A molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion

Kavanagh, Deirdre M. and Smyth, Annya M. and Martin, Kirsty J. and Dun, Alison and Brown, Euan R. and Gordon, Sarah and Smillie, Karen J. and Chamberlain, Luke H. and Wilson, Rhodri S. and Yang, Lei and Lu, Weiping and Cousin, Michael A. and Rickman, Colin and Duncan, Rory R. (2014) A molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion. Nature Communications, 5. 5774. ISSN 2041-1723 (https://doi.org/10.1038/ncomms6774)

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Neuronal synapses are among the most scrutinized of cellular systems, serving as a model for all membrane trafficking studies. Despite this, synaptic biology has proven difficult to interrogate directly in situ due to the small size and dynamic nature of central synapses and the molecules within them. Here we determine the spatial and temporal interaction status of presynaptic proteins, imaging large cohorts of single molecules inside active synapses. Measuring rapid interaction dynamics during synaptic depolarization identified the small number of syntaxin1a and munc18-1 protein molecules required to support synaptic vesicle exocytosis. After vesicle fusion and subsequent SNARE complex disassembly, a prompt switch in syntaxin1a and munc18-1-binding mode, regulated by charge alteration on the syntaxin1a N-terminal, sequesters monomeric syntaxin1a from other disassembled fusion complex components, preventing ectopic SNARE complex formation, readying the synapse for subsequent rounds of neurotransmission.


Kavanagh, Deirdre M., Smyth, Annya M., Martin, Kirsty J., Dun, Alison, Brown, Euan R., Gordon, Sarah, Smillie, Karen J., Chamberlain, Luke H. ORCID logoORCID: https://orcid.org/0000-0002-8701-4995, Wilson, Rhodri S., Yang, Lei, Lu, Weiping, Cousin, Michael A., Rickman, Colin and Duncan, Rory R.;