The X-ray crystal structure of neuronal Sec1 from squid sheds new light onthe role of this protein in exocytosis

Background: Sec1-like molecules have been implicated in a Variety of eukary otic vesicle transport processes including neurotransmitter release by exoc ytosis. They regulate vesicle transport by binding to a t-SNARE from the sy ntaxin 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 in teraction 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 homo logue from squid, s-Sec1, at 2.4 Angstrom resolution. Neuronal s-Sec1 is a modular protein that folds into a V-shaped three-domain assembly. Peptide a nd 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 in dicates conformational rearrangements in domain III induced by syntaxin bin ding. Conclusions: The crystal structure of s-Sec1 provides the molecular scaffol d for a number of molecular interactions that have been reported to affect Sec1 function. The structural differences observed between s-Sec1 and the s tructure of a rat n-Sec1-syntaxin-1a complex suggest that local conformatio nal changes are sufficient to release syntaxin-1a from neuronal Sec1, an ac tive process that is thought to involve additional effector molecule(s).