Prefusion structure of syntaxin-1A suggests pathway for folding into neuronal trans -SNARE complex fusion intermediate

Significance Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNAREs) are the key molecules that control fusion in intracellular vesicle traffic. A special case of vesicle-to-plasma membrane fusion is exocytosis of synaptic vesicles at the presynaptic membrane to release neurotransmitters into the synaptic cleft. Structures are known of postfusion SNARE complexes, including a famous four-helix bundle with parallel C-terminal transmembrane domains. However, prefusion structures and the structures of intermediatetrans -SNARE complexes remain much more elusive. Using nuclear magnetic resonance, we have determined the prefusion structure of the lipid-bound t-SNARE syntaxin-1A, with its transmembrane domain, and confirmed its lipid interactions and conformational transitions on co-t-SNARE SNAP-25 binding by high-resolution interference contrast microscopy in lipid bilayers. We discuss how these structures and their folding into later SNARE complexes might drive membrane fusion.