Helical extension of the neuronal SNARE complex into the membrane

SNAREs (soluble N-ethylmaleimide-sensitive factor attachment receptors) represent an evolutionarily conserved protein family that mediates membrane fusion in the secretory and endocytic pathways of eukaryotic cells (1–3). Upon membrane contact, these proteins assemble in trans between the membranes as a bundle of four α-helices, with the energy released upon assembly being thought to drive fusion (4–6). 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 syntaxin 1A, SNAP-25 and synaptobrevin 2, with the C-terminal linkers and transmembrane regions at a resolution of 3.4 Å. The structure shows that assembly proceeds beyond the already known core-SNARE complex (7), 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.