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SNAREs — engines for membrane fusion

Key Points

  • SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) form a superfamily of small fusion proteins that are each characterized by a conserved domain termed the SNARE motif, a membrane-anchor domain and a more variable N-terminal domain.

  • SNAREs mediate membrane fusion through the spontaneous assembly of four complementary SNARE motifs. The assembly process leads to a tight connection between the fusing membranes and initiates membrane fusion.

  • SNARE assembly and disassembly are complex multistep reactions that are subject to several layers of regulation. These steps include: the control of SNARE reactivity in the membrane; the formation of SNARE subcomplexes that function as acceptors for the final assembly step; trans-SNARE complexes that bridge the opposing membranes before fusion; and the disassembly of SNARE complexes by the AAA+ (ATPases associated with various cellular activities) protein NSF (N-ethylmaleimide-sensitive factor).

  • Accessory proteins, such as SM (Sec1/Munc18-related) proteins, synaptotagmins and complexins, regulate parts of the SNARE cycle. Some of these proteins are conserved and seem to function on many SNAREs, whereas others seem to be specific for a few SNAREs. In most cases, their mechanism of action is only partially clear.

  • SNAREs function in all fusion reactions of the secretory pathway. Some function in only one trafficking step, whereas others are less specialized, which provides a healthy mix of robustness and flexibility.

Abstract

Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.

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Figure 1: The structures of SNAREs.
Figure 2: SNARE core complexes.
Figure 3: The SNARE conformational cycle during vesicle docking and fusion.
Figure 4: Hypothetical transition states in SNARE-mediated fusion according to the stalk hypothesis.
Figure 5: The assignment of SNAREs to intracellular membrane-trafficking pathways.

References

  1. Bonifacino, J. S. & Glick, B. S. The mechanisms of vesicle budding and fusion. Cell 116, 153–166 (2004).

    CAS  PubMed  Google Scholar 

  2. Hong, W. SNAREs and traffic. Biochim. Biophys. Acta 1744, 120–144 (2005).

    CAS  PubMed  Google Scholar 

  3. Fasshauer, D. Structural insights into the SNARE mechanism. Biochim. Biophys. Acta 1641, 87–97 (2003).

    CAS  PubMed  Google Scholar 

  4. Brunger, A. T. Structure and function of SNARE and SNARE-interacting proteins. Q. Rev. Biophys. 38, 1–47 (2005).

    CAS  PubMed  Google Scholar 

  5. Rossi, V. et al. Longins and their longin domains: regulated SNAREs and multifunctional SNARE regulators. Trends Biochem. Sci. 29, 682–688 (2004).

    CAS  PubMed  Google Scholar 

  6. McNew, J. A. et al. Ykt6p, a prenylated SNARE essential for endoplasmic reticulum–Golgi transport. J. Biol. Chem. 272, 17776–17783 (1997).

    CAS  PubMed  Google Scholar 

  7. Valdez-Taubas, J. & Pelham, H. Swf1-dependent palmitoylation of the SNARE Tlg1 prevents its ubiquitination and degradation. EMBO J. 24, 2524–2532 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Söllner, T., Bennett, M. K., Whiteheart, S. W., Scheller, R. H. & Rothman, J. E. A protein assembly–disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75, 409–418 (1993). Shows that ATP cleavage by NSF is associated with the disassembly of a pre-existing SNARE complex, providing the first direct evidence for the existence of an assembly–disassembly cycle that underlies membrane fusion.

    PubMed  Google Scholar 

  9. McNew, J. A. et al. Compartmental specificity of cellular membrane fusion encoded in SNARE proteins. Nature 407, 153–159 (2000).

    CAS  PubMed  Google Scholar 

  10. Lewis, M. J., Rayner, J. C. & Pelham, H. R. A novel SNARE complex implicated in vesicle fusion with the endoplasmic reticulum. EMBO J. 16, 3017–3024 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Dilcher, M. et al. Use1p is a yeast SNARE protein required for retrograde traffic to the ER. EMBO J. 22, 3664–3674 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Burri, L. et al. A SNARE required for retrograde transport to the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 100, 9873–9877 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sutton, R. B., Fasshauer, D., Jahn, R. & Brunger, A. T. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution. Nature 395, 347–353 (1998). The first high-resolution structure of a SNARE complex.

    CAS  PubMed  Google Scholar 

  14. Antonin, W., Fasshauer, D., Becker, S., Jahn, R. & Schneider, T. R. Crystal structure of the endosomal SNARE complex reveals common structural principles of all SNAREs. Nature Struct. Biol. 9, 107–111 (2002).

    CAS  PubMed  Google Scholar 

  15. Fasshauer, D., Sutton, R. B., Brunger, A. T. & Jahn, R. Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs. Proc. Natl Acad. Sci. USA 95, 15781–15786 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bock, J. B., Matern, H. T., Peden, A. A. & Scheller, R. H. A genomic perspective on membrane compartment organization. Nature 409, 839–841 (2001).

    CAS  PubMed  Google Scholar 

  17. Misura, K. M., Scheller, R. H. & Weis, W. I. Self-association of the H3 region of syntaxin 1A. Implications for intermediates in SNARE complex assembly. J. Biol. Chem. 276, 13273–13282 (2001).

    CAS  PubMed  Google Scholar 

  18. Misura, K. M., Gonzalez, L. C. Jr, May, A. P., Scheller, R. H. & Weis, W. I. Crystal structure and biophysical properties of a complex between the N-terminal SNARE region of SNAP25 and syntaxin 1a. J. Biol. Chem. 276, 41301–41309 (2001).

    CAS  PubMed  Google Scholar 

  19. Margittai, M., Fasshauer, D., Pabst, S., Jahn, R. & Langen, R. Homo- and heterooligomeric SNARE complexes studied by site-directed spin labeling. J. Biol. Chem. 276, 13169–13177 (2001).

    CAS  PubMed  Google Scholar 

  20. Zhang, F., Chen, Y., Kweon, D. H., Kim, C. S. & Shin, Y. K. The four-helix bundle of the neuronal target membrane SNARE complex is neither disordered in the middle nor uncoiled at the C-terminal region. J. Biol. Chem. 277, 24294–24298 (2002).

    CAS  PubMed  Google Scholar 

  21. Weninger, K., Bowen, M. E., Chu, S. & Brunger, A. T. Single-molecule studies of SNARE complex assembly reveal parallel and antiparallel configurations. Proc. Natl Acad. Sci. USA 100, 14800–14805 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Dennison, S. M., Bowen, M. E., Brunger, A. T. & Lentz, B. Neuronal SNAREs do not trigger fusion between synthetic membranes but do promote PEG-mediated membrane fusion. Biophys. J. 90, 1661–1675 (2006).

    CAS  PubMed  Google Scholar 

  23. Misura, K. M., Bock, J. B., Gonzalez, L. C. Jr, Scheller, R. H. & Weis, W. I. Three-dimensional structure of the amino-terminal domain of syntaxin 6, a SNAP-25 C homolog. Proc. Natl Acad. Sci. USA 99, 9184–9189 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Dietrich, L. E., Boeddinghaus, C., Lagrassa, T. J. & Ungermann, C. Control of eukaryotic membrane fusion by N-terminal domains of SNARE proteins. Biochim. Biophys. Acta 1641, 111–119 (2003).

    CAS  PubMed  Google Scholar 

  25. Gonzalez, L. C., Weis, W. I. & Scheller, R. H. A novel SNARE N-terminal domain revealed by the crystal structure of Sec22b. J. Biol. Chem. 276, 24203–24211 (2001).

    CAS  PubMed  Google Scholar 

  26. Tochio, H., Tsui, M. M., Banfield, D. K. & Zhang, M. An autoinhibitory mechanism for nonsyntaxin SNARE proteins revealed by the structure of Ykt6p. Science 293, 698–702 (2001).

    CAS  PubMed  Google Scholar 

  27. Lu, J., Garcia, J., Dulubova, I., Sudhof, T. C. & Rizo, J. Solution structure of the Vam7p PX domain. Biochemistry 41, 5956–5962 (2002).

    CAS  PubMed  Google Scholar 

  28. Calakos, N., Bennett, M. K., Peterson, K. E. & Scheller, R. H. Protein–protein interactions contributing to the specificity of intracellular vesicular trafficking. Science 263, 1146–1149 (1994).

    CAS  PubMed  Google Scholar 

  29. Dulubova, I. et al. A conformational switch in syntaxin during exocytosis: role of munc18. EMBO J. 18, 4372–4382 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Toonen, R. F. & Verhage, M. Vesicle trafficking: pleasure and pain from SM genes. Trends Cell Biol. 13, 177–186 (2003).

    CAS  PubMed  Google Scholar 

  31. Dietrich, L. E., Gurezka, R., Veit, M. & Ungermann, C. The SNARE Ykt6 mediates protein palmitoylation during an early stage of homotypic vacuole fusion. EMBO J. 23, 45–53 (2004).

    CAS  PubMed  Google Scholar 

  32. Linder, M. E. & Deschenes, R. J. Model organisms lead the way to protein palmitoyltransferases. J. Cell Sci. 117, 521–526 (2004).

    CAS  PubMed  Google Scholar 

  33. Munson, M., Chen, X., Cocina, A. E., Schultz, S. M. & Hughson, F. M. Interactions within the yeast t-SNARE Sso1p that control SNARE complex assembly. Nature Struct. Biol. 7, 894–902 (2000).

    CAS  PubMed  Google Scholar 

  34. Van Komen, J. S., Bai, X., Scott, B. L. & McNew, J. A. An intramolecular t-SNARE complex functions in vivo without the syntaxin NH2-terminal regulatory domain. J. Cell Biol. 172, 295–307 (2006). Shows that the requirement for the N-terminal three-helix-bundle domain of a Qa-SNARE in S. cerevisiae exocytosis can be bypassed when Q-(t)-SNARE motifs are fused together.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Wang, Y., Dulubova, I., Rizo, J. & Südhof, T. C. Functional analysis of conserved structural elements in yeast syntaxin Vam3p. J. Biol. Chem. 276, 28598–28605 (2001).

    CAS  PubMed  Google Scholar 

  36. Südhof, T. C., De Camilli, P., Niemann, H. & Jahn, R. Membrane fusion machinery: insights from synaptic proteins. Cell 75, 1–4 (1993).

    PubMed  Google Scholar 

  37. Pelham, H. R., Banfield, D. K. & Lewis, M. J. SNAREs involved in traffic through the Golgi complex. Cold Spring Harb. Symp. Quant. Biol. 60, 105–111 (1995).

    CAS  PubMed  Google Scholar 

  38. Mayer, A., Wickner, W. & Haas, A. Sec18p (NSF)-driven release of Sec17p (α-SNAP) can precede docking and fusion of yeast vacuoles. Cell 85, 83–94 (1996). By studying the in vitro fusion of vacuoles, these authors show that NSF is not needed for fusion but functions as an activation or priming factor.

    CAS  PubMed  Google Scholar 

  39. Hanson, P. I., Roth, R., Morisaki, H., Jahn, R. & Heuser, J. E. Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick-freeze/deep-etch electron microscopy. Cell 90, 523–535 (1997).

    CAS  PubMed  Google Scholar 

  40. Lin, R. C. & Scheller, R. H. Structural organization of the synaptic exocytosis core complex. Neuron 19, 1087–1094 (1997). References 39 and 40 show that neuronal SNAREs are aligned in parallel in the SNARE complex, which led to the proposal of the 'zippering' hypothesis of SNARE function.

    CAS  PubMed  Google Scholar 

  41. Pennuto, M., Bonanomi, D., Benfenati, F. & Valtorta, F. Synaptophysin I controls the targeting of VAMP2/synaptobrevin II to synaptic vesicles. Mol. Biol. Cell 14, 4909–4919 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Mossessova, E., Bickford, L. C. & Goldberg, J. SNARE selectivity of the COPII coat. Cell 114, 483–495 (2003).

    CAS  PubMed  Google Scholar 

  43. Peden, A. A., Park, G. Y. & Scheller, R. H. The di-leucine motif of vesicle-associated membrane protein 4 is required for its localization and AP-1 binding. J. Biol. Chem. 276, 49183–49187 (2001).

    CAS  PubMed  Google Scholar 

  44. Siniossoglou, S. & Pelham, H. R. An effector of Ypt6p binds the SNARE Tlg1p and mediates selective fusion of vesicles with late Golgi membranes. EMBO J. 20, 5991–5998 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Collins, K. M., Thorngren, N. L., Fratti, R. A. & Wickner, W. T. Sec17p and HOPS, in distinct SNARE complexes, mediate SNARE complex disruption or assembly for fusion. EMBO J. 24, 1775–1786 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Kweon, D. H., Kim, C. S. & Shin, Y. K. The membrane-dipped neuronal SNARE complex: a site-directed spin labeling electron paramagnetic resonance study. Biochemistry 41, 9264–9268 (2002).

    CAS  PubMed  Google Scholar 

  47. Hu, K. et al. Vesicular restriction of synaptobrevin suggests a role for calcium in membrane fusion. Nature 415, 646–650 (2002).

    CAS  PubMed  Google Scholar 

  48. Nevins, A. K. & Thurmond, D. C. A direct interaction between Cdc42 and vesicle-associated membrane protein 2 regulates SNARE-dependent insulin exocytosis. J. Biol. Chem. 28, 1944–1952 (2004).

    Google Scholar 

  49. Lang, T., Margittai, M., Holzler, H. & Jahn, R. SNAREs in native plasma membranes are active and readily form core complexes with endogenous and exogenous SNAREs. J. Cell Biol. 158, 751–760 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Walch-Solimena, C. et al. The t-SNAREs syntaxin 1 and SNAP-25 are present on organelles that participate in synaptic vesicle recycling. J. Cell Biol. 128, 637–645 (1995).

    CAS  PubMed  Google Scholar 

  51. Lang, T. et al. SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J. 20, 2202–2213 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Chamberlain, L. H., Burgoyne, R. D. & Gould, G. W. SNARE proteins are highly enriched in lipid rafts in PC12 cells: implications for the spatial control of exocytosis. Proc. Natl Acad. Sci. USA 98, 5619–5624 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Predescu, S. A., Predescu, D. N., Shimizu, K., Klein, I. K. & Malik, A. B. Cholesterol-dependent syntaxin-4 and SNAP-23 clustering regulates caveolae fusion with the endothelial plasma membrane. J. Biol. Chem. 280, 37130–37138 (2005).

    CAS  PubMed  Google Scholar 

  54. Laage, R., Rohde, J., Brosig, B. & Langosch, D. A conserved membrane-spanning amino acid motif drives homomeric and supports heteromeric assembly of presynaptic SNARE proteins. J. Biol. Chem. 275, 17481–17487 (2000).

    CAS  PubMed  Google Scholar 

  55. Fiebig, K. M., Rice, L. M., Pollock, E. & Brunger, A. T. Folding intermediates of SNARE complex assembly. Nature Struct. Biol. 6, 117–123 (1999).

    CAS  PubMed  Google Scholar 

  56. Fasshauer, D. & Margittai, M. A transient N-terminal interaction of SNAP-25 and syntaxin nucleates SNARE assembly. J. Biol. Chem. 279, 7613–7621 (2004).

    CAS  PubMed  Google Scholar 

  57. Nicholson, K. L. et al. Regulation of SNARE complex assembly by an N-terminal domain of the t-SNARE Sso1p. Nature Struct. Biol. 5, 793–802 (1998).

    CAS  PubMed  Google Scholar 

  58. Peng, R. & Gallwitz, D. Sly1 protein bound to Golgi syntaxin Sed5p allows assembly and contributes to specificity of SNARE fusion complexes. J. Cell Biol. 157, 645–655 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Bryant, N. J. & James, D. E. Vps45p stabilizes the syntaxin homologue Tlg2p and positively regulates SNARE complex formation. EMBO J. 20, 3380–3388 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Misura, K. M., May, A. P. & Weis, W. I. Protein–protein interactions in intracellular membrane fusion. Curr. Opin. Struct. Biol. 10, 662–671 (2000).

    CAS  PubMed  Google Scholar 

  61. Weimer, R. M. et al. Defects in synaptic vesicle docking in unc-18 mutants. Nature Neurosci. 6, 1023–1030 (2003).

    CAS  PubMed  Google Scholar 

  62. Voets, T. et al. Munc18-1 promotes large dense-core vesicle docking. Neuron 31, 581–591 (2001).

    CAS  PubMed  Google Scholar 

  63. Grote, E., Carr, C. M. & Novick, P. J. Ordering the final events in yeast exocytosis. J. Cell Biol. 151, 439–452 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  64. An, S. J. & Almers, W. Tracking SNARE complex formation in live endocrine cells. Science 306, 1042–1046 (2004).

    CAS  PubMed  Google Scholar 

  65. Chen, Y. A., Scales, S. J. & Scheller, R. H. Sequential SNARE assembly underlies priming and triggering of exocytosis. Neuron 30, 161–170 (2001).

    CAS  PubMed  Google Scholar 

  66. Kraynack, B. A. et al. Dsl1p, Tip20p, and the novel Dsl3(Sec39) protein are required for the stability of the Q/t-SNARE complex at the endoplasmic reticulum in yeast. Mol. Biol. Cell 16, 3963–3977 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Hatsuzawa, K., Lang, T., Fasshauer, D., Bruns, D. & Jahn, R. The R-SNARE motif of tomosyn forms SNARE core complexes with syntaxin 1 and SNAP-25 and down-regulates exocytosis. J. Biol. Chem. 278, 31159–31166 (2003).

    CAS  PubMed  Google Scholar 

  68. Sakisaka, T. et al. Regulation of SNAREs by tomosyn and ROCK: implication in extension and retraction of neurites. J. Cell Biol. 166, 17–25 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Pobbati, A. V., Razeto, A., Boddener, M., Becker, S. & Fasshauer, D. Structural basis for the inhibitory role of tomosyn in exocytosis. J. Biol. Chem. 279, 47192–47200 (2004).

    CAS  PubMed  Google Scholar 

  70. Scales, S. J., Hesser, B. A., Masuda, E. S. & Scheller, R. H. Amisyn, a novel syntaxin-binding protein that may regulate SNARE complex assembly. J. Biol. Chem. 277, 28271–28279 (2002).

    CAS  PubMed  Google Scholar 

  71. Echarri, A., Lai, M. J., Robinson, M. R. & Pendergast, A. M. Abl interactor 1 (Abi-1) wave-binding and SNARE domains regulate its nucleocytoplasmic shuttling, lamellipodium localization, and wave-1 levels. Mol. Cell. Biol. 24, 4979–4993 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Nichols, B. J., Ungermann, C., Pelham, H. R., Wickner, W. T. & Haas, A. Homotypic vacuolar fusion mediated by t- and v-SNAREs. Nature 387, 199–202 (1997). By studying the in vitro fusion of vacuoles as a model, this work shows that fusion requires an interaction between complementary sets of SNAREs in the fusing membranes.

    CAS  PubMed  Google Scholar 

  73. Chen, Y. A., Scales, S. J., Patel, S. M., Doung, Y. C. & Scheller, R. H. SNARE complex formation is triggered by Ca2+ and drives membrane fusion. Cell 97, 165–174 (1999).

    CAS  PubMed  Google Scholar 

  74. Sørensen, J. B. Formation, stabilisation and fusion of the readily releasable pool of secretory vesicles. Pflugers Arch. 448, 347–362 (2004).

    PubMed  Google Scholar 

  75. Borisovska, M. et al. v-SNAREs control exocytosis of vesicles from priming to fusion. EMBO J. 24, 2114–2126 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Chapman, E. R. Synaptotagmin: a Ca2+ sensor that triggers exocytosis? Nature Rev. Mol. Cell Biol. 3, 498–508 (2002).

    CAS  Google Scholar 

  77. Südhof, T. C. The synaptic vesicle cycle. Annu. Rev. Neurosci. 27, 509–547 (2004).

    PubMed  Google Scholar 

  78. Südhof, T. C. Synaptotagmins: why so many? J. Biol. Chem. 277, 7629–7632 (2002).

    PubMed  Google Scholar 

  79. Reim, K. et al. Complexins regulate a late step in Ca2+-dependent neurotransmitter release. Cell 104, 71–81 (2001).

    CAS  PubMed  Google Scholar 

  80. Chen, X. et al. Three-dimensional structure of the complexin/SNARE complex. Neuron 33, 397–409 (2002).

    CAS  PubMed  Google Scholar 

  81. Jahn, R. & Grubmuller, H. Membrane fusion. Curr. Opin. Cell Biol. 14, 488–495 (2002).

    CAS  PubMed  Google Scholar 

  82. Chernomordik, L. V. & Kozlov, M. M. Protein–lipid interplay in fusion and fission of biological membranes. Annu. Rev. Biochem. 72, 175–207 (2003).

    CAS  PubMed  Google Scholar 

  83. Kiessling, V. & Tamm, L. K. Measuring distances in supported bilayers by fluorescence interference-contrast microscopy: polymer supports and SNARE proteins. Biophys. J. 84, 408–418 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Knecht, V. & Grubmüller, H. Mechanical coupling via the membrane fusion SNARE protein syntaxin 1A: a molecular dynamics study. Biophys. J. 84, 1527–1547 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Grote, E., Baba, M., Ohsumi, Y. & Novick, P. J. Geranylgeranylated SNAREs are dominant inhibitors of membrane fusion. J. Cell Biol. 151, 453–466 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  86. McNew, J. A., Weber, T., Engelman, D. M., Söllner, T. H. & Rothman, J. E. The length of the flexible SNAREpin juxtamembrane region is a critical determinant of SNARE-dependent fusion. Mol. Cell 4, 415–421 (1999).

    CAS  PubMed  Google Scholar 

  87. Montecucco, C., Schiavo, G. & Pantano, S. SNARE complexes and neuroexocytosis: how many, how close? Trends Biochem. Sci. 30, 367–372 (2005).

    CAS  PubMed  Google Scholar 

  88. Xu, Y., Zhang, F., Su, Z., McNew, J. A. & Shin, Y. K. Hemifusion in SNARE-mediated membrane fusion. Nature Struct. Mol. Biol. 12, 417–422 (2005).

    CAS  Google Scholar 

  89. Reese, C., Heise, F. & Mayer, A. Trans-SNARE pairing can precede a hemifusion intermediate in intracellular membrane fusion. Nature 436, 410–414 (2005).

    CAS  PubMed  Google Scholar 

  90. Giraudo, C. G. et al. SNAREs can promote complete fusion and hemifusion as alternative outcomes. J. Cell Biol. 170, 249–260 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Bentz, J. Membrane fusion mediated by coiled coils: a hypothesis. Biophys. J. 78, 886–900 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Langosch, D. et al. Peptide mimics of SNARE transmembrane segments drive membrane fusion depending on their conformational plasticity. J. Mol. Biol. 311, 709–721 (2001).

    CAS  PubMed  Google Scholar 

  93. Nelson, N. A journey from mammals to yeast with vacuolar H+-ATPase (V-ATPase). J. Bioenerg. Biomembr. 35, 281–289 (2003).

    CAS  PubMed  Google Scholar 

  94. Mayer, A. Membrane fusion in eukaryotic cells. Annu. Rev. Cell Dev. Biol. 18, 289–314 (2002).

    CAS  PubMed  Google Scholar 

  95. Hiesinger, P. R. et al. The v-ATPase V0 subunit a1 is required for a late step in synaptic vesicle exocytosis in Drosophila. Cell 121, 607–620 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Peters, C. et al. Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion. Nature 409, 581–588 (2001).

    CAS  PubMed  Google Scholar 

  97. Bayer, M. J., Reese, C., Buhler, S., Peters, C. & Mayer, A. Vacuole membrane fusion: V0 functions after trans-SNARE pairing and is coupled to the Ca2+-releasing channel. J. Cell Biol. 162, 211–222 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Hanson, P. I. & Whiteheart, S. W. AAA+ proteins: have engine, will work. Nature Rev. Mol. Cell Biol. 6, 519–529 (2005).

    CAS  Google Scholar 

  99. Fasshauer, D., Antonin, W., Subramaniam, V. & Jahn, R. SNARE assembly and disassembly exhibit a pronounced hysteresis. Nature Struct. Biol. 9, 144–151 (2002).

    CAS  PubMed  Google Scholar 

  100. Marz, K. E., Lauer, J. M. & Hanson, P. I. Defining the SNARE complex binding surface of α-SNAP: implications for SNARE complex disassembly. J. Biol. Chem. 278, 27000–27008 (2003).

    CAS  PubMed  Google Scholar 

  101. Scales, S. J., Yoo, B. Y. & Scheller, R. H. The ionic layer is required for efficient dissociation of the SNARE complex by α-SNAP and NSF. Proc. Natl Acad. Sci. USA 98, 14262–14267 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Martin, A., Baker, T. A. & Sauer, R. T. Rebuilt AAA+ motors reveal operating principles for ATP-fuelled machines. Nature 437, 1115–1120 (2005).

    CAS  PubMed  Google Scholar 

  103. Hanson, P. I., Otto, H., Barton, N. & Jahn, R. The N-ethylmaleimide-sensitive fusion protein and α-SNAP induce a conformational change in syntaxin. J. Biol. Chem. 270, 16955–16961 (1995).

    CAS  PubMed  Google Scholar 

  104. McMahon, H. T. & Südhof, T. C. Synaptic core complex of synaptobrevin, syntaxin, and SNAP25 forms high affinity α-SNAP binding site. J. Biol. Chem. 270, 2213–2217 (1995).

    CAS  PubMed  Google Scholar 

  105. Wickner, W. & Haas, A. Yeast homotypic vacuole fusion: a window on organelle trafficking mechanisms. Annu. Rev. Biochem. 69, 247–275 (2000).

    CAS  PubMed  Google Scholar 

  106. Ungermann, C. & Langosch, D. Functions of SNAREs in intracellular membrane fusion and lipid bilayer mixing. J. Cell Sci. 118, 3819–3828 (2005).

    CAS  PubMed  Google Scholar 

  107. Sogaard, M. et al. A rab protein is required for the assembly of SNARE complexes in the docking of transport vesicles. Cell 78, 937–948 (1994).

    CAS  PubMed  Google Scholar 

  108. Littleton, J. T. et al. Temperature-sensitive paralytic mutations demonstrate that synaptic exocytosis requires SNARE complex assembly and disassembly. Neuron 21, 401–413 (1998).

    CAS  PubMed  Google Scholar 

  109. Hay, J. C. et al. Localization, dynamics, and protein interactions reveal distinct roles for ER and Golgi SNAREs. J. Cell Biol. 141, 1489–1502 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Cao, X. & Barlowe, C. Asymmetric requirements for a Rab GTPase and SNARE proteins in fusion of COPII vesicles with acceptor membranes. J. Cell Biol. 149, 55–66 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Antonin, W., Holroyd, C., Tikkanen, R., Honing, S. & Jahn, R. The R-SNARE endobrevin/VAMP-8 mediates homotypic fusion of early endosomes and late endosomes. Mol. Biol. Cell 11, 3289–3298 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  112. West, A. E., Neve, R. L. & Buckley, K. M. Targeting of the synaptic vesicle protein synaptobrevin in the axon of cultured hippocampal neurons: evidence for two distinct sorting steps. J. Cell Biol. 139, 917–927 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Zeng, Q., Tran, T. T., Tan, H. X. & Hong, W. The cytoplasmic domain of Vamp4 and Vamp5 is responsible for their correct subcellular targeting: the N-terminal extension of Vamp4 contains a dominant autonomous targeting signal for the trans-Golgi network. J. Biol. Chem. 278, 23046–23054 (2003).

    CAS  PubMed  Google Scholar 

  114. Grote, E., Hao, J. C., Bennett, M. K. & Kelly, R. B. A targeting signal in VAMP regulating transport to synaptic vesicles. Cell 81, 581–589 (1995).

    CAS  PubMed  Google Scholar 

  115. Pfeffer, S. & Aivazian, D. Targeting Rab GTPases to distinct membrane compartments. Nature Rev. Mol. Cell Biol. 5, 886–896 (2004).

    CAS  Google Scholar 

  116. Fasshauer, D., Antonin, W., Margittai, M., Pabst, S. & Jahn, R. Mixed and non-cognate SNARE complexes. Characterization of assembly and biophysical properties. J. Biol. Chem. 274, 15440–15446 (1999).

    CAS  PubMed  Google Scholar 

  117. Yang, B. et al. SNARE interactions are not selective. Implications for membrane fusion specificity. J. Biol. Chem. 274, 5649–5653 (1999).

    CAS  PubMed  Google Scholar 

  118. Parlati, F. et al. Topological restriction of SNARE-dependent membrane fusion. Nature 407, 194–198 (2000).

    CAS  PubMed  Google Scholar 

  119. Paumet, F., Rahimian, V. & Rothman, J. E. The specificity of SNARE-dependent fusion is encoded in the SNARE motif. Proc. Natl Acad. Sci. USA 101, 3376–3380 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Brandhorst, D. et al. Homotypic fusion of early endosomes: SNAREs do not determine fusion specificity. Proc. Natl Acad. Sci. USA 103, 2701–2706 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Liu, Y. & Barlowe, C. Analysis of Sec22p in endoplasmic reticulum/Golgi transport reveals cellular redundancy in SNARE protein function. Mol. Biol. Cell 13, 3314–3324 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Sørensen, J. B. et al. Differential control of the releasable vesicle pools by SNAP-25 splice variants and SNAP-23. Cell 114, 75–86 (2003).

    PubMed  Google Scholar 

  123. Fischer von Mollard, G. & Stevens, T. H. The Saccharomyces cerevisiae v-SNARE Vti1p is required for multiple membrane transport pathways to the vacuole. Mol. Biol. Cell 10, 1719–1732 (1999).

    CAS  PubMed  Google Scholar 

  124. Tsui, M. M. & Banfield, D. K. Yeast Golgi SNARE interactions are promiscuous. J. Cell Sci. 113, 145–152 (2000).

    CAS  PubMed  Google Scholar 

  125. Antonin, W. et al. A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function. EMBO J. 19, 6453–6464 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Wang, C. C. et al. A role of VAMP8/endobrevin in regulated exocytosis of pancreatic acinar cells. Dev.Cell 7, 359–371 (2004).

    CAS  PubMed  Google Scholar 

  127. Scales, S. J. et al. SNAREs contribute to the specificity of membrane fusion. Neuron 26, 457–464 (2000).

    CAS  PubMed  Google Scholar 

  128. Link, E. et al. Cleavage of cellubrevin by tetanus toxin does not affect fusion of early endosomes. J. Biol. Chem. 268, 18423–18426 (1993).

    CAS  PubMed  Google Scholar 

  129. Weber, T. et al. SNAREpins: minimal machinery for membrane fusion. Cell 92, 759–772 (1998). Shows that SNAREs that are reconstituted into proteoliposomes are capable of fusing membranes without the need for other factors.

    CAS  PubMed  Google Scholar 

  130. Schuette, C. G. et al. Determinants of liposome fusion mediated by synaptic SNARE proteins. Proc. Natl Acad. Sci. USA 101, 2858–2863 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Tucker, W. C., Weber, T. & Chapman, E. R. Reconstitution of Ca2+-regulated membrane fusion by synaptotagmin and SNAREs. Science 304, 435–438 (2004).

    CAS  PubMed  Google Scholar 

  132. Mahal, L. K., Sequeira, S. M., Gureasko, J. M. & Söllner, T. H. Calcium-independent stimulation of membrane fusion and SNAREpin formation by synaptotagmin I. J. Cell Biol. 158, 273–282 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Chen, X. et al. SNARE-mediated lipid mixing depends on the physical state of the vesicles. Biophys. J. 90, 2062–2074 (2005).

    PubMed Central  PubMed  Google Scholar 

  134. Fix, M. et al. Imaging single membrane fusion events mediated by SNARE proteins. Proc. Natl Acad. Sci. USA 101, 7311–7316 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Bowen, M. E., Weninger, K., Brunger, A. T. & Chu, S. Single molecule observation of liposome-bilayer fusion thermally induced by soluble N-ethyl maleimide sensitive-factor attachment protein receptors (SNAREs). Biophys. J. 87, 3569–3584 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Liu, T., Tucker, W. C., Bhalla, A., Chapman, E. R. & Weisshaar, J. C. SNARE-driven, 25-millisecond vesicle fusion in vitro. Biophys. J. 89, 2473–2480 (2005).

    Google Scholar 

  137. Lerman, J. C., Robblee, J., Fairman, R. & Hughson, F. M. Structural analysis of the neuronal SNARE protein syntaxin-1A. Biochemistry 39, 8470–8479 (2000).

    CAS  PubMed  Google Scholar 

  138. Misura, K. M., Scheller, R. H. & Weis, W. I. Three-dimensional structure of the neuronal-Sec1–syntaxin 1a complex. Nature 404, 355–362 (2000).

    CAS  PubMed  Google Scholar 

  139. Novick, P., Field, C. & Schekman, R. Identification of 23 complementation groups required for post-translational events in the yeast secretory pathway. Cell 21, 205–215 (1980). Classical study in which many of the genes that are essential for various steps in the secretory pathway were identified for the first time.

    CAS  PubMed  Google Scholar 

  140. Eakle, K. A., Bernstein, M. & Emr, S. D. Characterization of a component of the yeast secretion machinery: identification of the SEC18 gene product. Mol. Cell. Biol. 8, 4098–4109 (1988).

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Wilson, D. W. et al. A fusion protein required for vesicle-mediated transport in both mammalian cells and yeast. Nature 339, 355–359 (1989).

    CAS  PubMed  Google Scholar 

  142. Clary, D. O., Griff, I. C. & Rothman, J. E. SNAPs, a family of NSF attachment proteins involved in intracellular membrane fusion in animals and yeast. Cell 61, 709–721 (1990). References 141 and 142 describe the first characterization of NSF and SNAPs, respectively, as soluble factors that are required for intracellular membrane-fusion reactions.

    CAS  PubMed  Google Scholar 

  143. Trimble, W. S., Cowan, D. M. & Scheller, R. H. VAMP-1: a synaptic vesicle-associated integral membrane protein. Proc. Natl Acad. Sci. USA 85, 4538–4542 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Baumert, M., Maycox, P. R., Navone, F., De Camilli, P. & Jahn, R. Synaptobrevin: an integral membrane protein of 18,000 daltons present in small synaptic vesicles of rat brain. EMBO J. 8, 379–384 (1989).

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Bennett, M. K., Calakos, N. & Scheller, R. H. Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257, 255–259 (1992).

    CAS  PubMed  Google Scholar 

  146. Dascher, C., Ossig, R., Gallwitz, D. & Schmitt, H. D. Identification and structure of four yeast genes (SLY) that are able to suppress the functional loss of YPT1, a member of the RAS superfamily. Mol. Cell. Biol. 11, 872–885 (1991).

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Gerst, J. E., Rodgers, L., Riggs, M. & Wigler, M. SNC1, a yeast homolog of the synaptic vesicle-associated membrane protein/synaptobrevin gene family: genetic interactions with the RAS and CAP genes. Proc. Natl Acad. Sci. USA 89, 4338–4342 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Bennett, M. K. & Scheller, R. H. The molecular machinery for secretion is conserved from yeast to neurons. Proc. Natl Acad. Sci. USA 90, 2559–2563 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Schiavo, G. et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359, 832–835 (1992). VAMP/synaptobrevin is shown to be proteolysed by the tetanus and botulinum neurotoxins. Together with references 150 and 151, this work shows that the toxins block membrane fusion by cleaving neuronal SNAREs.

    CAS  PubMed  Google Scholar 

  150. Blasi, J. et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365, 160–163 (1993).

    CAS  PubMed  Google Scholar 

  151. Blasi, J. et al. Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. EMBO J. 12, 4821–4828 (1993).

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Söllner, T. et al. SNAP receptors implicated in vesicle targeting and fusion. Nature 362, 318–324 (1993). The first identification of a complex of VAMP/synaptobrevin, SNAP-25 and syntaxin as a receptor for NSF and α-SNAP, and the introduction of the term SNARE.

    PubMed  Google Scholar 

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Acknowledgements

The authors are indebted to D. Fasshauer, E. Neher, S. Rizzoli and J. Sorensen for helpful comments and for critically reading the manuscript. We hope our colleagues will understand that, due to space limitations, only a fraction of the relevant work could be discussed. R.J. is supported by an award from the Gottfried Wilhelm Leibniz Program of the Deutsche Forschungsgemeinschaft and by a grant from the National Institutes of Health.

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Glossary

AAA+ proteins

('ATPases associated with various cellular activities' proteins). A superfamily of proteins with one or two nucleotide-binding domains, which often form ring-like oligomers and function as chaperones in diverse cellular processes. They can unfold aggregates or tightly packed structures.

Palmitoylation

A post-translational modification of proteins in which a palmitate fatty acyl chain is covalently attached to a cysteine side chain by a thioester bond.

CAAX box

A C-terminal motif of four amino acids — cysteine (C), two aliphatic amino acids (AA) and then any amino acid — (X) that is recognized as a substrate by farnesyltransferase and geranylgeranyltransferase I.

Farnesylation

A post-translational modification of proteins in which a 15-carbon farnesyl residue is covalently attached to the cysteine of a CAAX-box motif by a thioester bond.

Phox-homology (PX) domain

A conserved domain of 120 residues that is found in many proteins. PX domains preferably bind to phosphatidylinositol-3,4,5-trisphosphate, a polyphosphoinositide lipid that is enriched in endosomes and vacuoles.

COPII

(Coatomer protein complex-II). COPII assembles at the exit sites of the endoplasmic reticulum, which results in the formation of COPII-coated transport vesicles that are destined for the cis face of the Golgi apparatus or for an intermediate compartment.

Adaptor protein-1 (AP1) complex

The AP1 complex, which is one of four structurally related protein complexes, forms a bridge between the clathrin coat and membrane components (cargo) during the formation of clathrin-coated vesicles at the trans-Golgi network.

C2 domains

(Conserved region-2 of protein kinase C domains). Conserved and rigid domains that consist mainly of β-sheets and bind two to four Ca2+ ions. Their Ca2+ affinity is increased in the presence of acidic phospholipids, which leads to an association of C2 domains with membranes when the intracellular Ca2+ concentration rises.

Connexins

Connexins, and the related pannexins and invertebrate innexins, are oligomeric membrane proteins that are found in the plasma membrane. They can interact in trans to form gap-junction channels between two cells.

ClpA

A bacterial AAA+ (ATPases associated with various cellular activities) protein. It functions as an unfoldase that feeds its substrates into a tightly associated protease.

ClpX

A bacterial AAA+ (ATPases associated with various cellular activities) protein. It functions in a complex with an associated caseinolytic protease in a manner similar to ClpA.

Rab/Ypt (yeast protein transport) family

A family of Ras-related small GTPases. In their active GTP-bound form, members of this family can mediate the membrane attachment (tethering) of fusion partners through their interactions with specific effector proteins.

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Jahn, R., Scheller, R. SNAREs — engines for membrane fusion. Nat Rev Mol Cell Biol 7, 631–643 (2006). https://doi.org/10.1038/nrm2002

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