Different states of synaptotagmin regulate evoked versus spontaneous release

Nat Commun. 2016 Mar 22;7:10971. doi: 10.1038/ncomms10971.


The tandem C2-domains of synaptotagmin 1 (syt) function as Ca(2+)-binding modules that trigger exocytosis; in the absence of Ca(2+), syt inhibits spontaneous release. Here, we used proline linkers to constrain and alter the relative orientation of these C2-domains. Short poly-proline helices have a period of three, so large changes in the relative disposition of the C2-domains result from changing the length of the poly-proline linker by a single residue. The length of the linker was varied one residue at a time, revealing a periodicity of three for the ability of the linker mutants to interact with anionic phospholipids and drive evoked synaptic transmission; syt efficiently drove exocytosis when its tandem C2-domains pointed in the same direction. Analysis of spontaneous release revealed a reciprocal relationship between the activation and clamping activities of the linker mutants. Hence, different structural states of syt underlie the control of distinct forms of synaptic transmission.

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

  • Amino Acid Sequence
  • Animals
  • Cell Membrane / metabolism
  • Mice, Knockout
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutation
  • Neurotransmitter Agents / metabolism*
  • Proline / chemistry
  • Protein Structure, Tertiary
  • Rats
  • Synaptic Transmission
  • Synaptotagmin I / chemistry
  • Synaptotagmin I / metabolism*


  • Mutant Proteins
  • Neurotransmitter Agents
  • Synaptotagmin I
  • Proline