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Publication Detail
Rescue of Munc18-1 and -2 double knockdown reveals the essential functions of interaction between Munc18 and closed syntaxin in PC12 cells.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Han L, Jiang T, Han GA, Malintan NT, Xie L, Wang L, Tse FW, Gaisano HY, Collins BM, Meunier FA, Sugita S
  • Publication date:
  • Pagination:
    4962, 4975
  • Journal:
    Mol Biol Cell
  • Volume:
  • Issue:
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • Keywords:
    Animals, Binding Sites, Gene Knockdown Techniques, Humans, Models, Molecular, Munc18 Proteins, Mutation, PC12 Cells, Phenotype, Protein Binding, Protein Structure, Tertiary, Proteins, Qa-SNARE Proteins, Rats, Recombinant Fusion Proteins, Secretory Vesicles, Thermodynamics, Two-Hybrid System Techniques
Munc18-1 binds to syntaxin-1A via two distinct sites referred to as the "closed" conformation and N terminus binding. The latter has been shown to stimulate soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated exocytosis, whereas the former is believed to be inhibitory or dispensable. To precisely define the contributions of each binding mode, we have engineered Munc18-1/-2 double knockdown neurosecretory cells and show that not only syntaxin-1A and -1B but also syntaxin-2 and -3 are significantly reduced as a result of Munc18-1 and -2 knockdown. Syntaxin-1 was mislocalized and the regulated secretion was abolished. We next examined the abilities of Munc18-1 mutants to rescue the defective phenotypes. Mutation (K46E/E59K) of Munc18-1 that selectively prevents binding to closed syntaxin-1 was unable to restore syntaxin-1 expression, localization, or secretion. In contrast, mutations (F115E/E132A) of Munc18-1 that selectively impair binding to the syntaxin-1 N terminus could still rescue the defective phenotypes. Our results indicate that Munc18-1 and -2 act in concert to support the expression of a broad range of syntaxins and to deliver syntaxin-1 to the plasma membrane. Our studies also indicate that the binding to the closed conformation of syntaxin is essential for Munc18-1 stimulatory action, whereas the binding to syntaxin N terminus plays a more limited role in neurosecretory cells.
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