Document Detail


The Munc18-1 domain 3a loop is essential for neuroexocytosis but not for syntaxin-1A transport to the plasma membrane.
MedLine Citation:
PMID:  23761923     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Munc18-1 plays a dual role in transporting syntaxin-1A (Sx1a) to the plasma membrane and regulating SNARE-mediated membrane fusion. As impairment of either function leads to a common exocytic defect, assigning specific roles for various Munc18-1 domains has proved difficult. Structural analyses predict that a loop region in Munc18-1 domain 3a could catalyse the conversion of Sx1a from a 'closed', fusion-incompetent to an 'open', fusion-competent conformation. As this conversion occurs at the plasma membrane, mutations in this loop could potentially separate the chaperone and exocytic functions of Munc18-1. Expression of a Munc18-1 deletion mutant lacking 17 residues of the domain 3a loop (Munc18-1(Δ317-333)) in PC12 cells deficient in endogenous Munc18 (DKD-PC12 cells) fully rescued transport of Sx1a to the plasma membrane, but not exocytic secretory granule fusion. In vitro binding of Munc18-1(Δ317-333) to Sx1a was indistinguishable from that of full-length Munc18-1, consistent with the critical role of the closed conformation in Sx1a transport. However, in DKD-PC12 cells, Munc18-1(Δ317-333) binding to Sx1a was greatly reduced compared to that of full-length Munc18-1, suggesting that closed conformation binding contributes little to the overall interaction at the cell surface. Furthermore, we found that Munc18-1(Δ317-333) could bind SNARE complexes in vitro, suggesting that additional regulatory factors underpin the exocytic function of Munc18-1 in vivo. Together, these results point to a defined role for Munc18-1 in facilitating exocytosis linked to the loop region of domain 3a that is clearly distinct from its function in Sx1a transport.
Authors:
Sally Martin; Vanesa M Tomatis; Andreas Papadopulos; Michelle P Christie; Nancy T Malintan; Rachel S Gormal; Shuzo Sugita; Jennifer L Martin; Brett M Collins; Frederic A Meunier
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of cell science     Volume:  126     ISSN:  1477-9137     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  2353-60     Citation Subset:  IM    
Affiliation:
Queensland Brain Institute, The University of Queensland, Brisbane QLD 4072, Australia.
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