In Vivo Analysis of Membrane Fusion


Membranes provide a barrier that allows chemical reactions to be isolated from the environment. The plasma membrane, for example, delineates self from nonself, and thus must have played an essential role in the evolution of life. Yet under numerous circumstances it is equally important that membranes be breached. Numerous forces oppose the spontaneous fusion of membranes; thus, specialised proteins have evolved to fuse membranes. The most well‐understood fusion proteins are the viral fusion proteins and the SNARE proteins used in the secretory pathway. Recent discoveries have added to the list of fusogens for which necessity and sufficiency have been demonstrated. The list now includes the fusion family proteins, used in cell–cell fusion, and the dynamin‐related proteins, used in organelle fusion. Despite, the diverse structures of fusion proteins, it is likely that they all function to drive membranes through a series of common lipid intermediates. In this article, we review the mechanisms of fusion for biological membranes, and highlight the similarities and differences in these processes.

Key Concepts

  • Fusion proteins can be divided into three major classes: the secretory pathway uses SNARE proteins, cell–cell fusion uses proteins related to viral fusogens and organellar fusion is driven by dynamin‐related GTPases.
  • Fusion proteins are thought to lead membranes through the common set of lipid intermediates: lipid stalk, hemifusion diaphragm and pore formation.
  • Fusion proteins, either SNAREs or viral proteins, play an active role in all steps of the fusion process.
  • Multimerisation of fusogens improves efficiency and in many instances is a requirement for fusion.
  • Diverse proteins act as the fusogens in cell–cell fusion; many remain undiscovered.

Keywords: membrane fusion; virus; SNARE ; lipid; fusogen

Figure 1. Common lipid intermediates during fusion. The proximal leaflets of the plasma bilayers are brought into close proximity forming the hourglass‐like structure known as a lipid stalk. This stalk is then expanded forming a hemifusion diaphragm. In the hemifusion diaphragm the distal leaflets of the bilayer are now in direct contact. A rupture in the hemifusion diaphragm leads to the initial opening of a fusion pore that is then expanded leading to full fusion. The insert shows the shape of lysophosphatidylcholine (LPC), phosphatidylcholine (PC) and phosphatidylethanolamine (PE). LPC induces positive curvature, whereas PE induces negative curvature. Adding lipids with positive curvature to the proximal leaflets inhibits stalk formation (red lipid – ‘stalk’ and ‘two membranes’ steps). Adding lipids with positive curvature to the distal leaflets promotes fusion (red lipid – ‘pore step’). Arrowheads point to areas where the lipid must adopt a net negative curvature.
Figure 2. Viral fusion using the influenza HA fusion protein and the E fusion protein from flavivirus as the primary examples. Structural rearrangements of the E fusion protein from flavivirus are shown to illustrate commonalities and differences between type I and type II fusion proteins. (a) The influenza virus enters the host by being taken up through the endocytic pathway. On endocytosis, the acidic environment in the endosome activates the HA fusion proteins and the viral capsid is released into the cytoplasm. Structural rearrangements (detailed in c) lead to the fusion of viral and host membranes releasing the contents of the influenza virus into the cytoplasm. (b) While the primary sequence can vary widely, viral fusogens can clearly be classified into three structural classes – for simplicity only the postfusion trimers are shown. The illustrated examples are influenza HA (type I), tick‐borne encephalitis virus TBEV‐E (type II) and vesicular stomatitis virus VSV‐G (type III). Arrowheads indicate the position of the fusion‐peptides/fusion loops in the postfusion structures. Despite the structural differences, viral fusogens undergo many common rearrangements to catalyse fusion (compare c and d). (c and d) The schematics illustrate the rearrangements that HA and TBEV‐E undergo during fusion. Initially, HA and TBEV‐E are present only on the viral membrane (1). On activation, in this case by low pH, the fusion peptide (in red) is exposed and inserted into the host membrane (2). In the case of the type II E fusion protein, E dimer go through a monomeric state to then come together to form a trimer after low pH activation. By contrast, the type I HA fusion proteins exist as trimers before activation. The transition through a monomeric state is still controversial. After activation, the viral and host membranes are then brought into close proximity (3). Zippering of the HA and E proteins (in which the two ends of the fusion protein fold back on each other) induces lipid stalk formation in which the proximal leaflets of the membranes are fused (4). Full zippering induces pore formation, in which the distal leaflets have now become one (5). The postfusion HA and E proteins are left on the membranes of the host having accomplished their function – catalysing the release of the viral genome into the host cell (6). While they are based on experimental evidence, some individual rearrangements are by necessity hypothetical – for instance, the presence of a monomeric transition state in HA‐based fusion. Structures illustrated in (b) were rendered by Thien Vu.
Figure 3. Secretory vesicle fusion using neurotransmission as the example. (a) Synaptic vesicles fuse at synapses and release neurotransmitters into the synaptic cleft. SNARE proteins are present on synaptic vesicles (synaptobrevin – blue) and on the plasma membrane (syntaxin – red and SNAP25 – green). Structural rearrangements in the SNARE proteins are described in detail in (d). (b) The structure of the fully assembled SNARE complex. The example shown is of the SNAREs used in neurotransmission; however, fusion reactions in the secretory pathway all use related SNARE proteins. These proteins form a four‐helix bundle during fusion – the so‐called core complex. Syntaxin contains an additional inhibitory domain known as the Habc domain. (c) The four SNARE family members are characterised by conserved residues that face into the centre of the four‐helix bundle. Illustrated is a crosswise slice through the core complex showing the interactions between arginine on the R SNARE (synaptobrevin) and the three glutamines of the Qa‐SNARE (syntaxin) and the Qbc‐SNARE (SNAP25). In many fusion complexes the Qb and Qc helices are located on separate proteins rather than on a single molecule, as is the case with SNAP25. (d) Unlike viruses, SNAREs are initially located on both membranes destined to fuse (1). Before assembly into the core complex, the SNARE domains are unstructured except for syntaxin which adopts a closed confirmation where the inhibitory Habc domain folds over the SNARE motif. The plasma membrane SNAREs are thought to form an acceptor complex in which syntaxin and SNAP25 partially assemble (2). Synaptobrevin then joins the complex, by making initial contact at the ‐terminal membrane‐distal portion (3). The SNAREs become progressively more structured in an ‐ to ‐terminal direction as they zipper up. The zippering of the SNAREs pulls the proximal leaflets of the membranes together so that they fuse and form a lipid stalk (4). The continued zippering opens the initial fusion pore (5) – the distal leaflets of the membranes have now become one. Post fusion, all of the SNARE proteins are located in the plasma membrane (6). Like the viral fusogens, there is still considerable debate about the exact interaction of the SNAREs and the lipid membranes; thus, while the schematic diagram is based on experimental evidence, numerous individual rearrangements are by necessity hypothetical.
Figure 4. Cell–cell fusion reactions are catalysed by an assortment of unique fusion proteins. The cell–cell fusion reactions are divided into broad categories of those that sculpt organ and cell (left) and those that catalyse gamete fusion (right). The cell–cell fusogens of organ and cell sculpting are better understood – both EFF‐1 and the syncytins have been validated as fusogens. By contrast, the gamete fusogens are less well characterised. Indeed, at present, not a single gamete fusogen has been validated as function in heterologous systems. The gamete fusion molecules represent only the best guesses for the fusogen and in some case have instead been shown to play supporting roles (such as the tetraspanin molecules TET9, 11 and 12 used in ). (a) EFF‐1 is the primary cell–cell fusogen of , it was identified by virtue of its role in the formation of the hypodermis. The schematic represents a embryo at approximately the 1.5‐fold embryonic stage. At this stage the cells destined to become the hypodermis (shaded in purple) remain unfused. EFF‐1 mediates their eventual fusion. EFF‐1 catalyses homotypic fusion – it must be present on both membranes destined to fuse. It is initially upright in the membrane (Figure represents the structural rearrangements it undergoes during fusion). EFF‐1 is necessary and sufficient for fusion. (b) EFF‐1 also catalyses self fusion (that is, fusion of cell to self rather than fusion of cell to neighbour). This is dramatically illustrated in its role in sculpting the PVD neurons. (c) Along with EFF‐1 the other well understood fusion event is the cell–cell fusion underlying placental formation. Between child and mother, the placenta forms a large syncytium known as the syncytiotrophoblast. Mediating this large scale cell–cell fusion event is a class of fusogens, the syncytins, derived from endogenous retroviruses. Syncytins are structurally homologous to the type I viral fusogens. Moving to gamete fusion, (d) the best candidates for sperm–egg fusion in mammals are Izumo, localised on sperm, and its egg‐localised binding partner Juno. Izumo encodes a member of the immunoglobulin superfamily; Juno encodes a member of the folate receptor family. CD9 has also been experimentally linked to the fusion event. CD9 is a member of the tetraspanin superfamily. It is not known how Izumo, Juno and CD9 might catalyse fusion. (e) A more well conserved (and therefore more evolutionarily ancient) gamete fusion family are the asymmetrically localised HAP2/GSC1 proteins first identified in plants. Gamete fusion in involves two sperm being delivered via a pollen tube that enters the embryo sac. The two male gametes (sperm) fuse to the two female cells (egg and central cell). Like mammalian gamete fusion, tetraspanin molecules are also involved (TET9, 11 and 12); they are almost certainly acting to spatially organise a fusogen rather than being the fusogen themselves. (f) Yeast haploid cells fuse during mating. Molecules suggested to mediate yeast mating cell fusion are Prm1p, Fig1p and Fus1p. Prm1p is multipass membrane protein whose expression is induced by the mating pheromone. Fus1p is a single‐pass membrane protein in whose absence the fusion pore opening is delayed and inefficient. Fig1p is a multipass membrane protein. Fig1p fusion defects can be rescued by increasing calcium concentration.
Figure 5. EFF‐1 and syncytin – metazoan fusogens with viral origins. (a) The structure of EFF‐1 is strikingly similar to type II viral fusogens. The postfusion trimers of EFF‐1 and the simian foamy virus E1 fusogen are placed side by side for comparison (also compare to tick‐borne encephalitis virus TBEV‐E from Figure). Interestingly, EFF‐1 lacks the fusion‐loops (open arrowheads) that characterise type II viral fusogens (closed arrowheads). This is consistent with the observation that EFF‐1 is needed in both membranes destined to fuse unlike viral fusogens that begin life in a single membrane and need a mechanism to anchor to the host membrane. (b) The structure of syncytin is strikingly similar to type I viral fusogens. The postfusion trimers of syncytin 2 and the moloney murine leukaemia virus type I fusogen are shown for comparison (also compare to influenza HA from Figure). (c) Schematic of the structural intermediates that EFF‐1 undergoes during fusion. EFF‐1 begins life as an upright monomer present in both membranes destined to fuse (1). These monomers make initial contact across the space between the two cells (2). After initial contact, the monomers start to assemble into higher‐order trimers bringing the two membranes into closer proximity (3). Zippering of EFF‐1 (in which the two ends of the fusion protein fold back on each other) induces lipid stalk formation in which the proximal leaflets of the membranes are fused (4). Full zippering fuses the distal leaflets opening an initial fusion pore (5). The postfusion EFF‐1 trimers are left on the membranes facing out of the cell (6). Like in Figures and the schematic is based on experimental evidence, but also contains a fair degree of speculation partially derived from comparisons to viral fusion (Figure). Structures illustrated in (a and b) were rendered by Thien Vu.
Figure 6. Numerous organelles within cells undergo nonSNARE based fusion. Both mitochondria and endoplasmic reticulum (and potentially other organelles) undergo fusion that is catalysed by a family of membrane anchored GTPases collectively known as dynamin‐related proteins (DRPs) (a) Mitochondria are unique in that they contain an inner and outer membrane whose fusion must be coordinated. Fusion of the outer membrane is catalysed by fuzzy onions (Fzo1p), known as mitofusins in mammals. Fzo1p contains two transmembrane domains anchoring it in the outer membrane. The transmembrane domains are separated by a loop that extends into the space between outer and inner membranes and may play a role in coordinating the fusion of these two membranes. Facing into the cytoplasm, Fzo1p contains a GTPase domain (green oval) and α‐helices (yellow rods) that form coiled‐coils between two mitochondria destined to fuse. Inner membrane fusion is catalysed by Mgm1p, known as Opa1 in mammals. The dynamin‐related Mgm1p contains a GTPase domain (purple oval) and is localised to the inner membrane. In yeast the coordination of outer and inner membrane fusion might be accomplished by Ugo1p, however, Ugo1p is not conserved outside of yeast. (b) Endoplasmic reticulum (ER) membrane fusion is catalysed by DRPs. The ER fusion DRPs include: atlastin (mice and flies), RDH3 (plants) and Sey1p (yeast). They have been shown to be necessary and sufficient for fusion. Much like Fzo1p/mitofusin and Mgm1p/Opa1, they also contain two transmembrane domains (blue) a series of α‐helices (yellow rods), a cytoplasmic facing GTPase domain (purple oval), and a ‐terminal extension that might behave as a lipid disrupting domain (red rods). (c) The crystal structure of the postfusion atlastin dimer. (d) Schematic of the structural intermediates that atlastin undergoes during fusion. Atlastin begins life in both membranes destined to fuse (1). It is initially bound by GTP, and exists in a compact orientation. An unknown trigger leads to opening of atlastin (2). On opening, the GTPase domains form an initial interaction tethering the two membranes destined to fuse (3). This initial interaction between atlastins is converted to a stronger association that involves the α‐helices (yellow rods) (4). The association of the α‐helices trans brings the membranes into close proximity and potentially leads to proximal membrane fusion. The lipid disrupting domains (red rods) are now coordinated to open an initial fusion pore (5). The continued dilation of this initial fusion pore eventually completes the full fusion of the two membranes leaving the postfusion dimers in the fused membrane with the GTPase domains facing into the cytoplasm (6). The exact step at which GTP is hydrolysed to GDP is still a matter of significant debate and therefore, it is not indicated exactly at which step it might occur. The structures of atlastin illustrated in (c) were rendered by Thien Vu.


Abmayr SM and Pavlath GK (2012) Myoblast fusion: lessons from flies and mice. Development 139: 641–656.

Aguilar PS , Engel A and Walter P (2007) The plasma membrane proteins Prm1 and Fig1 ascertain fidelity of membrane fusion during yeast mating. Molecular Biology of the Cell 18: 547–556.

Albertini AA , Mérigoux C , Libersou S , et al. (2012) Characterization of monomeric intermediates during VSV glycoprotein structural transition. PLoS Pathogens 8: e1002556.

Alexander C , Votruba M , Pesch UE , et al. (2000) OPA1, encoding a dynamin‐related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genetics 26: 211–215.

Alper S and Kenyon C (2002) The zinc finger protein REF‐2 functions with the Hox genes to inhibit cell fusion in the ventral epidermis of C. elegans . Development 129: 3335–3348.

Anton F , Fres JM , Schauss A , et al. (2011) Ugo1 and Mdm30 act sequentially during Fzo1‐mediated mitochondrial outer membrane fusion. Journal of Cell Science 124: 1126–1135.

Anwar K , Klemm RW , Condon A , et al. (2012) The dynamin‐like GTPase Sey1p mediates homotypic ER fusion in S. cerevisiae . Journal of Cell Biology 197: 209–217.

Avinoam O , Fridman K , Valansi C , et al. (2011) Conserved eukaryotic fusogens can fuse viral envelopes to cells. Science 332: 589–592.

Baquero E , Albertini AA , Vachette P , et al. (2013) Intermediate conformations during viral fusion glycoprotein structural transition. Current Opinion in Virology 3: 143–150.

Bhattacharya S , Stewart BA , Niemeyer BA , et al. (2002) Members of the synaptobrevin/vesicle‐associated membrane protein (VAMP) family in Drosophila are functionally interchangeable in vivo for neurotransmitter release and cell viability. Proceedings of the National Academy of Sciences of the United States of America 99: 13867–13872.

Bian X , Klemm RW , Liu TY , et al. (2011) Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes. Proceedings of the National Academy of Sciences of the United States of America 108: 3976–3981.

Bianchi E , Doe B , Goulding D and Wright GJ (2014) Juno is the egg Izumo receptor and is essential for mammalian fertilization. Nature 508: 483–487.

Blaise S , de Parseval N , Bénit L and Heidmann T (2003) Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proceedings of the National Academy of Sciences of the United States of America 100: 13013–13018.

Borisovska M , Zhao Y , Tsytsyura Y , et al. (2005) v‐SNAREs control exocytosis of vesicles from priming to fusion. EMBO Journal 24: 2114–2126.

Brands A and Ho TH (2002) Function of a plant stress‐induced gene, HVA22. Synthetic enhancement screen with its yeast homolog reveals its role in vesicular traffic. Plant Physiology 130: 1121–1131.

Byrnes LJ and Sondermann H (2011) Structural basis for the nucleotide‐dependent dimerization of the large G protein atlastin‐1/SPG3A. Proceedings of the National Academy of Sciences of the United States of America 108: 2216–2221.

Byrnes LJ , Singh A , Szeto K , et al. (2013) Structural basis for conformational switching and GTP loading of the large G protein atlastin. EMBO Journal 32: 369–384.

del Campo JJ , Opoku‐Serebuoh E , Isaacson AB , et al. (2005) Fusogenic activity of EFF‐1 is regulated via dynamic localization in fusing somatic cells of C. elegans . Current Biology 15: 413–423.

Chanturiya A , Chernomordik LV and Zimmerberg J (1997) Flickering fusion pores comparable with initial exocytotic pores occur in protein‐free phospholipid bilayers. Proceedings of the National Academy of Sciences of the United States of America 94: 14423–14428.

Chatterjee I , Richmond A , Putiri E , Shakes DC and Singson A (2005) The Caenorhabditis elegans spe‐38 gene encodes a novel four‐pass integral membrane protein required for sperm function at fertilization. Development 132: 2795–2808.

Chen YA , Scales SJ and Scheller RH (2001) Sequential SNARE assembly underlies priming and triggering of exocytosis. Neuron 30: 161–170.

Chen H , Chomyn A and Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. Journal of Biological Chemistry 280: 26185–26192.

Chen J , Stefano G , Brandizzi F and Zheng H (2011) Arabidopsis RHD3 mediates the generation of the tubular ER network and is required for Golgi distribution and motility in plant cells. Journal of Cell Science 124: 2241–2252.

Chernomordik LV , Leikina E , Frolov V , Bronk P and Zimmerberg J (1997) An early stage of membrane fusion mediated by the low pH conformation of influenza hemagglutinin depends upon membrane lipids. Journal of Cell Biology 136: 81–93.

Chernomordik LV , Frolov VA , Leikina E , Bronk P and Zimmerberg J (1998) The pathway of membrane fusion catalyzed by influenza hemagglutinin: restriction of lipids, hemifusion, and lipidic fusion pore formation. Journal of Cell Biology 140: 1369–1382.

Chernomordik LV and Kozlov MM (2008) Mechanics of membrane fusion. Nature Structural and Molecular Biology 15: 675–683.

Chicka MC , Hui E , Liu H and Chapman ER (2008) Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca(2+). Nature Structural and Molecular Biology 15: 827–835.

Choi SY , Huang P , Jenkins GM , et al. (2006) A common lipid links Mfn‐mediated mitochondrial fusion and SNARE‐regulated exocytosis. Nature Cell Biology 8: 1255–1262.

Cohen FS and Melikyan GB (2004) The energetics of membrane fusion from binding, through hemifusion, pore formation, and pore enlargement. Journal of Membrane Biology 199: 1–14.

Cole ES , Cassidy‐Hanley D , Fricke Pinello J , et al. (2014) Function of the Male‐Gamete‐Specific Fusion Protein HAP2 in a Seven‐Sexed Ciliate. Current Biology 24: R831–R833.

Coonrod EM , Karren MA and Shaw JM (2007) Ugo1p is a multipass transmembrane protein with a single carrier domain required for mitochondrial fusion. Traffic 8: 500–511.

Cornelis G , Heidmann O , Degrelle SA , et al. (2013) Captured retroviral envelope syncytin gene associated with the unique placental structure of higher ruminants. Proceedings of the National Academy of Sciences of the United States of America 110: E828–E837.

Cornelis G , Vernochet C , Carradec Q , et al. (2015) Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials. Proceedings of the National Academy of Sciences of the United States of America 112 (5): E487–E496.

Curto MÁ , Sharifmoghadam MR , Calpena E , et al. (2014) Membrane organization and cell fusion during mating in fission yeast requires multipass membrane protein Prm1. Genetics 196: 1059–1076.

Danieli T , Pelletier SL , Henis YI and White JM (1996) Membrane fusion mediated by the influenza virus hemagglutinin requires the concerted action of at least three hemagglutinin trimers. Journal of Cell Biology 133: 559–569.

Delettre C , Lenaers G , Griffoin JM , et al. (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin‐related protein, is mutated in dominant optic atrophy. Nature Genetics 26: 207–210.

Deng H , Dodson MW , Huang H and Guo M (2008) The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila . Proceedings of the National Academy of Sciences of the United States of America 105: 14503–14508.

DeVay RM , Dominguez‐Ramirez L , Lackner LL , et al. (2009) Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion. Journal of Cell Biology 186: 793–803.

Diao J , Grob P , Cipriano DJ , et al. (2012) Synaptic proteins promote calcium‐triggered fast transition from point contact to full fusion. Elife 1: e00109.

Dupressoir A , Vernochet C , Bawa O , et al. (2009) Syncytin‐A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus‐derived, envelope gene. Proceedings of the National Academy of Sciences of the United States of America 106: 12127–12132.

Efrat A , Chernomordik LV and Kozlov MM (2007) Point‐like protrusion as a prestalk intermediate in membrane fusion pathway. Biophysical Journal 92: L61–L63.

Esnault C , Cornelis G , Heidmann O and Heidmann T (2013) Differential evolutionary fate of an ancestral primate endogenous retrovirus envelope gene, the EnvV syncytin, captured for a function in placentation. PLoS Genetics 9: e1003400.

Fanaei M , Monk PN and Partridge LJ (2011) The role of tetraspanins in fusion. Biochemical Society Transactions 39: 524–528.

Fasshauer D , Otto H , Eliason WK , Jahn R and Brunger AT (1997) Structural changes are associated with soluble N‐ethylmaleimide‐sensitive fusion protein attachment protein receptor complex formation. Journal of Biological Chemistry 272: 28036–28041.

Fdez E , Martínez‐Salvador M , Beard M , Woodman P and Hilfiker S (2010) Transmembrane‐domain determinants for SNARE‐mediated membrane fusion. Journal of Cell Science 123: 2473–2480.

Flanagan JJ and Barlowe C (2006) Cysteine‐disulfide cross‐linking to monitor SNARE complex assembly during endoplasmic reticulum‐Golgi transport. Journal of Biological Chemistry 281: 2281–2288.

Fratti RA , Collins KM , Hickey CM and Wickner W (2007) Stringent 3Q.1R composition of the SNARE 0‐layer can be bypassed for fusion by compensatory SNARE mutation or by lipid bilayer modification. Journal of Biological Chemistry 282: 14861–14867.

Frendo JL , Olivier D , Cheynet V , et al. (2003) Direct involvement of HERV‐W Env glycoprotein in human trophoblast cell fusion and differentiation. Molecular and Cellular Biology 23: 3566–3574.

Gao Y , Zorman S , Gundersen G , et al. (2012) Single reconstituted neuronal SNARE complexes zipper in three distinct stages. Science 337: 1340–1343.

Gibbons DL , Erk I , Reilly B , et al. (2003) Visualization of the target‐membrane‐inserted fusion protein of Semliki Forest virus by combined electron microscopy and crystallography. Cell 114: 573–583.

Giraudo CG , Hu C , You D , et al. (2005) SNAREs can promote complete fusion and hemifusion as alternative outcomes. Journal of Cell Biology 170: 249–260.

Griffin EE and Chan DC (2006) Domain interactions within Fzo1 oligomers are essential for mitochondrial fusion. Journal of Biological Chemistry 281: 16599–16606.

Grote E , Baba M , Ohsumi Y and Novick PJ (2000) Geranylgeranylated SNAREs are dominant inhibitors of membrane fusion. Journal of Cell Biology 151: 453–466.

Hales KG and Fuller MT (1997) Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell 90: 121–129.

Hammarlund M , Palfreyman MT , Watanabe S , Olsen S and Jorgensen EM (2007) Open syntaxin docks synaptic vesicles. PLoS Biology 5: e198.

Hanson PI , Roth R , Morisaki H , Jahn R and Heuser JE (1997) Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick‐freeze/deep‐etch electron microscopy. Cell 90: 523–535.

Hardwick KG and Pelham HR (1992) SED5 encodes a 39‐kD integral membrane protein required for vesicular transport between the ER and the Golgi complex. Journal of Cell Biology 119: 513–521.

Hayashi T , McMahon H , Yamasaki S , et al. (1994) Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO Journal 13: 5051–5061.

He L , Wu XS , Mohan R and Wu LG (2006) Two modes of fusion pore opening revealed by cell‐attached recordings at a synapse. Nature 444: 102–105.

Heiman MG and Walter P (2000) Prm1p, a pheromone‐regulated multispanning membrane protein, facilitates plasma membrane fusion during yeast mating. Journal of Cell Biology 151: 719–730.

Hermann GJ , Thatcher JW , Mills JP , et al. (1998) Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. Journal of Cell Biology 143: 359–373.

Hernandez JM , Stein A , Behrmann E , et al. (2012) Membrane fusion intermediates via directional and full assembly of the SNARE complex. Science 336: 1581–1584.

Hernandez JM , Kreutzberger AJ , Kiessling V , Tamm LK and Jahn R (2014) Variable cooperativity in SNARE‐mediated membrane fusion. Proceedings of the National Academy of Sciences of the United States of America 111: 12037–12042.

Hong W and Lev S (2014) Tethering the assembly of SNARE complexes. Trends in Cell Biology 24: 35–43.

Hu C , Ahmed M , Melia TJ , et al. (2003) Fusion of cells by flipped SNAREs. Science 300: 1745–1749.

Hu J , Shibata Y , Zhu PP , et al. (2009) A class of dynamin‐like GTPases involved in the generation of the tubular ER network. Cell 138: 549–561.

Hwa JJ , Hiller MA , Fuller MT and Santel A (2002) Differential expression of the Drosophila mitofusin genes fuzzy onions (fzo) and dmfn . Mechanisms of Development 16: 213–216.

Inoue N , Ikawa M , Isotani A and Okabe M (2005) The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature 434: 234–238.

Inoue N , Hamada D , Kamikubo H , et al. (2013) Molecular dissection of IZUMO1, a sperm protein essential for sperm‐egg fusion. Development 140: 3221–3229.

Ishihara N , Eura Y and Mihara K (2004) Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. Journal of Cell Science 117: 6535–6546.

Ivanovic T , Choi JL , Whelan SP , van Oijen AM and Harrison SC (2013) Influenza‐virus membrane fusion by cooperative fold‐back of stochastically induced hemagglutinin intermediates. Elife 2: e00333.

Johnson MA , von Besser K , Zhou Q , et al. (2004) Arabidopsis hapless mutations define essential gametophytic functions. Genetics 168: 971–982.

Jones BA and Fangman WL (1992) Mitochondrial DNA maintenance in yeast requires a protein containing a region related to the GTP‐binding domain of dynamin. Genes and Development 6: 380–389.

Jun Y and Wickner W (2007) Assays of vacuole fusion resolve the stages of docking, lipid mixing, and content mixing. Proceedings of the National Academy of Sciences of the United States of America 104: 13010–13015.

Jun Y , Xu H , Thorngren N and Wickner W (2007) Sec18p and Vam7p remodel trans‐SNARE complexes to permit a lipid‐anchored R‐SNARE to support yeast vacuole fusion. EMBO Journal 26: 4935–4945.

Kadandale P , Stewart‐Michaelis A , Gordon S , et al. (2005) The egg surface LDL receptor repeat‐containing proteins EGG‐1 and EGG‐2 are required for fertilization in Caenorhabditis elegans . Current Biology 15: 2222–2229.

Kaji K , Oda S , Shikano T , et al. (2000) The gamete fusion process is defective in eggs of Cd9‐deficient mice. Nature Genetics 24: 279–282.

Kanazawa T , Zappaterra MD , Hasegawa A , et al. (2008) The C. elegans Opa1 homologue EAT‐3 is essential for resistance to free radicals. PLoS Genetics 4: e1000022.

Karunakaran S and Fratti RA (2013) The lipid composition and physical properties of the yeast vacuole affect the hemifusion‐fusion transition. Traffic 14: 650–662.

Kemble GW , Danieli T and White JM (1994) Lipid‐anchored influenza hemagglutinin promotes hemifusion, not complete fusion. Cell 76: 383–391.

Kesavan J , Borisovska M and Bruns D (2007) v‐SNARE actions during Ca2+‐triggered exocytosis. Cell 131: 351–363.

Kloepper TH , Kienle CN and Fasshauer D (2007) An elaborate classification of SNARE proteins sheds light on the conservation of the eukaryotic endomembrane system. Molecular Biology of the Cell 18: 3463–3471.

Klyachko VA and Jackson MB (2002) Capacitance steps and fusion pores of small and large‐dense‐core vesicles in nerve terminals. Nature 418: 89–92.

Koh K , Peyrot SM , Wood CG , et al. (2002) Cell fates and fusion in the C. elegans vulval primordium are regulated by the EGL‐18 and ELT‐6 GATA factors – apparent direct targets of the LIN‐39 Hox protein. Development 129: 5171–5180.

Kontani K , Moskowitz IP and Rothman JH (2005) Repression of cell‐cell fusion by components of the C. elegans vacuolar ATPase complex. Developmental Cell 8: 787–794.

Kozlov MM and Markin VS (1983) Possible mechanism of membrane fusion. Biofizika 28: 242–247.

Kozlov MM , McMahon HT and Chernomordik LV (2010) Protein‐driven membrane stresses in fusion and fission. Trends in Biochemical Sciences 35: 699–706.

Kroschewski H , Allison SL , Heinz FX and Mandl CW (2003) Role of heparan sulfate for attachment and entry of tick‐borne encephalitis virus. Virology 308: 92–100.

Lai Y , Lou X , Wang C , Xia T and Tong J (2014) Synaptotagmin 1 and Ca2+ drive trans SNARE zippering. Scientific Reports 4: 4575.

Lanzrein M , Weingart R and Kempf C (1993) pH‐dependent pore formation in Semliki forest virus‐infected Aedes albopictus cells. Virology 193: 296–302.

Lauer JM , Dalal S , Marz KE , Nonet ML and Hanson PI (2006) SNARE complex zero layer residues are not critical for N‐ethylmaleimide‐sensitive factor‐mediated disassembly. Journal of Biological Chemistry 281: 14823–14832.

Lavialle C , Cornelis G , Dupressoir A , et al. (2013) Paleovirology of 'syncytins', retroviral env genes exapted for a role in placentation. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 368: 20120507.

Le Naour F , Rubinstein E , Jasmin C , Prenant M and Boucheix C (2000) Severely reduced female fertility in CD9‐deficient mice. Science 287: 319–321.

Liao M and Kielian M (2005) Domain III from class II fusion proteins functions as a dominant‐negative inhibitor of virus membrane fusion. Journal of Cell Biology 171: 111–120.

Lin RC and Scheller RH (1997) Structural organization of the synaptic exocytosis core complex. Neuron 19: 1087–1094.

Littleton JT , Chapman ER , Kreber R , et al. (1998) Temperature‐sensitive paralytic mutations demonstrate that synaptic exocytosis requires SNARE complex assembly and disassembly. Neuron 21: 401–413.

Liu Y and Barlowe C (2002) Analysis of Sec22p in endoplasmic reticulum/Golgi transport reveals cellular redundancy in SNARE protein function. Molecular Biology of the Cell 13: 3314–3324.

Liu T , Wang T , Chapman ER and Weisshaar J (2008) Productive Hemifusion Intermediates in Fast Vesicle Fusion Driven by Neuronal SNAREs. Biophysical Journal 94: 1303–1314.

Liu TY , Bian X , Sun S , et al. (2012) Lipid interaction of the C terminus and association of the transmembrane segments facilitate atlastin‐mediated homotypic endoplasmic reticulum fusion. Proceedings of the National Academy of Sciences of the United States of America 109: E2146–E2154.

Lollike K , Borregaard N and Lindau M (1995) The exocytotic fusion pore of small granules has a conductance similar to an ion channel. Journal of Cell Biology 129: 99–104.

Lollike K , Borregaard N and Lindau M (1998) Capacitance flickers and pseudoflickers of small granules, measured in the cell‐attached configuration. Biophysical Journal 75: 53–59.

Lu X , Zhang F , McNew JA and Shin YK (2005) Membrane fusion induced by neuronal SNAREs transits through hemifusion. Journal of Biological Chemistry 280: 30538–30541.

Luo M (2012) Influenza virus entry. Advances in Experimental Medicine and Biology 726: 201–221.

Malinin VS and Lentz BR (2004) Energetics of vesicle fusion intermediates: comparison of calculations with observed effects of osmotic and curvature stresses. Biophysical Journal 86: 2951–2964.

Markosyan RM , Cohen FS and Melikyan GB (2003) HIV‐1 envelope proteins complete their folding into six‐helix bundles immediately after fusion pore formation. Molecular Biology of the Cell 14: 926–938.

McNew JA , Parlati F , Fukuda R , et al. (2000a) Compartmental specificity of cellular membrane fusion encoded in SNARE proteins. Nature 407: 153–159.

McNew JA , Weber T , Parlati F , et al. (2000b) Close is not enough: SNARE‐dependent membrane fusion requires an active mechanism that transduces force to membrane anchors. Journal of Cell Biology 150: 105–117.

McNew JA , Sondermann H , Lee T , Stern M and Brandizzi F (2013) GTP‐dependent membrane fusion. Annual Review of Cell and Developmental Biology 29: 529–550.

McQuibban GA , Lee JR , Zheng L , Juusola M and Freeman M (2006) Normal mitochondrial dynamics requires rhomboid‐7 and affects Drosophila lifespan and neuronal function. Current Biology 16: 982–989.

Meeusen S , McCaffery JM and Nunnari J (2004) Mitochondrial fusion intermediates revealed in vitro. Science 305: 1747–1752.

Meeusen S , DeVay R , Block J , et al. (2006) Mitochondrial inner‐membrane fusion and crista maintenance requires the dynamin‐related GTPase Mgm1. Cell 127: 383–395.

Melikyan GB , Barnard RJ , Abrahamyan LG , Mothes W and Young JA (2005) Imaging individual retroviral fusion events: from hemifusion to pore formation and growth. Proceedings of the National Academy of Sciences of the United States of America 102: 8728–8733.

Melikyan GB (2014) HIV entry: a game of hide‐and‐fuse? Current Opinion in Virology 4: 1–7.

Melikyan GB , Brener SA , Ok DC and Cohen FS (1997) Inner but not outer membrane leaflets control the transition from glycosylphosphatidylinositol‐anchored influenza hemagglutinin‐induced hemifusion to full fusion. Journal of Cell Biology 136: 995–1005.

Mi S , Lee X , Li X , et al. (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403: 785–789.

Millay DP , O'Rourke JR , Sutherland LB , et al. (2013) Myomaker is a membrane activator of myoblast fusion and muscle formation. Nature 499: 301–305.

Min D , Kim K , Hyeon C , et al. (2013) Mechanical unzipping and rezipping of a single SNARE complex reveals hysteresis as a force‐generating mechanism. Nature Communications 4: 1705.

Miyado K , Yamada G , Yamada S , et al. (2000) Requirement of CD9 on the egg plasma membrane for fertilization. Science 287: 321–324.

Mohler WA , Shemer G , del Campo JJ , et al. (2002) The type I membrane protein EFF‐1 is essential for developmental cell fusion. Developmental Cell 2: 355–362.

Mohrmann R , de Wit H , Verhage M , Neher E and Sørensen JB (2010) Fast vesicle fusion in living cells requires at least three SNARE complexes. Science 330: 502–505.

Mohrmann R and Sørensen JB (2012) SNARE requirements en route to exocytosis: from many to few. Journal of Molecular Neuroscience 48: 387–394.

Mori T , Kuroiwa H , Higashiyama T and Kuroiwa T (2006) GENERATIVE CELL SPECIFIC 1 is essential for angiosperm fertilization. Nature Cell Biology 8: 64–71.

Morin‐Leisk J , Saini SG , Meng X , et al. (2011) An intramolecular salt bridge drives the soluble domain of GTP‐bound atlastin into the postfusion conformation. Journal of Cell Biology 195: 605–615.

Moss TJ , Andreazza C , Verma A , Daga A and McNew JA (2011) Membrane fusion by the GTPase atlastin requires a conserved C‐terminal cytoplasmic tail and dimerization through the middle domain. Proceedings of the National Academy of Sciences of the United States of America 108: 11133–11138.

Muller EM , Mackin NA , Erdman SE and Cunningham KW (2003) Fig1p facilitates Ca2+ influx and cell fusion during mating of Saccharomyces cerevisiae . Journal of Biological Chemistry 278: 38461–38469.

Muñoz‐Barroso I , Durell S , Sakaguchi K , Appella E and Blumenthal R (1998) Dilation of the human immunodeficiency virus‐1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41. Journal of Cell Biology 140: 315–323.

Nakai M , Endo T , Hase T and Matsubara H (1993) Intramitochondrial protein sorting. Isolation and characterization of the yeast MSP1 gene which belongs to a novel family of putative ATPases. Journal of Biological Chemistry 268: 24262–24269.

Nakanishi H , Morishita M , Schwartz CL , et al. (2006) Phospholipase D and the SNARE Sso1p are necessary for vesicle fusion during sporulation in yeast. Journal of Cell Science 119: 1406–1415.

Neumann B , Coakley S , Giordano‐Santini R , et al. (2015) EFF‐1‐mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517: 219–222.

Ngatchou AN , Kisler K , Fang Q , et al. (2010) Role of the synaptobrevin C terminus in fusion pore formation. Proceedings of the National Academy of Sciences of the United States of America 107: 18463–18468.

Nichols BJ , Ungermann C , Pelham HR , Wickner WT and Haas A (1997) Homotypic vacuolar fusion mediated by t‐ and v‐SNAREs. Nature 387: 199–202.

Nishimura H and L'Hernault SW (2010) Spermatogenesis‐defective (spe) mutants of the nematode Caenorhabditis elegans provide clues to solve the puzzle of male germline functions during reproduction. Developmental Dynamics 239: 1502–1514.

Nolan S , Cowan AE , Koppel DE , Jin H and Grote E (2006) FUS1 regulates the opening and expansion of fusion pores between mating yeast. Molecular Biology of the Cell 17: 2439–2450.

Oren‐Suissa M , Hall DH , Treinin M , Shemer G and Podbilewicz B (2010) The fusogen EFF‐1 controls sculpting of mechanosensory dendrites. Science 328: 1285–1288.

Orso G , Pendin D , Liu S , et al. (2009) Homotypic fusion of ER membranes requires the dynamin‐like GTPase atlastin. Nature 460: 978–983.

Ossig R , Schmitt HD , de Groot B , et al. (2000) Exocytosis requires asymmetry in the central layer of the SNARE complex. EMBO Journal 19: 6000–6010.

Parlati F , McNew JA , Fukuda R , et al. (2000) Topological restriction of SNARE‐dependent membrane fusion. Nature 407: 194–198.

Parlati F , Varlamov O , Paz K , et al. (2002) Distinct SNARE complexes mediating membrane fusion in Golgi transport based on combinatorial specificity. Proceedings of the National Academy of Sciences of the United States of America 99: 5424–5429.

Patel SK , Indig FE , Olivieri N , Levine ND and Latterich M (1998) Organelle membrane fusion: a novel function for the syntaxin homolog Ufe1p in ER membrane fusion. Cell 92: 611–620.

Pendin D , Tosetto J , Moss TJ , et al. (2011) GTP‐dependent packing of a three‐helix bundle is required for atlastin‐mediated fusion. Proceedings of the National Academy of Sciences of the United States of America 108: 16283–16288.

Pérez‐Vargas J , Krey T , Valansi C , et al. (2014) Structural basis of eukaryotic cell‐cell fusion. Cell 157: 407–419.

Perotti ME (1973) The mitochondrial derivative of the spermatozoon of Drosophila before and after fertilization. Journal of Ultrastructure Research 44: 181–198.

Pobbati AV , Stein A and Fasshauer D (2006) N‐ to C‐terminal SNARE complex assembly promotes rapid membrane fusion. Science 313: 673–676.

Podbilewicz B , Leikina E , Sapir A , et al. (2006) The C. elegans developmental fusogen EFF‐1 mediates homotypic fusion in heterologous cells and in vivo . Developmental Cell 11: 471–481.

Podbilewicz B (2014) Virus and cell fusion mechanisms. Annual Review of Cell and Developmental Biology 30: 111–139.

Poirier MA , Xiao W , Macosko JC , et al. (1998) The synaptic SNARE complex is a parallel four‐stranded helical bundle. Nature Structural Biology 5: 765–769.

Primakoff P , Hyatt H and Tredick‐Kline J (1987) Identification and purification of a sperm surface protein with a potential role in sperm‐egg membrane fusion. Journal of Cell Biology 104: 141–149.

Rapaport D , Brunner M , Neupert W and Westermann B (1998) Fzo1p is a mitochondrial outer membrane protein essential for the biogenesis of functional mitochondria in Saccharomyces cerevisiae. Journal of Biological Chemistry 273: 20150–20155.

Redelsperger F , Cornelis G , Vernochet C , et al. (2014) Capture of syncytin‐Mar1, a fusogenic endogenous retroviral envelope gene involved in placentation in the Rodentia squirrel‐related clade. Journal of Virology 88: 7915–7928.

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

Reeves JD , Gallo SA , Ahmad N , et al. (2002) Sensitivity of HIV‐1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proceedings of the National Academy of Sciences of the United States of America 99: 16249–16254.

Rickman C , Hu K , Carroll J and Davletov B (2005) Self‐assembly of SNARE fusion proteins into star‐shaped oligomers. Biochemical Journal 388: 75–79.

Rismanchi N , Soderblom C , Stadler J , Zhu PP and Blackstone C (2008) Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. Human Molecular Genetics 17: 1591–1604.

Risselada HJ and Grubmüller H (2012) How SNARE molecules mediate membrane fusion: recent insights from molecular simulations. Current Opinion in Structural Biology 22: 187–196.

Risselada HJ , Bubnis G and Grubmüller H (2014) Expansion of the fusion stalk and its implication for biological membrane fusion. Proceedings of the National Academy of Sciences of the United States of America 111: 11043–11048.

Rizo J and Südhof TC (2012) The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices – guilty as charged? Annual Review of Cell and Developmental Biology 28: 279–308.

Rogers JV , Arlow T , Inkellis ER , Koo TS and Rose MD (2013) ER‐associated SNAREs and Sey1p mediate nuclear fusion at two distinct steps during yeast mating. Molecular Biology of the Cell 24: 3896–3908.

Russell CJ , Jardetzky TS and Lamb RA (2001) Membrane fusion machines of paramyxoviruses: capture of intermediates of fusion. EMBO Journal 20: 4025–4034.

Sabatini BL and Regehr WG (1996) Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384: 170–172.

Saini SG , Liu C , Zhang P and Lee TH (2014) Membrane tethering by the atlastin GTPase depends on GTP hydrolysis but not on forming the crossover configuration. Molecular Biology of the Cell 25: 3942–3953.

Sánchez‐San Martín C , Nanda S , Zheng Y , Fields W and Kielian M (2013) Cross‐inhibition of chikungunya virus fusion and infection by alphavirus E1 domain III proteins. Journal of Virology 87: 7680–7687.

Santel A and Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. Journal of Cell Science 114: 867–874.

Sapir A , Choi J , Leikina E , et al. (2007) AFF‐1, a FOS‐1‐regulated fusogen, mediates fusion of the anchor cell in C. elegans . Developmental Cell 12: 683–698.

Scales SJ , Chen YA , Yoo BY , et al. (2000) SNAREs contribute to the specificity of membrane fusion. Neuron 26: 457–464.

Scales SJ , Yoo BY and Scheller RH (2001) The ionic layer is required for efficient dissociation of the SNARE complex by alpha‐SNAP and NSF. Proceedings of the National Academy of Sciences of the United States of America 98: 14262–14267.

Schoch S , Deak F , Konigstorfer A , et al. (2001) SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science 294: 1117–1122.

Schulze KL , Broadie K , Perin MS and Bellen HJ (1995) Genetic and electrophysiological studies of Drosophila syntaxin‐1A demonstrate its role in nonneuronal secretion and neurotransmission. Cell 80: 311–320.

Sesaki H and Jensen RE (2001) UGO1 encodes an outer membrane protein required for mitochondrial fusion. Journal of Cell Biology 152: 1123–1134.

Sesaki H and Jensen RE (2004) Ugo1p links the Fzo1p and Mgm1p GTPases for mitochondrial fusion. Journal of Biological Chemistry 279: 28298–28303.

Shemer G , Suissa M , Kolotuev I , et al. (2004) EFF‐1 is sufficient to initiate and execute tissue‐specific cell fusion in C. elegans . Current Biology 14: 1587–1591.

Shi L , Shen QT , Kiel A , et al. (2012) SNARE proteins: one to fuse and three to keep the nascent fusion pore open. Science 335: 1355–1359.

Shmulevitz M and Duncan R (2000) A new class of fusion‐associated small transmembrane (FAST) proteins encoded by the non‐enveloped fusogenic reoviruses. EMBO Journal 19: 902–912.

Singson A , Mercer KB and L'Hernault SW (1998) The C. elegans spe‐9 gene encodes a sperm transmembrane protein that contains EGF‐like repeats and is required for fertilization. Cell 93: 71–79.

Sinha R , Ahmed S , Jahn R and Klingauf J (2011) Two synaptobrevin molecules are sufficient for vesicle fusion in central nervous system synapses. Proceedings of the National Academy of Sciences of the United States of America 108: 14318–14323.

Söllner T , Bennett MK , Whiteheart SW , Scheller RH and Rothman JE (1993a) A protein assembly‐disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75: 409–418.

Söllner T , Whiteheart SW , Brunner M , et al. (1993b) SNAP receptors implicated in vesicle targeting and fusion. Nature 362: 318–324.

Spruce AE , Iwata A , White JM and Almers W (1989) Patch clamp studies of single cell‐fusion events mediated by a viral fusion protein. Nature 342: 555–558.

Spruce AE , Breckenridge LJ , Lee AK and Almers W (1990) Properties of the fusion pore that forms during exocytosis of a mast cell secretory vesicle. Neuron 4: 643–654.

Starai VJ , Thorngren N , Fratti RA and Wickner W (2005) Ion regulation of homotypic vacuole fusion in Saccharomyces cerevisiae . Journal of Biological Chemistry 280: 16754–16762.

Stegmann T , Delfino JM , Richards FM and Helenius A (1991) The HA2 subunit of influenza hemagglutinin inserts into the target membrane prior to fusion. Journal of Biological Chemistry 266: 18404–18410.

Stein A , Weber G , Wahl MC and Jahn R (2009) Helical extension of the neuronal SNARE complex into the membrane. Nature 460: 525–528.

Südhof TC (2013) Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80: 675–690.

Sutton RB , Fasshauer D , Jahn R and Brunger AT (1998) Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature 395: 347–353.

Van Den Bogaart G , Holt MG , Bunt G , et al. (2010) One SNARE complex is sufficient for membrane fusion. Nature Structural and Molecular Biology 17: 358–364.

Vicogne J , Vollenweider D , Smith JR , et al. (2006) Asymmetric phospholipid distribution drives in vitro reconstituted SNARE‐dependent membrane fusion. Proceedings of the National Academy of Sciences of the United States of America 103: 14761–14766.

Wang H , Lockwood SK , Hoeltzel MF and Schiefelbein JW (1997) The ROOT HAIR DEFECTIVE3 gene encodes an evolutionarily conserved protein with GTP‐binding motifs and is required for regulated cell enlargement in Arabidopsis . Genes and Development 11: 799–811.

Wang Y , Dulubova I , Rizo J and Südhof TC (2001) Functional analysis of conserved structural elements in yeast syntaxin Vam3p. Journal of Biological Chemistry 276: 28598–28605.

Weber T , Zemelman BV , McNew JA , et al. (1998) SNAREpins: minimal machinery for membrane fusion. Cell 92: 759–772.

Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nature Reviews. Molecular Cell Biology 11: 872–884.

White JM , Delos SE , Brecher M and Schornberg K (2008) Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Critical Reviews in Biochemistry and Molecular Biology 43: 189–219.

Wong ED , Wagner JA , Gorsich SW , et al. (2000) The dynamin‐related GTPase, Mgm1p, is an intermembrane space protein required for maintenance of fusion competent mitochondria. Journal of Cell Biology 151: 341–352.

Wong ED , Wagner JA , Scott SV , et al. (2003) The intramitochondrial dynamin‐related GTPase, Mgm1p, is a component of a protein complex that mediates mitochondrial fusion. Journal of Cell Biology 160: 303–311.

Wong JL , Koppel DE , Cowan AE and Wessel GM (2007) Membrane hemifusion is a stable intermediate of exocytosis. Developmental Cell 12: 653–659.

Wong JL and Johnson MA (2010) Is HAP2‐GCS1 an ancestral gamete fusogen? Trends in Cell Biology 20: 134–141.

Xu Y , Zhang F , Su Z , McNew JA and Shin YK (2005) Hemifusion in SNARE‐mediated membrane fusion. Nature Structural and Molecular Biology 12: 417–422.

Xu H , Zick M , Wickner WT and Jun Y (2011) A lipid‐anchored SNARE supports membrane fusion. Proceedings of the National Academy of Sciences of the United States of America 108: 17325–17330.

Yang L and Huang HW (2002) Observation of a membrane fusion intermediate structure. Science 297: 1877–1879.

Yang X , Kurteva S , Ren X , Lee S and Sodroski J (2005) Stoichiometry of envelope glycoprotein trimers in the entry of human immunodeficiency virus type 1. Journal of Virology 79: 12132–12147.

Zaitseva E , Mittal A , Griffin DE and Chernomordik LV (2005) Class II fusion protein of alphaviruses drives membrane fusion through the same pathway as class I proteins. Journal of Cell Biology 169: 167–177.

Zeev‐Ben‐Mordehai T , Vasishtan D , Siebert CA and Grünewald K (2014) The full‐length cell‐cell fusogen EFF‐1 is monomeric and upright on the membrane. Nature Communications 5: 3912.

Zhang M , Wu F , Shi J , et al. (2013) ROOT HAIR DEFECTIVE3 family of dynamin‐like GTPases mediates homotypic endoplasmic reticulum fusion and is essential for Arabidopsis development. Plant Physiology 163: 713–720.

Zhao X , Alvarado D , Rainier S , et al. (2001) Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nature Genetics 29: 326–331.

Zhou P , Bacaj T , Yang X , Pang ZP and Südhof TC (2013) Lipid‐anchored SNAREs lacking transmembrane regions fully support membrane fusion during neurotransmitter release. Neuron 80: 470–483.

Zhu PP , Patterson A , Lavoie B , et al. (2003) Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. Journal of Biological Chemistry 287: 49063–49071.

Zick M , Duvezin‐Caubet S , Schäfer A , et al. (2009) Distinct roles of the two isoforms of the dynamin‐like GTPase Mgm1 in mitochondrial fusion. FEBS Letters 583: 2237–2243.

Zorman S , Rebane AA , Ma L , et al. (2014) Common intermediates and kinetics, but different energetics, in the assembly of SNARE proteins. Elife 3: e03348.

Further Reading

Aguilar PS , Baylies MK , Fleissner A , et al. (2013) Genetic basis of cell‐cell fusion mechanisms. Trends in Genetics 29 (7): 427–437.

Baquero E , Albertini AA , Vachette P , et al. (2013) Intermediate conformations during viral fusion glycoprotein structural transition. Current Opinion in Virology 3 (2): 143–150.

Escobar‐Henriques M and Anton F (2013) Mechanistic perspective of mitochondrial fusion: tubulation vs. fragmentation. Biochimica et Biophysica Acta 1833 (1): 162–175.

Harrison SC (2008) Viral membrane fusion. Nature Structural Molecular Biology 15: 690–698.

Hoppins S and Nunnari J (2009) The molecular mechanism of mitochondrial fusion. Biochimica et Biophysica Acta 1793: 20–26.

Jahn R and Fasshauer D (2012) Molecular machines governing exocytosis of synaptic vesicles. Nature 490 (7419): 201–207.

McNew JA , Sondermann H , Lee T , Stern M and Brandizzi F (2013) GTP‐dependent membrane fusion. Annual Review of Cell and Developmental Biology 29: 529–550.

Podbilewicz B (2014) Virus and cell fusion mechanisms. Annual Review of Cell and Developmental Biology 30: 111–139.

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Palfreyman, Mark T, and Jorgensen, Erik M(Jul 2015) In Vivo Analysis of Membrane Fusion. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020891.pub2]