, 2007 and Shen et al , 2007) and is essential for fusion (Verhag

, 2007 and Shen et al., 2007) and is essential for fusion (Verhage et al., 2000, Khvotchev et al., 2007, Rathore et al., 2010 and Zhou et al., 2013). Multiple studies suggest that in addition to the SNARE motifs of synaptobrevin-2, syntaxin-1, and SNAP-25 that mediate SNARE-complex this website formation, the transmembrane regions (TMRs) of synaptobrevin-2 and syntaxin-1 are essential for membrane fusion and may induce fusion-pore opening (Han et al., 2004, Xu et al., 2005, Deák et al., 2006, Kesavan et al., 2007, Bretou et al., 2008, Lu et al., 2008, Stein et al., 2009, Fdez et al., 2010, Guzman et al., 2010, Ngatchou et al., 2010, Risselada et al., 2011 and Shi

et al., 2012). In yeast, replacement of the TMR of the synaptobrevin CFTR modulator homolog Snc1p with a geranylgeranyl anchor not only blocked membrane fusion during exocytosis, but also even transformed Snc1p into an inhibitor of exocytosis (Grote et al., 2000).

In PC12 cells, overexpression of syntaxin-1 altered the computed fusion-pore conductance during exocytosis dependent on the TMR sequence, suggesting that the TMRs line the fusion pore (Han et al., 2004). Moreover, partial deletion of the synaptobrevin-2 TMR blocked fusion (Fdez et al., 2010), and addition of residues to the C-terminal TMR of synaptobrevin-2 impeded fusion as well (Ngatchou et al., 2010). At the molecular level, the TMRs of synaptobrevin-2 and syntaxin-1 interact with each other in vitro (Margittai et al., 1999 and Laage et al., 2000). A crystal structure of the neuronal SNARE complex with attached TMRs revealed that the SNARE motifs and the TMRs of syntaxin-1 and synaptobrevin-2 form single continuously interacting α helices (Stein et al., 2009). This compelling result further supported the notion that the SNARE TMRs open the fusion pore, a model that was reinforced by liposome fusion experiments (Xu et al., 2005, Lu et al., 2008 and Shi et al., 2012). Sophisticated computer simulations also indicated that SNARE TMRs initiate fusion by distorting the lipid packing of the outer Bumetanide membrane

leaflets and by forming the fusion pore (Risselada et al., 2011). Moreover, increasing the distance of the SNARE complex from the TMR in synaptobrevin-2 impairs membrane fusion (Deák et al., 2006, Kesavan et al., 2007, Bretou et al., 2008 and Guzman et al., 2010), corroborating the notion that SNARE-complex assembly needs to be tightly coupled to the SNARE TMRs in order to promote fusion-pore formation by the TMRs. Although at present the predominant model of SNARE-mediated fusion thus suggests that the SNARE TMRs play an essential role in fusion, not all experiments support such a model. Only one to three SNARE complexes are required for fusion (van den Bogaart et al., 2010, Mohrmann et al., 2010 and Sinha et al., 2011), suggesting that the SNARE TMRs cannot form a ringed fusion pore.

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