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bioRxiv · 10.1101/2023.06.20.545669

Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes

Meijer, M.·Ottl, M.·Yang, J.·Subkhangulova, A.·Kumar, A.·Groffen, A. J.·van Weering, J. R. T.·Zhang, Y.·Verhage, M.
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Abstract

Tomosyns are soluble SNARE proteins proposed to attenuate membrane fusion by competing with synaptobrevin-2/VAMP2 for SNARE-complex assembly. Here, we present evidence against this scenario using a novel mouse model, energy barrier recordings, and single-molecule force measurements. Tomosyn-1/2 deficiency drastically enhanced the probability that synaptic vesicles fuse at synapses, resulting in stronger synapses with faster depression and slower recovery. While wildtype tomosyn-1m rescued these phenotypes, substitution of its SNARE motif with that of synaptobrevin-2/VAMP2 did not. Force measurements revealed that tomosyns SNARE motif cannot substitute synaptobrevin-2/VAMP2 to form template complexes with Munc18-1 and syntaxin-1, an essential intermediate for SNARE assembly. Instead, tomosyns bind synaptobrevin-2/VAMP2-containing template complexes and prevent SNAP-25 association. Structure-function analyses indicate that regions outside the SNARE motif contribute to tomosyns inhibitory function. These results reveal that tomosyns regulate synaptic transmission by preventing SNAP-25 binding to template complexes, increasing the energy barrier for synaptic vesicle fusion, and limiting synaptic depression.

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Meijer, M., Ottl, M., Yang, J., Subkhangulova, A., Kumar, A., Groffen, A. J., van Weering, J. R. T., Zhang, Y., Verhage, M.. 2023-06-23. Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes. https://doi.org/10.1101/2023.06.20.545669

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