title: Munc13 mediates the transition from the closed syntaxin-Munc18 complex to the SNARE complex.
abstract: During the priming step that leaves synaptic vesicles ready for neurotransmitter release, the SNARE syntaxin-1 transitions from a closed conformation that binds Munc18-1 tightly to an open conformation within the highly stable SNARE complex. Control of this conformational transition is important for brain function, but the underlying mechanism is unknown. NMR and fluorescence experiments now show that the Munc13-1 MUN domain, which plays a central role in vesicle priming, markedly accelerates the transition from the syntaxin-1-Munc18-1 complex to the SNARE complex. This activity depends on weak interactions of the MUN domain with the syntaxin-1 SNARE motif, and probably with Munc18-1. Together with available physiological data, these results provide a defined molecular basis for synaptic vesicle priming, and they illustrate how weak protein-protein interactions can play crucial biological roles by promoting transitions between high-affinity macromolecular assemblies.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xu
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D051938:Munc18 Proteins / Q000737:chemistry* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D051381:Rats; D050600:SNARE Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry / Q000378:metabolism; D050827:Syntaxin 1 / Q000737:chemistry* / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000737:chemistry / Q000378:metabolism
chemical_list: D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; C494208:SNAP25 protein, human; D050600:SNARE Proteins; C497939:Stxbp1 protein, rat; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; C103912:Unc13a protein, rat; C494706:Vamp2 protein, rat; D050988:Vesicle-Associated Membrane Protein 2