Different regions of synaptic vesicle membrane regulate VAMP2 conformation for the SNARE assembly

Nat Commun. 2020 Mar 24;11(1):1531. doi: 10.1038/s41467-020-15270-4.


Vesicle associated membrane protein 2 (VAMP2/synaptobrevin2), a core SNARE protein residing on synaptic vesicles (SVs), forms helix bundles with syntaxin-1 and SNAP25 for the SNARE assembly. Prior to the SNARE assembly, the structure of VAMP2 is unclear. Here, by using in-cell NMR spectroscopy, we describe the dynamic membrane association of VAMP2 SNARE motif in mammalian cells, and the structural change of VAMP2 upon the change of intracellular lipid environment. We analyze the lipid compositions of the SV membrane by mass-spectrometry-based lipidomic profiling, and further reveal that VAMP2 forms distinctive conformations in different membrane regions. In contrast to the non-raft region, the membrane region of cholesterol-rich lipid raft markedly weakens the membrane association of VAMP2 SNARE motif, which releases the SNARE motif and facilitates the SNARE assembly. Our work reveals the regulation of different membrane regions on VAMP2 structure and sheds light on the spatial regulation of SNARE assembly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cholesterol / metabolism
  • HEK293 Cells
  • Humans
  • Intravital Microscopy
  • Lipid Metabolism
  • Lipidomics
  • Magnetic Resonance Spectroscopy
  • Membrane Fusion
  • Membrane Lipids / metabolism*
  • Membrane Microdomains / metabolism*
  • Protein Domains / genetics
  • Protein Multimerization
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • SNARE Proteins / metabolism*
  • Spatial Analysis
  • Synaptic Vesicles / metabolism*
  • Vesicle-Associated Membrane Protein 2 / genetics
  • Vesicle-Associated Membrane Protein 2 / metabolism*


  • Membrane Lipids
  • Recombinant Proteins
  • SNARE Proteins
  • Vamp2 protein, rat
  • Vesicle-Associated Membrane Protein 2
  • Cholesterol