties between specific transmembrane ligand-receptor pairs. In neurons, synaptic adhesion molecules provide a physical linkage between pre- and post-synaptic compartments, but the strength and the dynamic of these complexes in their actual membrane environments remain essentially unknown. To access such information, we developed a versatile assay to measure the affinity and binding kinetics of synaptic ligand-receptor interactions, based on the immobilization of Fc-tagged ligands on micropatterned substrates combined with live imaging of fluorescently-tagged counter receptors in heterologous cells. We applied this strategy to study the heterophilic complex formed between neurexin-1{beta} (Nrx1{beta}) and neuroligin-1 (Nlg1), compared to the homophilic SynCAM1 complex. First, the control of ligand density combined to the measurement of steady-state receptor enrichment at micropatterns demonstrates the high specificity of the matching molecular interactions and allows for the quantification of the two-dimensional affinity of the interaction in a membrane environment. Second, long-term FRAP experiments performed on the two molecular complexes and fitted with analytical models, demonstrate a diffusion-limited regime for SynCAM1 and a reaction-limited regime for Nlg1. This analysis provides a very long bond lifetime of the Nrx1{beta}-Nlg1 complex, which by comparison with a monomeric mutant of Nlg1, can be attributed to the constitutive dimerization of Nlg1. Finally, we used the stable Nrx1{beta}-Nlg1 complex as a pseudo-synaptic platform to analyze the rapid binding kinetics between the scaffolding protein PSD-95 and the intracellular domain of Nlg1, dissecting the contribution of the different PDZ domains through the use of specific PSD-95 point mutants.

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Piette, N., Strale, P.-O., Lagardere, M., Saphy, C., Reissner, C., Munier, M., Missler, M., Chamma, I., Sainlos, M., Thoumine, o., Studer, V.. 2024-03-17. Dissecting the binding mechanisms of synaptic membrane adhesion complexes using a micropattern based cellular model. https://doi.org/10.1101/2024.03.17.584836

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