Journal
FEBS LETTERS
Volume 581, Issue 22, Pages 4318-4324Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.febslet.2007.07.083
Keywords
SNARE; syntaxin 3; Munc18b; CDK5; exocytosis
Funding
- NCI NIH HHS [R01 CA164133, P50 CA089019, U56 CA092080] Funding Source: Medline
- NIDDK NIH HHS [R01 DK056292, DK 56292, R01 DK115812] Funding Source: Medline
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Syntaxin and Munc18 are essential for regulated exocytosis in all eukaryotes. It was shown that Munc18 inhibition of neuronal syntaxin I can be overcome by CDK5 phosphorylation, indicating that structural change disrupts the syntaxin-Munc18 interaction. Here, we show that this phosphorylation promotes the assembly of Munc18b-syntaxin 3-SNAP25 tripartite complex and membrane fusion machinery SNARE. Using siRNAs to screen for genes required for regulated epithelial secretion, we identified the requirements of CDK5 and Munc18b in cAMP-dependent gastric acid secretion. Biochemical characterization revealed that Munc18b bears a syntaxin 3-selective binding site located at its most C-terminal 53 amino acids. Significantly, the phosphorylation of Thr572 by CDK5 attenuates Munc18b-syntaxin 3 interaction and promotes formation of Munc18b-syntaxin 3-SNAP25 tripartite complex, leading to an assembly of functional Munc18b-syntaxin 3-SNAP25VAMP2 membrane fusion machinery. Thus, our studies suggest a novel regulatory mechanism in which phosphorylation of Munc18b operates vesicle docking and fusion in regulated exocytosis. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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