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

Membrane-destabilizing peptides have not been known to exist in the SNARE-SM vesicle fusion machinery, raising the possibility that intracellular vesicle fusion might proceed through a route distinct from other membrane fusion pathways. In this work, we discovered that the juxtamembrane motif of the v-SNARE directly perturbs the lipid bilayer structure in a manner reminiscent of viral fusion proteins. Mutations of the juxtamembrane motif abrogate SNARE-SM-mediated fusion in vitro, correlating with the essential role of the juxtamembrane motif in vesicle fusion in the cell. Importantly, the juxtamembrane motif can be functionally replaced by an unrelated membrane-disrupting peptide in membrane fusion. Thus, intracellular vesicle fusion also requires a membrane-destabilizing peptide, supporting the notion that membrane-destabilizing peptides constitute a universal element in membrane fusion reactions. These findings suggest that biological membrane fusion pathways, although driven by disparate fusion proteins, are governed by common underlying mechanisms.