title: The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors.
abstract: 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.
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors: Wei
authors: W
authors: Li
authors: Cong
authors: C
authors: Ma
authors: Rong
authors: R
authors: Guan
authors: Yibin
authors: Y
authors: Xu
authors: Diana R
authors: DR
authors: Tomchick
authors: Josep
authors: J
authors: Rizo
mesh_terms: D000818:Animals; D006801:Humans; D007425:Intracellular Membranes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008561:Membrane Fusion; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry*; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000737:chemistry; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry; D050827:Syntaxin 1 / Q000737:chemistry; D050988:Vesicle-Associated Membrane Protein 2 / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C494208:SNAP25 protein, human; C494213:Stx1a protein, rat; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; C103912:Unc13a protein, rat; C494706:Vamp2 protein, rat; D050988:Vesicle-Associated Membrane Protein 2