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A central step in synaptic vesicle priming is the transition of syntaxin-1 between two very stable complexes: with Munc18 and with the other SNARE complex components. How this transition is promoted is now explored by NMR and FRET studies, revealing that the MUN domain of Munc13 uses weak interactions to pry open the closed syntaxin-1 in complex with Munc18.

Researchers working on synaptic vesicle fusion and neurotransmitter release share their views on the most interesting developments in their field and the challenges that lie ahead.

The time course of folding of a small β-sheet protein reveals formation of a central ligand binding cavity before the consolidation of the native hydrogen bonding network. These results suggest that side chain interactions and not stable hydrogen bonding determine the β-sheet architecture and play crucial roles in the overall chain topology.

Opening of the UNC-64/syntaxin closed conformation by UNC-13/Munc13 to form the neuronal SNARE complex is critical for neurotransmitter release. Here the authors show that facilitating the opening of syntaxin enhances exocytosis not only in unc-13 nulls as well as in diverse C. elegans mutants.

Munc18-1 and Munc13-1 are key for the exquisite regulation of neurotransmitter release. Here biophysical experiments show how αSNAP inhibits liposome fusion mediated by the neuronal SNAREs and how Munc18-1 overcomes this inhibition, ensuring that release depends on Munc18-1 and Munc13-1.

The high stability of SNARE complexes is probably crucial for their role in membrane fusion, but it has been difficult to measure. A surface-forces apparatus has now been used to measure the stabilization energy of a partially assembled SNARE complex, and the result (35 k_BT) is among the highest protein-folding free energies ever observed. Moreover, this approach offers a bright future for further structural and energetic studies of membrane fusion machineries.

Synaptotagmins and SNAREs are known to couple Ca²⁺ sensing to membrane fusion during Ca²⁺-triggered exocytosis, but unraveling the mechanism of this coupling has proven extremely difficult. Two studies in this issue now provide crucial insights into the nature of synaptotagmin-SNARE interactions and reveal unsuspected similarities between synaptotagmins and viral fusion proteins.

Crystallographic and functional studies reveal the arch-shaped architecture of the Munc13 MUN domain and show the molecular basis for Munc13's role in synaptic-vesicle priming by mediating syntaxin-1 opening and SNARE-complex assembly.

The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of the JASMONATE ZIM DOMAIN (JAZ) family of transcriptional repressors. These authors elucidate the mechanism of jasmonate perception. They present structural and pharmacological data to show that the true jasmonate receptor is a complex of both COI1 and JAZ. In addition, inositol pentakisphosphate functions as a critical component of the hormone receptor complex.

The interaction between RIM and the C₂A domain of Munc13 is known to be required for synaptic vesicle priming. Here the authors show new implications of the C₂A domain of Munc13, through its dynamic interaction with RIM, in orchestrating a wide range of modulatory operations that shape vesicle docking, priming and neurotransmitter release.

The NMR-derived structural model of the dynamic interaction between synaptotagmin-1 and the SNARE complex contributes to addressing the longstanding problem of how synaptotagmin-1 triggers neurotransmitter release.

The Ca²⁺ binding loops of the C₂A and C₂B domains of synaptotagmin-1 are known to be important in Ca²⁺-triggered neurotransmitter release. Biophysical and in vivo data now indicate that a basic patch on the opposite face of the C₂B domain has an equally crucial but Ca²⁺-independent role.

Complexins facilitate and inhibit neurotransmitter release through distinct domains, and their function is thought to be coupled to the Ca2+ sensor synaptotagmin-1. Biophysical and physiological analyses suggest that the N terminus of complexin stabilizes the C terminus of the SNARE complex and that this interaction increases synaptic vesicle fusogenicity at a step that precedes Ca2+ triggering.

Munc13 primes synaptic vesicles for exocytosis. Studies now reveal that the central C2B domain of Munc13 contains a structurally unusual Ca²⁺ binding site that confers specific phospholipid-binding properties to Munc13 and is essential for regulating exocytosis upon trains of action potentials.

The notion that SNARE proteins constitute the minimal machinery for intracellular membrane fusion has been accepted by many scientists. An EPR study now brings new structural data on the neuronal SNARE VAMP-2 and emphasizes the importance of rigorous evidence before a hypothesis becomes a dogma.

Secreted C-type lectins protect the intestinal epithelium from Gram-positive bacteria; this study shows that for the C-type lectin RegIIIα, bacterial killing occurs in a two-step process whereby the lectin first binds to bacterial peptidoglycans then oligomerizes on the bacterial membrane to form a permeabilizing pore.

The NMR structure of Bcl-2 bound to a recently discovered inhibitor reveals a binding site that may provide the possibility of selectively disrupting binding of Bcl-2 to Beclin 1.

This protocol monitors how fusion of proteoliposomes containing the vesicle-associated SNARE synaptobrevin with proteoliposomes containing the target-associated SNAREs syntaxin-1 and SNAP-25 depends on Munc18-1, Munc13-1, synaptotagmin-1, NSF and α-SNAP.