Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation.
The membrane fusion potential of influenza HA, like many viral membrane-fusion glycoproteins, is generated by proteolytic cleavage of a biosynthetic precursor. The three-dimensional structure of ectodomain of the 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 nonpolar amino acids near the new amino terminus bury ionizable residues in the cavity that are implicated in the low-pH-induced conformational change. Amino acid insertions at the cleavage site in HAs of virulent avian viruses and those of viruses isolated from the recent severe outbreak of influenza in humans in Hong Kong would extend this surface loop, facilitating intracellular cleavage.
Chen
J
J
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Lee
K H
KH
Steinhauer
D A
DA
Stevens
D J
DJ
Skehel
J J
JJ
Wiley
D C
DC
D001963:Bromelains / Q000378:metabolism; D002460:Cell Line; D002499:Centrifugation, Density Gradient; D018360:Crystallography, X-Ray; D010450:Endopeptidases / Q000378:metabolism*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009975:Orthomyxoviridae / Q000737:chemistry / Q000378:metabolism / Q000472:pathogenicity*; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D014357:Trypsin / Q000378:metabolism; D014774:Virulence
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D001963:Bromelains; D010450:Endopeptidases; D014357:Trypsin