Regulation of Membrane Fusion in Synaptic Excitation-Secretion Coupling: Speed and Accuracy Matter  Sonja M. Wojcik, Nils Brose  Neuron  Volume 55, Issue 1, Pages 11-24 (July 2007) DOI: 10.1016/j.neuron.2007.06.013 Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 1 SNARE Complex Assembly and the Transduction of the Ca2+ Signal (A) On the plasma membrane the SNARE proteins Syntaxin 1 and SNAP-25 may form (B) a heterodimeric docking platform as part of a protein complex X that functions as (C) an acceptor for zippering with the vesicular SNARE protein Synaptobrevin 2 (Syb2). Munc13 and Munc18-1 are likely candidates for enabling the formation of the SNARE complex. (D) Complexin (Cpx) binds the fully assembled SNARE complexes in a highly fusogenic, metastable configuration. (E) Binding of Ca2+ to the C2A and C2B domains of Synaptotagmin 1 (Syt1) may displace Complexin form the SNARE complex. Deformation of the membranes induced by partial insertion of the Syt1 C2 domains into the phospholipid layers and induced by electrostatic changes in the C2B domain, which can interact simultaneously with the vesicular and the plasma membrane, may be an important factor in (F) triggering membrane fusion. Neuron 2007 55, 11-24DOI: (10.1016/j.neuron.2007.06.013) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 2 A Permissive and Essential Role for Unc-18/Munc18-1 in SNARE-Mediated Membrane Fusion (A) Munc18-1 binds Syntaxin 1 in a closed conformation that is incompatible with SNARE complex formation, but (B) in the presence of SNAP-25, Munc18-1 does not prevent SNARE complex formation and may in fact function in setting up a Syntaxin 1/SNAP-25 heterodimer. Whether Munc18-1 (C) catalyzes SNARE zippering and membrane fusion by simultaneously binding to the SNARE core complex and the N terminus of Syntaxin 1 (D) or whether Munc18-1 is displaced from the SNARE complex upon SNARE zippering and is not involved in the subsequent steps that lead to vesicle fusion (outlined in Figure 1) remains to be determined. Neuron 2007 55, 11-24DOI: (10.1016/j.neuron.2007.06.013) Copyright © 2007 Elsevier Inc. Terms and Conditions

Figure 3 Directed SNARE Complex Assembly at Active Zones (A) The plasma membrane SNARE proteins Syntaxin 1 and SNAP-25 can form a (A′) SNARE-like complex with Tomosyn that is unavailable for SNARE complex formation with the vesicular SNARE protein Synaptobrevin 2 (Syb2). (B) Munc13 and Munc18-1 are candidates for enabling the formation of a Syntaxin 1/SNAP-25 docking platform as part of a protein complex X. (B′) Munc13 functions as an antagonist of Tomosyn, potentially by resolving or preventing the formation of the Tomosyn-SNARE-like complex at active zones where Munc13 is localized. The interaction between Munc13 and αRIMs is responsible for the efficient targeting of Munc13 to active zones. (C) The protein complex X, which enables SNARE complex formation and thus vesicle docking at active zones, may in part correspond to (C′) a heterotrimeric complex between the active zone proteins Munc13 and αRIMs and the vesicular small GTPase Rab3. Neuron 2007 55, 11-24DOI: (10.1016/j.neuron.2007.06.013) Copyright © 2007 Elsevier Inc. Terms and Conditions