Biology Reference
In-Depth Information
finding is in good agreement with the hypothesis proposed by Simmons
and his colleagues that SARS-CoV takes an endosomal pathway and enters
cells after cleavage of the S protein with protease in the endosome.
43,45
Interestingly, entry from cell surface mediated by proteases results in more
efficient infection than the infection via the endosomal pathway.
44
Mechanism of Cell Entry
The cell entry mechanisms of MHV and SARS-CoV are thought to be
similar to that of a well-known mechanism found in HIV or influenza
virus studies (Fig. 3).
46
A portion of S1N330 of the MHV S protein
binds to the CC´-loop in the N domain of CEACAM1, which removes
the S1 fragment from the envelope-anchored S2.
47,48
A fusion peptide
in S2 then penetrates the plasma membrane of the target cells, which
would trigger the conformational changes of S2.
49
The conformational
changes involve the formation of the so-called six helix bundles, com-
posed of a trimeric coiled-coil inside HR1 and three copies of HR2
that overhang onto the coiled-coil inside HR1s. These conformational
changes of S2 place the viral envelope and cell membrane in close
proximity and facilitate the fusion of these two membranes.
SARS-CoV S protein binds to ACE2 with an internal region of an
S1 counterpart. After transport to the endosome, the S protein is pre-
sumably cleaved by a protease, most likely cathepsin L which is functional
in a low pH environment in the endosome. The conformational changes
similar to that of the MHV S protein could follow. The fusion of the enve-
lope and endosomal membrane then takes place and the genome of SARS-
CoV is internalized into the cell cytoplasm. Six helix bundles are formed
with the SARS-CoV S protein and a peptide corresponding to HR2 blocks
its infection, as was shown in HIV and MHV infections.
23,46
Thus, the
fusion mechanism of the SARS-CoV envelope and cellular membrane is
thought not to differ from those reported thus far in other enveloped
viruses; however, the fusogenic activation process of the SARS-CoV S
protein is quite unique in that it requires a protease for this activation.
Receptor-independent Entry Mechanism
A particular murine coronavirus, MHV-JHMV, is believed to enter cells
in a receptor-independent fashion. This observation was first reported by
