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

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. Ca 2+ binding to the synaptotagmin-1 molecules unlocks the complex, allows full zippering of the SNARE complex, and triggers membrane fusion. In conclusion, 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:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1]
  1. Stanford Univ., Stanford, CA (United States)
  2. The Univ. of Chicago, Chicago, IL (United States); Stanford Univ., Stanford, CA (United States)
Publication Date:
Grant/Contract Number:
AC02-76SF00515
Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 548; Journal Issue: 7668; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1394066

Zhou, Qiangjun, Zhou, Peng, Wang, Austin L., Wu, Dick, Zhao, Minglei, Sudhof, Thomas C., and Brunger, Axel T.. The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis. United States: N. p., Web. doi:10.1038/nature23484.
Zhou, Qiangjun, Zhou, Peng, Wang, Austin L., Wu, Dick, Zhao, Minglei, Sudhof, 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, Sudhof, Thomas C., and Brunger, Axel T.. 2017. "The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis". United States. doi:10.1038/nature23484. https://www.osti.gov/servlets/purl/1394066.
@article{osti_1394066,
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 Sudhof, 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. In conclusion, 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)},
number = 7668,
volume = 548,
place = {United States},
year = {2017},
month = {8}
}

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