Intracellular Vesicle Fusion Requires a Membrane-Destabilizing Peptide Located at the Juxtamembrane Region of the v-SNARE

Rathore, Shailendra S.; Liu, Yinghui; Yu, Haijia; Wan, Chun; Lee, MyeongSeon; Yin, Qian; Stowell, Michael H.B.; Shen, Jingshi

Theoretical modeling suggests that, to overcome the energy barrier of membrane fusion, the lipid bilayer structure must be disrupted after the two membranes are brought into close proximity (Chernomordik and Kozlov, 2008; Kozlov et al., 2010; Risselada and Grubmüller, 2012) . In viral fusion, another type of extensively studied membrane fusion, viral fusion proteins possess membrane-destabilizing peptides required for the fusion of enveloped viruses with host cell membranes (Earp et al., 2005; Harrison, 2008) . Virus-anchored fusion proteins bring the viral limiting membrane and the host cell membrane (the plasma membrane or the endosome) into close apposition as they refold between the membrane bilayers, analogous to the role of the trans-SNARE complex in intracellular vesicle fusion (Chlanda et al., 2016; Harrison, 2008; Lamb and Jardetzky, 2007; Martens and McMahon, 2008; Top et al., 2005) . Viral fusion proteins use fusion peptides to anchor the virus to the host cell (Harrison, 2008) . Interestingly, in addition to their membrane-anchoring function, fusion peptides can directly destabilize lipid bilayers to promote viral membrane fusion (Düzgüneş and Shavnin, 1992; Earp et al., 2005; Epand, 2003; Haldar et al., 2018; Huang et al., 2004; Shmulevitz et al., 2004) . Besides fusion peptides, the membrane-proximal external regions of viral fusion proteins can also destabilize membrane bilayers (Allison et al., 1999; Buzon et al., 2010; Howard et al., 2008; Jeetendra et al., 2003; Muñoz-Barroso et al., 1999; Vishwanathan and Hunter, 2008) . More recently, membrane-destabilizing peptides were also discovered in non-viral fusion proteins such as atlastins, which drive homotypic endoplasmic reticulum (ER) fusion (Faust et al., 2015; Liu et al., 2012) .