Influenza virus hemagglutinin (HA), a homotrimer of subunits with two polypeptide chains, HA, and HA2, mediates binding of the virus to sialic acid-containing cell-surface receptors, initiating endocytosis, and the subsequent fusion of the viral and endosomal membranes by an acid-induced conformational change. A domain formed by the HA, chain contains the receptor-binding site and a significant proportion of the antigenic epitopes. The HA2 chain anchors HA in the viral membrane and contains the fusion peptide, a stretch of negatively charged and hydrophobic residues beginning at the N-terminus that interacts with target.

HA, a major influenza surface glycoprotein, is translated as a single protein, HA0. For viral activation, HA0 (assembled as trimers) must be cleaved by a trypsin-like serine endoprotease at a specific site, normally coded for by a single basic amino acid (usually arginine) between the HA1 and HA2 domains of the protein. After cleavage, the two disulfide-bonded protein domains produce the mature form of the protein subunits as a prerequisite for the conformational change necessary for fusion and hence viral infectivity.