STRUCTURE OF THE HEMAGGLUTININ PRECURSOR CLEAVAGE SITE, A DETERMINANTOF INFLUENZA PATHOGENICITY AND THE ORIGIN OF THE LABILE CONFORMATION

The membrane fusion potential of influenza HA, like many viral membran e-fusion glycoproteins, is generated by proteolytic cleavage of a bios ynthetic precursor. The three-dimensional structure of ectodomain of t he precursor HA0 has been determined and compared with that of cleaved HA. The cleavage site is a prominent surface loop adjacent to a novel cavity; cleavage results in structural rearrangements in which the no npolar amino acids near the new amino terminus bury ionizable residues in the cavity that are implicated in the low-pH-induced conformationa l change. Amino acid insertions at the cleavage site in HAs of virulen t avian viruses and those of viruses isolated from the recent severe o utbreak of influenza in humans in Hong Kong would extend this surface loop, facilitating intracellular cleavage.