A conformational switch in syntaxin during exocytosis: Role of munc18

Irina Dulubova, Shuzo Sugita, Sandra Hill, Masahiro Hosaka, Imma Fernandez, Thomas C. Südhof, Jose Rizo-Rey

Research output: Contribution to journalArticlepeer-review

560 Scopus citations


Syntaxin 1, an essential protein in synaptic membrane fusion, contains a helical autonomously folded N-terminal domain, a C-terminal SNARE motif and a transmembrane region. The SNARE motif binds to synaptobrevin and SNAP-25 to assemble the core complex, whereas almost the entire cytoplasmic sequence participates in a complex with munc18-1, a neuronal Sec1 homolog. We now demonstrate by NMR spectroscopy that, in isolation, syntaxin adopts a 'closed' conformation. This default conformation of syntaxin is incompatible with core complex assembly which requires an 'open' syntaxin conformation. Using site-directed mutagenesis, we find that disruption of the closed conformation abolishes the ability of syntaxin to bind to munc18-1 and to inhibit secretion in PC12 cells. These results indicate that syntaxin binds to munc18-1 in a closed conformation and suggest that this conformation represents an essential intermediate in exocytosis. Our data suggest a model whereby, during exocytosis, syntaxin undergoes a large conformational switch that mediates the transition between the syntaxin-munc18-1 complex and the core complex.

Original languageEnglish (US)
Pages (from-to)4372-4382
Number of pages11
JournalEMBO Journal
Issue number16
StatePublished - Aug 16 1999


  • Exocytosis
  • Munc18
  • Protein NMR
  • Syntaxin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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