Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis

Nature. 2015 Sep 3;525(7567):62-7. doi: 10.1038/nature14975. Epub 2015 Aug 17.


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 Ca(2+)- and Mg(2+)-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, Ca(2+)-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca(2+)-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca(2+)-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca(2+) triggering, moves en bloc as Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Calcium / chemistry
  • Calcium / metabolism
  • Cell Membrane / metabolism
  • Crystallography, X-Ray
  • Electrons
  • Exocytosis*
  • Hippocampus / cytology
  • Lasers
  • Magnesium / chemistry
  • Magnesium / metabolism
  • Membrane Fusion
  • Mice
  • Models, Biological
  • Models, Molecular
  • Mutation / genetics
  • Neurons / chemistry
  • Neurons / cytology
  • Neurons / metabolism*
  • SNARE Proteins / chemistry*
  • SNARE Proteins / genetics
  • SNARE Proteins / metabolism*
  • Synaptic Transmission
  • Synaptic Vesicles / chemistry
  • Synaptic Vesicles / metabolism
  • Synaptotagmins / chemistry*
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism*


  • SNARE Proteins
  • Synaptotagmins
  • Magnesium
  • Calcium

Associated data

  • PDB/5CCG
  • PDB/5CCH
  • PDB/5CCI
  • PDB/5CCJ