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Publication Detail
Abrogating Munc18-1-SNARE complex interaction has limited impact on exocytosis in PC12 cells.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Malintan NT, Nguyen TH, Han L, Latham CF, Osborne SL, Wen PJ, Lim SJT, Sugita S, Collins BM, Meunier FA
  • Publication date:
    07/08/2009
  • Pagination:
    21637, 21646
  • Journal:
    J Biol Chem
  • Volume:
    284
  • Issue:
    32
  • Status:
    Published
  • Country:
    United States
  • Print ISSN:
    0021-9258
  • PII:
    M109.013508
  • Language:
    eng
  • Keywords:
    Amino Acid Motifs, Amino Acid Sequence, Animals, Calcium, Exocytosis, Models, Biological, Molecular Conformation, Molecular Sequence Data, Munc18 Proteins, PC12 Cells, Protein Structure, Tertiary, Qa-SNARE Proteins, Rats, Recombinant Proteins, SNARE Proteins
Abstract
Neuronal communication relies on the fusion of neurotransmitter-containing vesicles with the plasma membrane. The soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) proteins initiate membrane fusion through the formation of the SNARE complex, a process tightly regulated by Sec1/Munc18-1 (SM) proteins. The emerging trend is that SM proteins promote SNARE-mediated membrane fusion by binding to a Syntaxin N-terminal motif. Here we report that mutations in the hydrophobic pocket of Munc18-1 (F115E and E132A), predicted to disrupt the N-terminal Sx1a interaction have a modest effect on binding to Sx1a in its free state, but abolish binding to the SNARE complex. Overexpression of the Munc18-1 mutant in PC12 cells lacking Munc18-1 rescues both neuroexocytosis and the plasma membrane localization of Syntaxin. However, total internal reflection fluorescence microscopy analysis reveals that expression of a Munc18-1 double mutant reduces the rate of vesicle fusion, an effect only detectable at the onset of stimulation. The Munc18-1 hydrophobic pocket is therefore critical for SNARE complex binding. However, mutations abrogating this interaction have a limited impact on Ca(2+)-dependent exocytosis in PC12 cells.
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