1. Department of Neurobiology,
2. Research Group X-ray Crystallography, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
3. Freie Universität Berlin, Fachbereich Biologie, Chemie, Pharmazie, Institut für Chemie und Biochemie, AG Strukturbiochemie, Takustrae 6, D-14195 Berlin, Germany

Correspondence to: Reinhard Jahn¹ Correspondence and requests for materials should be addressed to R.J. (Email: rjahn@gwdg.de).

Abstract

Neurotransmission relies on synaptic vesicles fusing with the membrane of nerve cells to release their neurotransmitter content into the synaptic cleft, a process requiring the assembly of several members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) family. SNAREs represent an evolutionarily conserved protein family that mediates membrane fusion in the secretory and endocytic pathways of eukaryotic cells^{1, 2, 3}. On membrane contact, these proteins assemble in trans between the membranes as a bundle of four -helices, with the energy released during assembly being thought to drive fusion^{4, 5, 6}. However, it is unclear how the energy is transferred to the membranes and whether assembly is conformationally linked to fusion. Here, we report the X-ray structure of the neuronal SNARE complex, consisting of rat syntaxin 1A, SNAP-25 and synaptobrevin 2, with the carboxy-terminal linkers and transmembrane regions at 3.4 Å resolution. The structure shows that assembly proceeds beyond the already known core SNARE complex⁷, resulting in a continuous helical bundle that is further stabilized by side-chain interactions in the linker region. Our results suggest that the final phase of SNARE assembly is directly coupled to membrane merger.

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