Analyzing the fusion process of influenza hemagglutinin by mutagenesis and molecular modeling

Abstract

Hemagglutinin (HA) is a protein on the surface of influenza virus that binds to sialic acid on cell membranes and leads to fusion of viral and cell membranes. Its crystal structure (Wilson et aI., 1981) shows that HA consists of two disulfide linked glycopolypeptide chains, HAl and HAl, which extend as a trimeric spike 13.7 nm from the virus membrane (Booy et aI., 1985). The spike is surmounted by globular domains of three HAl's that contain the sialic acid binding sites. The fusion peptide, the apolar HAl amino terminus, is buried near the base of the spike between three HA monomers. In an acidic environment, as found in endosomes, the protein undergoes an irreversible conformational change which exposes the fusion peptide. The fusion peptide is thought to interact with the target membrane and trigger membrane fusion. The pH-dependent conformational change of HA appears to be only part of a complicated fusion process (White, 1990). To examine the fusion mechanism in more detail, we have studied effects of mutations on the fusion peptide and have used computer graphics and computational chemistry methods to develop plausible models for how HA may change conformations and associate with adjacent HA trimers during the fusion process.