title: Possible roles for Munc18-1 domain 3a and Syntaxin1 N-peptide and C-terminal anchor in SNARE complex formation.
abstract: Munc18-1 and Syntaxin1 are essential proteins for SNARE-mediated neurotransmission. Munc18-1 participates in synaptic vesicle fusion via dual roles: as a docking/chaperone protein by binding closed Syntaxin1, and as a fusion protein that binds SNARE complexes in a Syntaxin1 N-peptide dependent manner. The two roles are associated with a closed-open Syntaxin1 conformational transition. Here, we show that Syntaxin N-peptide binding to Munc18-1 is not highly selective, suggesting that other parts of the SNARE complex are involved in binding to Munc18-1. We also find that Syntaxin1, with an N peptide and a physically anchored C terminus, binds to Munc18-1 and that this complex can participate in SNARE complex formation. We report a Munc18-1-N-peptide crystal structure that, together with other data, reveals how Munc18-1 might transit from a conformation that binds closed Syntaxin1 to one that may be compatible with binding open Syntaxin1 and SNARE complexes. Our results suggest the possibility that structural transitions occur in both Munc18-1 and Syntaxin1 during their binary interaction. We hypothesize that Munc18-1 domain 3a undergoes a conformational change that may allow coiled-coil interactions with SNARE complexes.
authors.affiliation: Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Hu
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Christie
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Saez
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Latham
authors.forename: Russell
authors.initials: R
authors.lastname: Jarrott
authors.forename: Linda H L
authors.initials: LH
authors.lastname: Lua
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D003461:Crystallography; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D051938:Munc18 Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D050600:SNARE Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D009435:Synaptic Transmission / Q000502:physiology*; D050827:Syntaxin 1 / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D051938:Munc18 Proteins; D050600:SNARE Proteins; D050827:Syntaxin 1