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Publication Detail
Munc18-1 domain-1 controls vesicle docking and secretion by interacting with syntaxin-1 and chaperoning it to the plasma membrane.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Han GA, Malintan NT, Saw NMN, Li L, Han L, Meunier FA, Collins BM, Sugita S
  • Publication date:
  • Pagination:
    4134, 4149
  • Journal:
    Mol Biol Cell
  • Volume:
  • Issue:
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • Keywords:
    Amino Acid Substitution, Animals, Calorimetry, Cell Membrane, Gene Expression, Humans, Microscopy, Electron, Transmission, Microscopy, Fluorescence, Molecular Chaperones, Munc18 Proteins, Norepinephrine, PC12 Cells, Protein Binding, Protein Interaction Domains and Motifs, Protein Transport, Rats, Secretory Vesicles, Syntaxin 1, Thermodynamics, Titrimetry
Munc18-1 plays pleiotropic roles in neurosecretion by acting as 1) a molecular chaperone of syntaxin-1, 2) a mediator of dense-core vesicle docking, and 3) a priming factor for soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated membrane fusion. However, how these functions are executed and whether they are correlated remains unclear. Here we analyzed the role of the domain-1 cleft of Munc18-1 by measuring the abilities of various mutants (D34N, D34N/M38V, K46E, E59K, K46E/E59K, K63E, and E66A) to bind and chaperone syntaxin-1 and to restore the docking and secretion of dense-core vesicles in Munc18-1/-2 double-knockdown cells. We identified striking correlations between the abilities of these mutants to bind and chaperone syntaxin-1 with their ability to restore vesicle docking and secretion. These results suggest that the domain-1 cleft of Munc18-1 is essential for binding to syntaxin-1 and thereby critical for its chaperoning, docking, and secretory functions. Our results demonstrate that the effect of the alleged priming mutants (E59K, D34N/M38V) on exocytosis can largely be explained by their reduced syntaxin-1-chaperoning functions. Finally, our data suggest that the intracellular expression and distribution of syntaxin-1 determines the level of dense-core vesicle docking.
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