title: The X-ray crystal structure of neuronal Sec1 from squid sheds new light on the role of this protein in exocytosis.
abstract: BACKGROUND
  Sec1-like molecules have been implicated in a variety of eukaryotic vesicle transport processes including neurotransmitter release by exocytosis. They regulate vesicle transport by binding to a t-SNARE from the syntaxin family. This process is thought to prevent SNARE complex formation, a protein complex required for membrane fusion. Whereas Sec1 molecules are essential for neurotransmitter release and other secretory events, their interaction with syntaxin molecules seems to represent a negative regulatory step in secretion.
  
  
  RESULTS
  Here we report the X-ray crystal structure of a neuronal Sec1 homologue from squid, s-Sec1, at 2.4 A resolution. Neuronal s-Sec1 is a modular protein that folds into a V-shaped three-domain assembly. Peptide and mutagenesis studies are discussed with respect to the mechanism of Sec1 regulation. Comparison of the structure of squid s-Sec1 with the previously determined structure of rat neuronal Sec1 (n-Sec1) bound to syntaxin-1a indicates conformational rearrangements in domain III induced by syntaxin binding.
  
  
  CONCLUSIONS
  The crystal structure of s-Sec1 provides the molecular scaffold for a number of molecular interactions that have been reported to affect Sec1 function. The structural differences observed between s-Sec1 and the structure of a rat n-Sec1-syntaxin-1a complex suggest that local conformational changes are sufficient to release syntaxin-1a from neuronal Sec1, an active process that is thought to involve additional effector molecule(s).
authors.affiliation: European Molecular Biology Laboratory (EMBL), Grenoble, 38000, France.
authors.forename: A
authors.initials: A
authors.lastname: Bracher
authors.forename: A
authors.initials: A
authors.lastname: Perrakis
authors.forename: T
authors.initials: T
authors.lastname: Dresbach
authors.forename: H
authors.initials: H
authors.lastname: Betz
authors.forename: W
authors.initials: W
authors.lastname: Weissenhorn
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D018360:Crystallography, X-Ray; D049832:Decapodiformes / Q000737:chemistry*; D005089:Exocytosis; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051938:Munc18 Proteins; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011487:Protein Conformation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D050600:SNARE Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000378:metabolism; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins
chemical_list: D000596:Amino Acids; D000954:Antigens, Surface; D008565:Membrane Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D050600:SNARE Proteins; C494213:Stx1a protein, rat; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins