The spike
glycoproteins of the
lipid-enveloped orthomyxoviruses and paramyxoviruses have three functions: to recognize the receptor on the cell surface, to mediate viral fusion with the cell membrane, and to destroy the receptor. In influenza C virus, a single
glycoprotein, the haemagglutinin-
esterase-fusion (HEF)
protein, possesses all three functions. In
influenza A and B, the first two activities are mediated by haemagglutinin and the third by a second
glycoprotein,
neuraminidase. Here we report the crystal structure of the HEF envelope
glycoprotein of influenza C virus. We have identified the receptor-binding site and the receptor-destroying
enzyme (9-O-acetylesterase) sites, by using receptor analogues. The receptor-binding domain is structurally similar to the
sialic acid-binding domain of
influenza A haemagglutinin, but binds
9-O-acetylsialic acid. The
esterase domain has a structure similar to the
esterase from Streptomyces scabies and a brain acetylhydrolase. The receptor domain is inserted into a surface loop of the
esterase domain and the
esterase domain is inserted into a surface loop of the stem. The stem domain is similar to that of
influenza A haemagglutinin, except that the triple-stranded, alpha-helical bundle diverges at both of its ends, and the amino terminus of HEF2, the fusion
peptide, is partially exposed. The segregation of HEF's three functions into structurally distinct domains suggests that the entire stem region, including sequences at the amino and carboxy termini of HEF1 which precede the post-translational cleavage site between HEF1 and HEF2, forms an independent fusion domain which is probably derived from an ancestral membrane fusion
protein.