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Biochemistry. 2008 Feb 12;47(6):1474-81. doi: 10.1021/bi702345m. Epub 2008 Jan 18.

Binding of the Munc13-1 MUN domain to membrane-anchored SNARE complexes.

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Department of Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390, USA.


The core of the membrane fusion machinery that governs neurotransmitter release includes the SNARE proteins syntaxin-1, SNAP-25 and synaptobrevin, which form a tight "SNARE complex", and Munc18-1, which binds to the SNARE complex and to syntaxin-1 folded into a closed conformation. Release is also controlled by specialized proteins such as complexins, which also bind to the SNARE complex, and unc13/Munc13s, which are crucial for synaptic vesicle priming and were proposed to open syntaxin-1, promoting SNARE complex assembly. However, the biochemical basis for unc13/Munc13 function and its relationship to other SNARE interactions are unclear. To address this question, we have analyzed interactions of the MUN domain of Munc13-1, which is key for this priming function, using solution binding assays and cofloatation experiments with SNARE-containing proteoliposomes. Our results indicate that the Munc13-1 MUN domain binds to membrane-anchored SNARE complexes, even though binding is barely detectable in solution. The MUN domain appears to compete with Munc18-1 but not with complexin-1 for SNARE complex binding, although more quantitative assays will be required to verify these conclusions. Moreover, our data also uncover interactions of membrane-anchored syntaxin-1/SNAP-25 heterodimers with the MUN domain, Munc18-1 and complexin-1. The interaction with complexin-1 is surprising, as it was not observed in previous solution studies. Our results emphasize the importance of studying interactions within the neurotransmitter release machinery in a native membrane environment, and suggest that unc13/Munc13s may provide a template to assemble syntaxin-1/SNAP-25 heterodimers, leading to an acceptor complex for synaptobrevin.

[Indexed for MEDLINE]

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