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

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. 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. Lastly, 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]
  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:
OSTI Identifier:
1221448
Grant/Contract Number:
AC02-76SF00515; P41GM103393
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
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Contributing Orgs:
National Institutes of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES