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

The juxtamembrane motif of the v-SNARE is dispensable for the basal SNARE-driven membrane fusion, again demonstrating that the basal fusion reaction differs fundamentally from SNARE-SM-mediated membrane fusion (Yu et al., , 2018 . Only the SNARE-SM-mediated fusion recapitulates the intracellular vesicle fusion reaction. We posit that, without activation by a cognate SM protein, SNARE zippering proceeds through a different route that is not properly coupled to the activity of the juxtamembrane motif. Consistent with this model, the basal SNARE-driven fusion is insensitive to linker insertions, in stark contrast to the SNARE-SM-mediated fusion reaction. In a reconstituted fusion assay containing the Vc peptide, mutations of the juxtamembrane motif of VAMP2 decreased fusion kinetics (Hernandez et al., 2012) . This observation can be explained by the discovery that the Vc peptide-assisted fusion reaction mimics SNARE-SM-mediated membrane fusion rather than the basal fusion reaction (Yu et al., 2018) . Although the juxtamembrane motif of VAMP2 can associate with t-SNARE and Munc18-1 Xu et al., 2010) , our and others' data showed that the juxtamembrane motif is dispensable for SNARE-SNARE and SNARE-Munc18-1 interactions (Figure 3 ; Jiao et al., 2018) .