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S-nitrosylation of syntaxin 1 at Cys(145) is a regulatory switch controlling Munc18-1 binding.

Authors
  • Palmer, Zoë J
  • Duncan, Rory R
  • Johnson, James R
  • Lian, Lu-Yun
  • Mello, Luciane V
  • Booth, David
  • Barclay, Jeff W
  • Graham, Margaret E
  • Burgoyne, Robert D
  • Prior, Ian A
  • Morgan, Alan
Type
Published Article
Journal
Biochemical Journal
Publisher
Portland Press
Publication Date
Aug 01, 2008
Volume
413
Issue
3
Pages
479–491
Identifiers
DOI: 10.1042/BJ20080069
PMID: 18452404
Source
Medline
License
Unknown

Abstract

Exocytosis is regulated by NO in many cell types, including neurons. In the present study we show that syntaxin 1a is a substrate for S-nitrosylation and that NO disrupts the binding of Munc18-1 to the closed conformation of syntaxin 1a in vitro. In contrast, NO does not inhibit SNARE {SNAP [soluble NSF (N-ethylmaleimide-sensitive fusion protein) attachment protein] receptor} complex formation or binding of Munc18-1 to the SNARE complex. Cys(145) of syntaxin 1a is the target of NO, as a non-nitrosylatable C145S mutant is resistant to NO and novel nitrosomimetic Cys(145) mutants mimic the effect of NO on Munc18-1 binding in vitro. Furthermore, expression of nitrosomimetic syntaxin 1a in living cells affects Munc18-1 localization and alters exocytosis release kinetics and quantal size. Molecular dynamic simulations suggest that NO regulates the syntaxin-Munc18 interaction by local rearrangement of the syntaxin linker and H3c regions. Thus S-nitrosylation of Cys(145) may be a molecular switch to disrupt Munc18-1 binding to the closed conformation of syntaxin 1a, thereby facilitating its engagement with the membrane fusion machinery.

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