Membrane fusion is blocked by mutations in the HA leash region (right).


The only confirmed mechanism for protein-mediated membrane fusion involves the formation of helix bundles, in which helices attached to two membranes pack against one another to draw together the membranes. In the final fused state, six-helix bundles are formed by HIV Env and paramyxovirus F proteins, members of the class I group of viral fusion proteins. Although the class I founding member, influenza HA, also forms a six-helix bundle, Heather Park, Jennifer Gruenke, and Judith White (University of Virginia, Charlottesville, VA) now show that this bundle is not sufficient for fusion.

For HA, interactions between a nonhelical region and a trimer of helices cause fusion. Using mutational analyses, the group shows that fusion requires contacts between a long chain, which they call the leash, near the viral membrane with the helices near the target membrane (usually a host endosome as the virus escapes into the cytoplasm). They suggest that packing of the leash into the grooves of the helices condenses HA, thus bringing together viral and host membranes. “There's nothing holy about helix–helix interactions as a means to pull membranes together,” says White. “You can do it with other types of interactions.” This may help explain why class II viral fusion proteins work although they do not have a lot of helical structure. ▪


Park, H.E., et al. 2003. Nat. Struct. Biol. 10.1038/nsb1012.