title: Munc18-1 binds directly to the neuronal SNARE complex.
abstract: Both SM proteins (for Sec1/Munc18-like proteins) and SNARE proteins (for soluble NSF-attachment protein receptors) are essential for intracellular membrane fusion, but the general mechanism of coupling between their functions is unclear, in part because diverse SM protein/SNARE binding modes have been described. During synaptic vesicle exocytosis, the SM protein Munc18-1 is known to bind tightly to the SNARE protein syntaxin-1, but only when syntaxin-1 is in a closed conformation that is incompatible with SNARE complex formation. We now show that Munc18-1 also binds tightly to assembled SNARE complexes containing syntaxin-1. The newly discovered Munc18-1/SNARE complex interaction involves contacts of Munc18-1 with the N-terminal H(abc) domain of syntaxin-1 and the four-helical bundle of the assembled SNARE complex. Together with earlier studies, our results suggest that binding of Munc18-1 to closed syntaxin-1 is a specialization that evolved to meet the strict regulatory requirements of neuronal exocytosis, whereas binding of Munc18-1 to assembled SNARE complexes reflects a general function of SM proteins involved in executing membrane fusion.
authors.affiliation: Department of Biochemistry and Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Dulubova
authors.forename: Mikhail
authors.initials: M
authors.lastname: Khvotchev
authors.forename: Siqi
authors.initials: S
authors.lastname: Liu
authors.forename: Iryna
authors.initials: I
authors.lastname: Huryeva
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
mesh_terms: D000818:Animals; D002850:Chromatography, Gel; D003432:Cross-Linking Reagents / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D051938:Munc18 Proteins / Q000302:isolation & purification / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D050600:SNARE Proteins / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D051938:Munc18 Proteins; D050600:SNARE Proteins