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Title: Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis

Abstract

Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca2+-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca2+-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca2+-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca2+triggering, moves en bloc as Ca2+influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.

Authors:
 [1];  [1];  [2];  [1];  [1];  [1];  [1];  [3];  [3];  [4];  [4];  [4];  [4];  [4];  [1];  [1];  [5];  [1];  [2];  [1]
+ Show Author Affiliations
  1. Stanford Univ., CA (United States). Howard Hughes Medical Institute; Stanford Univ., CA (United States). Departments of Neurology and Neurological Sciences, Photon Science, and Structural Biology
  2. Stanford Univ., CA (United States). Howard Hughes Medical Institute
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  4. SLAC National Accelerator Lab., Stanford, CA (United States)
  5. Stanford Univ., CA (United States). Departments of Structural Biology, Molecular and Cellular Physiology, and Photon Science
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Contributing Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1221448
Alternate Identifier(s):
OSTI ID: 1512250
Grant/Contract Number:  
AC02-76SF00515; P41GM103393; AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 525; Journal Issue: 7567; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Zhou, Qiangjun, Lai, Ying, Bacaj, Taulant, Zhao, Minglei, Lyubimov, Artem Y., Uervirojnangkoorn, Monarin, Zeldin, Oliver B., Brewster, Aaron S., Sauter, Nicholas K., Cohen, Aina E., Soltis, S. Michael, Alonso-Mori, Roberto, Chollet, Matthieu, Lemke, Henrik T., Pfuetzner, Richard A., Choi, Ucheor B., Weis, William I., Diao, Jiajie, Südhof, Thomas C., and Brunger, Axel T. Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis. United States: N. p., 2015. Web. doi:10.1038/nature14975.
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Zhou, Qiangjun, Lai, Ying, Bacaj, Taulant, Zhao, Minglei, Lyubimov, Artem Y., Uervirojnangkoorn, Monarin, Zeldin, Oliver B., Brewster, Aaron S., Sauter, Nicholas K., Cohen, Aina E., Soltis, S. Michael, Alonso-Mori, Roberto, Chollet, Matthieu, Lemke, Henrik T., Pfuetzner, Richard A., Choi, Ucheor B., Weis, William I., Diao, Jiajie, Südhof, Thomas C., & Brunger, Axel T. Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis. United States. https://doi.org/10.1038/nature14975
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Zhou, Qiangjun, Lai, Ying, Bacaj, Taulant, Zhao, Minglei, Lyubimov, Artem Y., Uervirojnangkoorn, Monarin, Zeldin, Oliver B., Brewster, Aaron S., Sauter, Nicholas K., Cohen, Aina E., Soltis, S. Michael, Alonso-Mori, Roberto, Chollet, Matthieu, Lemke, Henrik T., Pfuetzner, Richard A., Choi, Ucheor B., Weis, William I., Diao, Jiajie, Südhof, Thomas C., and Brunger, Axel T. Mon . "Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis". United States. https://doi.org/10.1038/nature14975. https://www.osti.gov/servlets/purl/1221448.
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@article{osti_1221448,
title = {Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis},
author = {Zhou, Qiangjun and Lai, Ying and Bacaj, Taulant and Zhao, Minglei and Lyubimov, Artem Y. and Uervirojnangkoorn, Monarin and Zeldin, Oliver B. and Brewster, Aaron S. and Sauter, Nicholas K. and Cohen, Aina E. and Soltis, S. Michael and Alonso-Mori, Roberto and Chollet, Matthieu and Lemke, Henrik T. and Pfuetzner, Richard A. and Choi, Ucheor B. and Weis, William I. and Diao, Jiajie and Südhof, Thomas C. and Brunger, Axel T.},
abstractNote = {Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca2+-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca2+-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca2+-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca2+triggering, moves en bloc as Ca2+influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.},
doi = {10.1038/nature14975},
journal = {Nature (London)},
number = 7567,
volume = 525,
place = {United States},
year = {Mon Aug 17 00:00:00 EDT 2015},
month = {Mon Aug 17 00:00:00 EDT 2015}
}
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https://doi.org/10.1038/nature14975
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Cited by: 201 works
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Figures / Tables:

Extended Data Figure 1 Extended Data Figure 1: Purification and crystallization of the Syt1-SNARE complex a, Diagram of the Duet co-expression vectors (Novagen) that express the fragments of the neuronal SNARE complex and the C2AB-linker-SNAP-25_C chimera used for purification and crystallization of the Syt1-SNARE37aa-linker complex. The rat syntaxin-1A and His-tagged rat synaptobrevin-2 fragments weremore » cloned into the vector pACYCDuet-1; the C2AB-linker-SNAP-25_C chimera and the SNAP-25_N fragment were cloned into the vector pETDuet-1 with amino acid ranges labeled. Dashed lines represent the 37 amino acid linker (Methods). b, The purified Syt1-SNARE37aa-linker complex eluted as a single peak during size-exclusion chromatography (profile on the left). Left gel, Coomassie blue-stained SDS-PAGE gel of the purified Syt1-SNARE37aa-linker complex (unboiled and boiled). Right gel, Coomassie blue-stained SDS-PAGE gel of dissolved crystals of the Syt1-SNARE complex that were grown over a period of two months starting from purified Syt1-SNARE37aa-linker (unboiled and boiled). Although Syt1 was initially covalently linked to SNAP-25_C, the linker was cleaved during crystallization. The comparison between boiled and un-boiled lanes is a hallmark showing that neuronal SNARE complex is fully formed. c, Boiled Coomassie blue-stained SDS-PAGE gel of the purified Syt1-SNARE complex in solution at ambient temperature at the specified time after purification. Cleavage is apparent on day one and progresses slowly over several days. d, Schema showing the commonly used vapor-diffusion technique: the drop contains a lower concentration of the precipitant than the reservoir. The crystallization of the quintuple mutant of Syt1 C2B is used as an example. e, Schema showing a reverse vapor-diffusion method that was used for crystallization of the Ca2+-bound Syt1-SNARE37aa-linker complex: the drop contains a higher concentration of the precipitant than the reservoir.« less
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  • Nature Protocols, Vol. 8, Issue 1
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Membrane fusion
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  • Wickner, William; Schekman, Randy
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The Janus-faced nature of the C2B domain is fundamental for synaptotagmin-1 function
journal, October 2008

  • Xue, Mingshan; Ma, Cong; Craig, Timothy K.
  • Nature Structural & Molecular Biology, Vol. 15, Issue 11
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Single-molecule FRET–derived model of the synaptotagmin 1–SNARE fusion complex
journal, February 2010

  • Choi, Ucheor B.; Strop, Pavel; Vrljic, Marija
  • Nature Structural & Molecular Biology, Vol. 17, Issue 3
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Dynamic binding mode of a Synaptotagmin-1–SNARE complex in solution
journal, June 2015

  • Brewer, Kyle D.; Bacaj, Taulant; Cavalli, Andrea
  • Nature Structural & Molecular Biology, Vol. 22, Issue 7
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The synaptotagmin 1 linker may function as an electrostatic zipper that opens for docking but closes for fusion pore opening
journal, October 2013

  • Lai, Ying; Lou, Xiaochu; Jho, Yongseok
  • Biochemical Journal, Vol. 456, Issue 1
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Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1
journal, December 2005

  • Rhee, J. -S.; Li, L. Y.; Shin, O. -H.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 51
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Energetics of stalk intermediates in membrane fusion are controlled by lipid composition
journal, May 2012

  • Aeffner, S.; Reusch, T.; Weinhausen, B.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 25
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Calcium sensitive ring-like oligomers formed by synaptotagmin
journal, September 2014

  • Wang, J.; Bello, O.; Auclair, S. M.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 38
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Conserved Prefusion Protein Assembly in Regulated Exocytosis
journal, January 2006

  • Rickman, Colin; Jiménez, José L.; Graham, Margaret E.
  • Molecular Biology of the Cell, Vol. 17, Issue 1
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Linker length and composition influence the flexibility of Oct-1 DNA binding
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Three-dimensional structure of the complexin/snare complex
journal, August 2002

  • Tomchick, D. R.; Chen, X.; Kovrigin, E.
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Data Exploration Toolkit for serial diffraction experiments
journal, January 2015

  • Zeldin, Oliver B.; Brewster, Aaron S.; Hattne, Johan
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Synaptotagmin: a calcium sensor on the synaptic vesicle surface
journal, May 1992

Synaptotagmin Interaction with SNAP-25 Governs Vesicle Docking, Priming, and Fusion Triggering
journal, September 2013

A distinct tethering step is vital for vacuole membrane fusion
journal, September 2014

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