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Vol. 10, Issue 8, 2759-2769, August 1999
and
We showed previously that substitution of the first residue of the
influenza hemagglutinin (HA) fusion peptide Gly1 with Glu abolishes
fusion activity. In the present study we asked whether this striking
phenotype was due to the charge or side-chain volume of the substituted
Glu. To do this we generated and characterized six mutants with
substitutions at position 1: Gly1 to Ala, Ser, Val, Glu, Gln, or Lys.
We found the following. All mutants were expressed at the cell surface,
could be cleaved from the precursor (HA0) to the fusion permissive form
(HA1-S-S-HA2), bound antibodies against the major antigenic site, bound
red blood cells, and changed conformation at low pH. Only Gly, Ala, and
Ser supported lipid mixing during fusion with red blood cells. Only Gly
and Ala supported content mixing. Ser HA, therefore, displayed a
hemifusion phenotype. The hemifusion phenotype of Ser HA was confirmed
by electrophysiological studies. Our findings indicate that the first
residue of the HA fusion peptide must be small (e.g., Gly, Ala, or Ser)
to promote lipid mixing and must be small and apolar (e.g., Gly or Ala)
to support both lipid and content mixing. The finding that Val HA displays no fusion activity underscores the idea that hydrophobicity is
not the sole factor dictating fusion peptide function. The surprising
finding that Ser HA displays hemifusion suggests that the HA ectodomain
functions not only in the first stage of fusion, lipid mixing, but
also, either directly or indirectly, in the second stage of fusion,
content mixing.
Department of Cell Biology, University of Virginia,
Charlottesville, Virginia 22908; and Department of
Molecular Biophysics and Physiology, Rush Medical College, Chicago,
Illinois 60612
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