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Title: The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis

Abstract

Synaptotagmin, complexin, and neuronal SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins mediate evoked synchronous neurotransmitter release, but the molecular mechanisms mediating the cooperation between these molecules remain unclear. Here we determine crystal structures of the primed pre-fusion SNARE–complexin–synaptotagmin-1 complex. These structures reveal an unexpected tripartite interface between synaptotagmin-1 and both the SNARE complex and complexin. Simultaneously, a second synaptotagmin-1 molecule interacts with the other side of the SNARE complex via the previously identified primary interface. Mutations that disrupt either interface in solution also severely impair evoked synchronous release in neurons, suggesting that both interfaces are essential for the primed pre-fusion state. Ca2+ binding to the synaptotagmin-1 molecules unlocks the complex, allows full zippering of the SNARE complex, and triggers membrane fusion. The tripartite SNARE–complexin–synaptotagmin-1 complex at a synaptic vesicle docking site has to be unlocked for triggered fusion to start, explaining the cooperation between complexin and synaptotagmin-1 in synchronizing evoked release on the sub-millisecond timescale.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1390868
Resource Type:
Journal Article
Journal Name:
Nature (London)
Additional Journal Information:
Journal Volume: 548; Journal Issue: 7668; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Zhou, Qiangjun, Zhou, Peng, Wang, Austin L., Wu, Dick, Zhao, Minglei, Südhof, Thomas C., and Brunger, Axel T. The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis. United States: N. p., 2017. Web. doi:10.1038/nature23484.
Zhou, Qiangjun, Zhou, Peng, Wang, Austin L., Wu, Dick, Zhao, Minglei, Südhof, Thomas C., & Brunger, Axel T. The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis. United States. doi:10.1038/nature23484.
Zhou, Qiangjun, Zhou, Peng, Wang, Austin L., Wu, Dick, Zhao, Minglei, Südhof, Thomas C., and Brunger, Axel T. Wed . "The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis". United States. doi:10.1038/nature23484.
@article{osti_1390868,
title = {The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis},
author = {Zhou, Qiangjun and Zhou, Peng and Wang, Austin L. and Wu, Dick and Zhao, Minglei and Südhof, Thomas C. and Brunger, Axel T.},
abstractNote = {Synaptotagmin, complexin, and neuronal SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins mediate evoked synchronous neurotransmitter release, but the molecular mechanisms mediating the cooperation between these molecules remain unclear. Here we determine crystal structures of the primed pre-fusion SNARE–complexin–synaptotagmin-1 complex. These structures reveal an unexpected tripartite interface between synaptotagmin-1 and both the SNARE complex and complexin. Simultaneously, a second synaptotagmin-1 molecule interacts with the other side of the SNARE complex via the previously identified primary interface. Mutations that disrupt either interface in solution also severely impair evoked synchronous release in neurons, suggesting that both interfaces are essential for the primed pre-fusion state. Ca2+ binding to the synaptotagmin-1 molecules unlocks the complex, allows full zippering of the SNARE complex, and triggers membrane fusion. The tripartite SNARE–complexin–synaptotagmin-1 complex at a synaptic vesicle docking site has to be unlocked for triggered fusion to start, explaining the cooperation between complexin and synaptotagmin-1 in synchronizing evoked release on the sub-millisecond timescale.},
doi = {10.1038/nature23484},
journal = {Nature (London)},
issn = {0028-0836},
number = 7668,
volume = 548,
place = {United States},
year = {2017},
month = {8}
}

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