Figure 1.

Schematic SNARE/SM cycle. SNARE and SM proteins undergo a cycle of assembly and disassembly. At the beginning of docking, syntaxin1 is present in a “closed” conformation in which its Habc domain (purple) blocks its SNARE motif (dark blue rectangle). In this position, Munc18-1 binds monomeric syntaxin1. For the SNARE complex to assemble, syntaxin1 has to ‘‘open’’. During this conformational change, the SNARE complex assembly and Munc18-1 change their binding to syntaxin1 by binding to assemble the trans-SNARE complexes via interacting with the syntaxin1 N-peptide. Once the SNARE complexes have partly assembled, complexin binds to further tighten secretory vesicle priming. The ‘‘superprimed’’ SNARE/SM protein complexes are then ready for the Ca²⁺-trigger. Ca²⁺ binds to synaptotagmin, which causes an interaction between synaptotagmin and SNAREs and phospholipids of the plasma membrane. After fusion pore opening, the vesicular membrane and plasma membrane merge, resulting in a change from trans- to cis-SNARE complexes. The association of NSF/SNAP ATPases disassembles SNARE complexes to free SNAREs, and the vesicle is recycled, can be refilled with neurotransmitters, and reused for another release (modified from [98]).