The Synaptic Vesicle Release Machinery.

Extensive research has yielded crucial insights into the mechanism of neurotransmitter release, and working models for the functions of key proteins involved in release. The SNAREs Syntaxin-1, Synaptobrevin, and SNAP-25 play a central role in membrane fusion, forming SNARE complexes that bridge the vesicle and plasma membranes and that are disassembled by NSF-SNAPs. Exocytosis likely starts with Syntaxin-1 folded into a self-inhibited closed conformation that binds to Munc18-1. Munc13s open Syntaxin-1, orchestrating SNARE complex assembly in an NSF-SNAP-resistant manner together with Munc18-1. In the resulting primed state, with partially assembled SNARE complexes, fusion is inhibited by Synaptotagmin-1 and Complexins, which also perform active functions in release. Upon influx of Ca(2+), Synaptotagmin-1 activates fast release, likely by relieving the inhibition caused by Complexins and cooperating with the SNAREs in bringing the membranes together. Although alternative models exist and fundamental questions remain unanswered, a definitive description of the basic release mechanism may be available soon.

[1]  J. Briggs,et al.  SNARE and regulatory proteins induce local membrane protrusions to prime docked vesicles for fast calcium‐triggered fusion , 2014, EMBO reports.

[2]  Demet Araç,et al.  Unraveling the mechanisms of synaptotagmin and SNARE function in neurotransmitter release. , 2006, Trends in cell biology.

[3]  E. Jorgensen,et al.  One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction , 1999, Nature Neuroscience.

[4]  T. Südhof,et al.  Complexin Controls the Force Transfer from SNARE Complexes to Membranes in Fusion , 2009, Science.

[5]  J. Malsam,et al.  Resolving the Function of Distinct Munc18-1/SNARE Protein Interaction Modes in a Reconstituted Membrane Fusion Assay* , 2011, The Journal of Biological Chemistry.

[6]  J. Rizo,et al.  Analysis of SNARE complex/synaptotagmin-1 interactions by one-dimensional NMR spectroscopy. , 2013, Biochemistry.

[7]  T. Südhof,et al.  Sly1 binds to Golgi and ER syntaxins via a conserved N-terminal peptide motif. , 2002, Developmental cell.

[8]  Jennifer L. Martin,et al.  Possible roles for Munc18-1 domain 3a and Syntaxin1 N-peptide and C-terminal anchor in SNARE complex formation , 2010, Proceedings of the National Academy of Sciences.

[9]  Edwin R Chapman,et al.  Ca2+–synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion , 2006, Nature Structural &Molecular Biology.

[10]  M. Kozlov,et al.  How Synaptotagmin Promotes Membrane Fusion , 2007, Science.

[11]  J. Rizo,et al.  Subtle Interplay between synaptotagmin and complexin binding to the SNARE complex. , 2013, Journal of molecular biology.

[12]  T. Südhof,et al.  Microsecond Dissection of Neurotransmitter Release: SNARE-Complex Assembly Dictates Speed and Ca2+ Sensitivity , 2014, Neuron.

[13]  E. Jorgensen,et al.  An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming , 2001, Nature.

[14]  C. Chiu,et al.  Yeast Sec1p functions before and after vesicle docking. , 2009, Molecular biology of the cell.

[15]  T. Südhof,et al.  Differential but convergent functions of Ca2+ binding to synaptotagmin-1 C2 domains mediate neurotransmitter release , 2009, Proceedings of the National Academy of Sciences.

[16]  F. Hughson,et al.  Tethering factors as organizers of intracellular vesicular traffic. , 2010, Annual review of cell and developmental biology.

[17]  A. Brunger,et al.  Accessory proteins stabilize the acceptor complex for synaptobrevin, the 1:1 syntaxin/SNAP-25 complex. , 2008, Structure.

[18]  B. Dasgupta,et al.  N-Ethylmaleimide-sensitive Factor Acts at a Prefusion ATP-dependent Step in Ca2+-activated Exocytosis* , 1996, The Journal of Biological Chemistry.

[19]  Josep Rizo,et al.  Dual Modes of Munc18-1/SNARE Interactions Are Coupled by Functionally Critical Binding to Syntaxin-1 N Terminus , 2007, The Journal of Neuroscience.

[20]  G. Melikyan,et al.  The Energetics of Membrane Fusion from Binding, through Hemifusion, Pore Formation, and Pore Enlargement , 2004, The Journal of Membrane Biology.

[21]  J. Bessereau,et al.  UNC-13 and UNC-10/Rim Localize Synaptic Vesicles to Specific Membrane Domains , 2006, The Journal of Neuroscience.

[22]  Reinhard Jahn,et al.  Two synaptobrevin molecules are sufficient for vesicle fusion in central nervous system synapses , 2011, Proceedings of the National Academy of Sciences.

[23]  Nam Ki Lee,et al.  Solution single‐vesicle assay reveals PIP2‐mediated sequential actions of synaptotagmin‐1 on SNAREs , 2012, The EMBO journal.

[24]  P. Novick,et al.  The structures of exocyst subunit Exo70p and the Exo84p C-terminal domains reveal a common motif , 2005, Nature Structural &Molecular Biology.

[25]  N. Grishin,et al.  Remote homology between Munc13 MUN domain and vesicle tethering complexes. , 2009, Journal of molecular biology.

[26]  A. Lai,et al.  Synaptotagmin 1 and SNAREs form a complex that is structurally heterogeneous. , 2011, Journal of molecular biology.

[27]  J. Dittman,et al.  Synaptic Vesicles Position Complexin to Block Spontaneous Fusion , 2013, Neuron.

[28]  Shailendra S. Rathore,et al.  SNARE bundle and syntaxin N-peptide constitute a minimal complement for Munc18-1 activation of membrane fusion , 2010, The Journal of cell biology.

[29]  Hugo J. Bellen,et al.  Tilting the Balance between Facilitatory and Inhibitory Functions of Mammalian and Drosophila Complexins Orchestrates Synaptic Vesicle Exocytosis , 2009, Neuron.

[30]  J. Rothman,et al.  Complexin cross-links prefusion SNAREs into a zigzag array. , 2011, Nature structural & molecular biology.

[31]  J. Briggs,et al.  Complexin arrests a pool of docked vesicles for fast Ca2+‐dependent release , 2012, The EMBO journal.

[32]  Thomas C. Südhof,et al.  A Complexin/Synaptotagmin 1 Switch Controls Fast Synaptic Vesicle Exocytosis , 2006, Cell.

[33]  Nikhil R. Gandasi,et al.  Contact-induced clustering of syntaxin and munc18 docks secretory granules at the exocytosis site , 2014, Nature Communications.

[34]  Nancy T. Malintan,et al.  Munc18-1 domain-1 controls vesicle docking and secretion by interacting with syntaxin-1 and chaperoning it to the plasma membrane , 2011, Molecular biology of the cell.

[35]  G. van den Bogaart,et al.  Controlling synaptotagmin activity by electrostatic screening , 2012, Nature Structural &Molecular Biology.

[36]  J. Troy Littleton,et al.  Complexin Controls Spontaneous and Evoked Neurotransmitter Release by Regulating the Timing and Properties of Synaptotagmin Activity , 2012, The Journal of Neuroscience.

[37]  Y. Shin,et al.  Membrane topologies of neuronal SNARE folding intermediates. , 2002, Biochemistry.

[38]  H. Grubmüller,et al.  Synaptotagmin-1 may be a distance regulator acting upstream of SNARE nucleation , 2011, Nature Structural &Molecular Biology.

[39]  J. Rothman,et al.  A Clamping Mechanism Involved in SNARE-Dependent Exocytosis , 2006, Science.

[40]  Richard H. Scheller,et al.  Three-dimensional structure of the neuronal-Sec1–syntaxin 1a complex , 2000, Nature.

[41]  J. Rothman,et al.  Energetics and dynamics of SNAREpin folding across lipid bilayers , 2007, Nature Structural &Molecular Biology.

[42]  T. Südhof,et al.  Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin , 1993, Nature.

[43]  J. Rizo,et al.  Binding of the Munc13-1 MUN domain to membrane-anchored SNARE complexes. , 2008, Biochemistry.

[44]  R. Pfuetzner,et al.  Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms , 2014, eLife.

[45]  V. Parpura,et al.  Single Molecule Measurements of Interaction Free Energies Between the Proteins Within Binary and Ternary SNARE Complexes. , 2009, Journal of nanoneuroscience.

[46]  A. Brunger,et al.  Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Ralf Schneggenburger,et al.  A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? , 2005, The EMBO journal.

[48]  C. Stegmann,et al.  Primordial neurosecretory apparatus identified in the choanoflagellate Monosiga brevicollis , 2011, Proceedings of the National Academy of Sciences.

[49]  T. Südhof,et al.  Complexin Activates Exocytosis of Distinct Secretory Vesicles Controlled by Different Synaptotagmins , 2013, The Journal of Neuroscience.

[50]  T. Südhof,et al.  C-Terminal Complexin Sequence Is Selectively Required for Clamping and Priming But Not for Ca2+ Triggering of Synaptic Exocytosis , 2012, The Journal of Neuroscience.

[51]  Thomas C. Südhof,et al.  Complexins: Cytosolic proteins that regulate SNAP receptor function , 1995, Cell.

[52]  J. Rizo,et al.  Complexin/Synaptotagmin Interplay Controls Acrosomal Exocytosis* , 2007, Journal of Biological Chemistry.

[53]  Shigeki Watanabe,et al.  Complexin Maintains Vesicles in the Primed State in C. elegans , 2011, Current Biology.

[54]  T. Südhof,et al.  Neurotransmitter Release: The Last Millisecond in the Life of a Synaptic Vesicle , 2013, Neuron.

[55]  J. Rizo,et al.  Prevalent mechanism of membrane bridging by synaptotagmin-1 , 2013, Proceedings of the National Academy of Sciences.

[56]  Gregory W. Gundersen,et al.  Single Reconstituted Neuronal SNARE Complexes Zipper in Three Distinct Stages , 2012, Science.

[57]  Edwin R. Chapman,et al.  Synaptotagmin-Mediated Bending of the Target Membrane Is a Critical Step in Ca2+-Regulated Fusion , 2009, Cell.

[58]  M. Munson,et al.  Dimerization of the exocyst protein Sec6p and its interaction with the t-SNARE Sec9p. , 2005, Biochemistry.

[59]  Josep Ubach,et al.  Three-Dimensional Structure of an Evolutionarily Conserved N-Terminal Domain of Syntaxin 1A , 1998, Cell.

[60]  M. Mayer,et al.  An Extended Helical Conformation in Domain 3a of Munc18-1 Provides a Template for SNARE (Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor) Complex Assembly* , 2014, The Journal of Biological Chemistry.

[61]  T. Südhof,et al.  Synaptic assembly of the brain in the absence of neurotransmitter secretion. , 2000, Science.

[62]  W. Wickner,et al.  A lipid-anchored SNARE supports membrane fusion , 2011, Proceedings of the National Academy of Sciences.

[63]  D. Bruns,et al.  Complexin synchronizes primed vesicle exocytosis and regulates fusion pore dynamics , 2014, The Journal of cell biology.

[64]  Patricia Grob,et al.  In vitro system capable of differentiating fast Ca2+-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release , 2011, Proceedings of the National Academy of Sciences.

[65]  J. Littleton,et al.  Genetic Analysis of Synaptotagmin C2 Domain Specificity in Regulating Spontaneous and Evoked Neurotransmitter Release , 2013, The Journal of Neuroscience.

[66]  J. Rizo,et al.  The Janus-Faced Nature of the C2B Domain Is Fundamental for Synaptotagmin-1 Function , 2008, Nature Structural &Molecular Biology.

[67]  N. Grishin,et al.  A minimal domain responsible for Munc13 activity , 2005, Nature Structural &Molecular Biology.

[68]  Reinhard Jahn,et al.  Helical extension of the neuronal SNARE complex into the membrane , 2009, Nature.

[69]  R. Jahn,et al.  Molecular machines governing exocytosis of synaptic vesicles , 2012, Nature.

[70]  I. Robinson,et al.  The C2B Ca2+-binding motif of synaptotagmin is required for synaptic transmission in vivo , 2002, Nature.

[71]  C. Creutz,et al.  Synergistic membrane interactions of the two C2 domains of synaptotagmin. , 1994, The Journal of biological chemistry.

[72]  Frederick M. Hughson,et al.  Regulation of SNARE complex assembly by an N-terminal domain of the t-SNARE Sso1p , 1998, Nature Structural Biology.

[73]  Christopher M Hickey,et al.  Reconstituted membrane fusion requires regulatory lipids, SNAREs and synergistic SNARE chaperones , 2008, The EMBO journal.

[74]  T. Südhof,et al.  Synaptotagmin I functions as a calcium regulator of release probability , 2001, Nature.

[75]  T. Südhof,et al.  A conformational switch in syntaxin during exocytosis: role of munc18 , 1999, The EMBO journal.

[76]  Nancy T. Malintan,et al.  Rescue of Munc18-1 and -2 double knockdown reveals the essential functions of interaction between Munc18 and closed syntaxin in PC12 cells. , 2009, Molecular biology of the cell.

[77]  T. Südhof,et al.  The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices--guilty as charged? , 2012, Annual review of cell and developmental biology.

[78]  W. Wickner,et al.  A distinct tethering step is vital for vacuole membrane fusion , 2014, eLife.

[79]  T. Südhof,et al.  Membrane Fusion: Grappling with SNARE and SM Proteins , 2009, Science.

[80]  Christian Rosenmund,et al.  Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system , 2008, Proceedings of the National Academy of Sciences.

[81]  T. Südhof,et al.  Close membrane-membrane proximity induced by Ca2+-dependent multivalent binding of synaptotagmin-1 to phospholipids , 2006, Nature Structural &Molecular Biology.

[82]  D. Bruns,et al.  v-SNARE Actions during Ca2+-Triggered Exocytosis , 2007, Cell.

[83]  Dietmar Riedel,et al.  Synaptotagmin-1 Docks Secretory Vesicles to Syntaxin-1/SNAP-25 Acceptor Complexes , 2009, Cell.

[84]  T. Südhof,et al.  Syntaxin‐1 N‐peptide and Habc‐domain perform distinct essential functions in synaptic vesicle fusion , 2012, The EMBO journal.

[85]  E. Jorgensen,et al.  Syntaxin N-terminal peptide motif is an initiation factor for the assembly of the SNARE–Sec1/Munc18 membrane fusion complex , 2010, Proceedings of the National Academy of Sciences.

[86]  Christian Rosenmund,et al.  Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[87]  T. Südhof,et al.  Munc18-1 binds directly to the neuronal SNARE complex , 2007, Proceedings of the National Academy of Sciences.

[88]  T. Südhof,et al.  Ca2+ binding to synaptotagmin: how many Ca2+ ions bind to the tip of a C2‐domain? , 1998, The EMBO journal.

[89]  Reinhard Jahn,et al.  Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution , 1998, Nature.

[90]  W. Xiao,et al.  The synaptic SNARE complex is a parallel four-stranded helical bundle , 1998, Nature Structural Biology.

[91]  T. Südhof,et al.  Ultrahigh-resolution imaging reveals formation of neuronal SNARE/Munc18 complexes in situ , 2013, Proceedings of the National Academy of Sciences.

[92]  M. Kozlov,et al.  Mechanics of membrane fusion , 2008, Nature Structural &Molecular Biology.

[93]  A. Brunger,et al.  Single-molecule studies of the neuronal SNARE fusion machinery. , 2009, Annual review of biochemistry.

[94]  G. van den Bogaart,et al.  Cis- and trans-membrane interactions of synaptotagmin-1 , 2012, Proceedings of the National Academy of Sciences.

[95]  Mark T. Handley,et al.  A gain-of-function mutant of Munc18-1 stimulates secretory granule recruitment and exocytosis and reveals a direct interaction of Munc18-1 with Rab3. , 2008, The Biochemical journal.

[96]  Changbong Hyeon,et al.  Dynamic Ca2+-Dependent Stimulation of Vesicle Fusion by Membrane-Anchored Synaptotagmin 1 , 2010, Science.

[97]  T. Südhof,et al.  Three-Dimensional Structure of the Complexin/SNARE Complex , 2002, Neuron.

[98]  H. McMahon,et al.  Synaptotagmin-1 utilizes membrane bending and SNARE binding to drive fusion pore expansion. , 2008, Molecular biology of the cell.

[99]  Mark K. Bennett,et al.  A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion , 1993, Cell.

[100]  T. Ha,et al.  Complexin and Ca2+ stimulate SNARE-mediated membrane fusion , 2008, Nature Structural &Molecular Biology.

[101]  T. Walz,et al.  A Structure-Based Mechanism for Vesicle Capture by the Multisubunit Tethering Complex Dsl1 , 2009, Cell.

[102]  W. Weissenhorn,et al.  Structural basis for the Golgi membrane recruitment of Sly1p by Sed5p , 2002, The EMBO journal.

[103]  F. Wouters,et al.  One SNARE complex is sufficient for membrane fusion , 2010, Nature Structural &Molecular Biology.

[104]  A. Mayer,et al.  Sec18p (NSF)-Driven Release of Sec17p (α-SNAP) Can Precede Docking and Fusion of Yeast Vacuoles , 1996, Cell.

[105]  J. Rothman,et al.  Genetic analysis of the Complexin trans-clamping model for cross-linking SNARE complexes in vivo , 2014, Proceedings of the National Academy of Sciences.

[106]  J. Rothman,et al.  A Half-Zippered SNARE Complex Represents a Functional Intermediate in Membrane Fusion , 2014, Journal of the American Chemical Society.

[107]  J. Yates,et al.  HOPS prevents the disassembly of trans‐SNARE complexes by Sec17p/Sec18p during membrane fusion , 2010, The EMBO journal.

[108]  T. Südhof,et al.  Synaptotagmin–Syntaxin Interaction: The C2 Domain as a Ca2+-Dependent Electrostatic Switch , 1997, Neuron.

[109]  R B Sutton,et al.  Calcium Binding by Synaptotagmin's C2A Domain is an Essential Element of the Electrostatic Switch That Triggers Synchronous Synaptic Transmission , 2012, The Journal of Neuroscience.

[110]  Joseph M. Esquibel,et al.  Munc 13-4 reconstitutes calcium-dependent SNARE-mediated membrane fusion , 2022 .

[111]  T. Südhof,et al.  Vam3p structure reveals conserved and divergent properties of syntaxins , 2001, Nature Structural Biology.

[112]  Benedikt Westermann,et al.  SNAREpins: Minimal Machinery for Membrane Fusion , 1998, Cell.

[113]  T. Südhof,et al.  Convergence and divergence in the mechanism of SNARE binding by Sec1/Munc18-like proteins , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[114]  Reinhard Jahn,et al.  SNAREs — engines for membrane fusion , 2006, Nature Reviews Molecular Cell Biology.

[115]  J. Rothman,et al.  Alternative Zippering as an On-Off Switch for SNARE-Mediated Fusion , 2009, Science.

[116]  J. Malsam,et al.  Membrane traffic in the secretory pathway , 2008, Cellular and Molecular Life Sciences.

[117]  I. Dulubova,et al.  NMR analysis of the closed conformation of syntaxin-1 , 2008, Journal of biomolecular NMR.

[118]  Kendal Broadie,et al.  Drosophila Unc-13 is essential for synaptic transmission , 1999, Nature Neuroscience.

[119]  T. Südhof,et al.  Complexin Clamps Asynchronous Release by Blocking a Secondary Ca2+ Sensor via Its Accessory α Helix , 2010, Neuron.

[120]  J. Rizo,et al.  Reconstitution of the Vital Functions of Munc18 and Munc13 in Neurotransmitter Release , 2013, Science.

[121]  Edwin R Chapman,et al.  How does synaptotagmin trigger neurotransmitter release? , 2008, Annual review of biochemistry.

[122]  T. Weber,et al.  Reconstitution of Ca2+-Regulated Membrane Fusion by Synaptotagmin and SNAREs , 2004, Science.

[123]  Reinhard Jahn,et al.  Structure and Conformational Changes in NSF and Its Membrane Receptor Complexes Visualized by Quick-Freeze/Deep-Etch Electron Microscopy , 1997, Cell.

[124]  J. B. Sørensen,et al.  Conflicting views on the membrane fusion machinery and the fusion pore. , 2009, Annual review of cell and developmental biology.

[125]  T. Südhof,et al.  Three-Dimensional Structure of the Synaptotagmin 1 C2B-Domain Synaptotagmin 1 as a Phospholipid Binding Machine , 2001, Neuron.

[126]  T. Salditt,et al.  Energetics of stalk intermediates in membrane fusion are controlled by lipid composition , 2012, Proceedings of the National Academy of Sciences.

[127]  E. Jorgensen,et al.  UNC-13 is required for synaptic vesicle fusion in C. elegans , 1999, Nature Neuroscience.

[128]  Axel T. Brunger,et al.  Single-molecule FRET-derived model of the synaptotagmin 1–SNARE fusion complex , 2010, Nature Structural &Molecular Biology.

[129]  J. Rothman,et al.  Snarepins Are Functionally Resistant to Disruption by Nsf and αSNAP , 2000, The Journal of cell biology.

[130]  Colin Rickman,et al.  Conserved prefusion protein assembly in regulated exocytosis. , 2005, Molecular biology of the cell.

[131]  J. Rizo,et al.  The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors. , 2011, Structure.

[132]  T. Südhof,et al.  How Tlg2p/syntaxin 16 'snares’ Vps45 , 2002, The EMBO journal.

[133]  E. Chapman,et al.  Direct Interaction of a Ca2+-binding Loop of Synaptotagmin with Lipid Bilayers* , 1998, The Journal of Biological Chemistry.

[134]  Wei Li,et al.  Munc13 Mediates the Transition from the Closed Syntaxin–Munc18 complex to the SNARE complex , 2011, Nature Structural &Molecular Biology.

[135]  Y. Shin,et al.  Hemifusion arrest by complexin is relieved by Ca2+–synaptotagmin I , 2006, Nature Structural &Molecular Biology.

[136]  T. Südhof,et al.  Structural Determinants of Synaptobrevin 2 Function in Synaptic Vesicle Fusion , 2006, The Journal of Neuroscience.

[137]  T. Südhof,et al.  Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[138]  J. Rothman,et al.  Selective Activation of Cognate SNAREpins by Sec1/Munc18 Proteins , 2007, Cell.

[139]  Josep Rizo,et al.  Binding of Munc18-1 to synaptobrevin and to the SNARE four-helix bundle. , 2010, Biochemistry.

[140]  B. L. de Groot,et al.  Sequential N‐ to C‐terminal SNARE complex assembly drives priming and fusion of secretory vesicles , 2006, The EMBO journal.

[141]  T. Südhof,et al.  Lipid-Anchored SNAREs Lacking Transmembrane Regions Fully Support Membrane Fusion during Neurotransmitter Release , 2013, Neuron.

[142]  J. Rizo,et al.  Re-examining how complexin inhibits neurotransmitter release , 2014, eLife.

[143]  P. Novick,et al.  Sec1p Binds to Snare Complexes and Concentrates at Sites of Secretion , 1999, The Journal of cell biology.

[144]  H. Cai,et al.  Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. , 2007, Developmental cell.

[145]  J. Rizo,et al.  Binding of the complexin N terminus to the SNARE complex potentiates synaptic-vesicle fusogenicity , 2010, Nature Structural &Molecular Biology.

[146]  M. Verhage,et al.  Munc18-1 in secretion: lonely Munc joins SNARE team and takes control , 2007, Trends in Neurosciences.

[147]  V. Parpura,et al.  SNAREs: Could They be the Answer to an Energy Landscape Riddle in Exocytosis? , 2010, TheScientificWorldJournal.

[148]  E. Neher,et al.  Fast Vesicle Fusion in Living Cells Requires at Least Three SNARE Complexes , 2010, Science.

[149]  J. Rizo,et al.  At the junction of SNARE and SM protein function. , 2010, Current opinion in cell biology.

[150]  Thomas C. Südhof,et al.  Synaptotagmin-1 and Synaptotagmin-7 Trigger Synchronous and Asynchronous Phases of Neurotransmitter Release , 2013, Neuron.

[151]  T. Südhof,et al.  Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming , 2009, The Journal of cell biology.

[152]  T. Südhof,et al.  Selective Interaction of Complexin with the Neuronal SNARE Complex , 2000, The Journal of Biological Chemistry.

[153]  Nia J. Bryant,et al.  The N-terminal peptide of the syntaxin Tlg2p modulates binding of its closed conformation to Vps45p , 2009, Proceedings of the National Academy of Sciences.

[154]  E. Chapman,et al.  Mechanism and function of synaptotagmin-mediated membrane apposition , 2011, Nature Structural &Molecular Biology.

[155]  D. Featherstone,et al.  Membrane Penetration by Synaptotagmin Is Required for Coupling Calcium Binding to Vesicle Fusion In Vivo , 2011, The Journal of Neuroscience.

[156]  E. Chapman,et al.  Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+ , 2008, Nature Structural &Molecular Biology.

[157]  Frédéric Pincet,et al.  SNARE Proteins: One to Fuse and Three to Keep the Nascent Fusion Pore Open , 2012, Science.

[158]  J. Dittman,et al.  Complexin Has Opposite Effects on Two Modes of Synaptic Vesicle Fusion , 2011, Current Biology.

[159]  M. Verhage,et al.  Munc18‐1 mutations that strongly impair SNARE‐complex binding support normal synaptic transmission , 2012, The EMBO journal.

[160]  Patricia Grob,et al.  Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion , 2012, eLife.

[161]  S. Boxer,et al.  Effects of linker sequences on vesicle fusion mediated by lipid-anchored DNA oligonucleotides , 2009, Proceedings of the National Academy of Sciences.

[162]  W. Xiao,et al.  The neuronal t-SNARE complex is a parallel four-helix bundle , 2001, Nature Structural Biology.

[163]  J. Rizo,et al.  A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release. , 2007, Journal of molecular biology.

[164]  Y. Shin,et al.  The importance of an asymmetric distribution of acidic lipids for synaptotagmin 1 function as a Ca2+ sensor. , 2012, The Biochemical journal.

[165]  Nils Brose,et al.  Distinct domains of Complexin I differentially regulate neurotransmitter release , 2007, Nature Structural &Molecular Biology.

[166]  K. Schulten,et al.  Fusion pore formation and expansion induced by Ca2+ and synaptotagmin 1 , 2013, Proceedings of the National Academy of Sciences.

[167]  Thomas C. Südhof,et al.  Complexins Regulate a Late Step in Ca2+-Dependent Neurotransmitter Release , 2001, Cell.

[168]  Xiaodong Zhang,et al.  Ca2+-Dependent Synaptotagmin Binding to SNAP-25 Is Essential for Ca2+-Triggered Exocytosis , 2002, Neuron.

[169]  T. Südhof,et al.  Solution structures of the Ca2+-free and Ca2+-bound C2A domain of synaptotagmin I: does Ca2+ induce a conformational change? , 1998, Biochemistry.

[170]  W. Regehr.  Short-term presynaptic plasticity. , 2012, Cold Spring Harbor perspectives in biology.

[171]  Dirk Fasshauer,et al.  Munc18a controls SNARE assembly through its interaction with the syntaxin N‐peptide , 2008, The EMBO journal.

[172]  J. Rizo,et al.  Synaptic vesicle fusion , 2008, Nature Structural &Molecular Biology.

[173]  J. Malsam,et al.  A role of complexin–lipid interactions in membrane fusion , 2009, FEBS letters.

[174]  T. Südhof,et al.  Titration of Syntaxin1 in Mammalian Synapses Reveals Multiple Roles in Vesicle Docking, Priming, and Release Probability , 2013, The Journal of Neuroscience.

[175]  Christian Rosenmund,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to 12 Tables S1 and S2 References and Notes Conformational Switch of Syntaxin-1 Controls Synaptic Vesicle Fusion , 2022 .

[176]  Y. Shin,et al.  Multiple conformations of a single SNAREpin between two nanodisc membranes reveal diverse pre-fusion states. , 2014, The Biochemical journal.

[177]  Shigeki Watanabe,et al.  Open Syntaxin Docks Synaptic Vesicles , 2007, PLoS biology.

[178]  C. Schwieters,et al.  Solution and membrane-bound conformations of the tandem C2A and C2B domains of synaptotagmin 1: Evidence for bilayer bridging. , 2009, Journal of molecular biology.

[179]  R. Jahn,et al.  Membrane Fusion Intermediates via Directional and Full Assembly of the SNARE Complex , 2012, Science.

[180]  O. Pascual,et al.  A common molecular basis for membrane docking and functional priming of synaptic vesicles , 2009, The European journal of neuroscience.

[181]  Subhas Banerjee,et al.  Apobec-1 Interacts with a 65-kDa Complementing Protein to Edit Apolipoprotein-B mRNA in Vitro * , 1996, The Journal of Biological Chemistry.

[182]  J. Littleton,et al.  A complexin fusion clamp regulates spontaneous neurotransmitter release and synaptic growth , 2007, Nature Neuroscience.

[183]  L. Lian,et al.  Binding of UNC-18 to the N-terminus of syntaxin is essential for neurotransmission in Caenorhabditis elegans. , 2009, The Biochemical journal.

[184]  S. Sprang,et al.  Structure of the first C2 domain of synaptotagmin I: A novel Ca2+/phospholipid-binding fold , 1995, Cell.

[185]  T. Südhof,et al.  Mechanism of phospholipid binding by the C2A-domain of synaptotagmin I. , 1998, Biochemistry.

[186]  W. Wickner.  Membrane fusion: five lipids, four SNAREs, three chaperones, two nucleotides, and a Rab, all dancing in a ring on yeast vacuoles. , 2010, Annual review of cell and developmental biology.