The trimer-of-hairpins motif in membrane fusion: Visna virus

Structural studies of viral membrane fusion proteins suggest that a "trimer -of-hairpins" motif plays a critical role in the membrane fusion process of many enveloped viruses. In this motif, a coiled coil (formed by homotrimer ic association of the N-terminal regions of the protein) is surrounded by t hree C-terminal regions that pack against the coiled coil in an oblique ant iparallel manner. The resulting trimer-of-hairpins structure serves to brin g the viral and cellular membranes together for fusion, LEARNCOIL-VMF, a co mputational program developed to recognize coiled coil-like regions that fo rm the trimer-of-hairpins motif, predicts these regions in the membrane fus ion protein of the Visna virus. Peptides corresponding to the computational ly identified sequences were synthesized, and the soluble core of the Visna membrane fusion protein was reconstituted in solution. Its crystal structu re at 1.5-Angstrom resolution demonstrates that a trimer-of-hairpins struct ure is formed. Remarkably, despite less than 23% sequence identity, the ect odomains in Visna and HIV-1 envelope glycoproteins show detailed structural conservation, especially within the area of a hydrophobic pocket in the ce ntral coiled coil currently being targeted for the development of new anti- HIV drugs.