Structure
Volume 19, Issue 10, 12 October 2011, Pages 1443-1455
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Article
The Crystal Structure of a Munc13 C-terminal Module Exhibits a Remarkable Similarity to Vesicle Tethering Factors

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Summary

Unc13/Munc13s play a crucial function in neurotransmitter release through their MUN domain, which mediates the transition from the Syntaxin-1/Munc18-1 complex to the SNARE complex. The MUN domain was suggested to be related to tethering factors, but no MUN-domain structure is available to experimentally validate this notion and address key unresolved questions about the interactions and minimal structural unit required for Unc13/Munc13 function. Here we identify an autonomously folded module within the MUN domain (MUN-CD) and show that its crystal structure is remarkably similar to several tethering factors. We also show that the activity in promoting the Syntaxin-1/Munc18-1 to SNARE complex transition is strongly impaired in MUN-CD. These results show that MUN domains and tethering factors indeed belong to the same family and may have a common role in membrane trafficking. We propose a model whereby the MUN-CD module is central for Munc13 function but full activity requires adjacent sequences.

Highlights

► The crystal structure of a C-terminal module of Munc13-1 (MUN-CD) is described ► MUN-CD is at the heart of Munc13 function, but full activity requires adjacent modules ► The structure of MUN-CD is very similar to those of diverse tethering factors ► MUN-domain containing proteins and tethering factors form a protein family

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These authors contributed equally to this work.

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Present Address: ArQule, Inc., Woburn, MA, USA