Biology Reference
In-Depth Information
convertase SKI-1 that cleaves at hydrophobic residues. Similarly, blocking of
SKI-1 activity by a specific inhibitor has also shown to affect the processing and
the stability of the glycoproteins of these viruses (Pullikotil
, 2004).
For all highly pathogenic avian influenza (HPAI) viruses of subtypes H5
and H7 known to date, the cleavage of HA occurs at the C-terminal R residue
in the consensus multibasic motifs, such as
R-
X-K/R-R with
R
atpositionP4and
K
-K/R-K/T-R with
K
at P4, and leads to systemic infection. Early studies demon-
strated that the ubiquitously expressed furin and proprotein convertases (PCs 5
and 6) are activating proteases for HPAI viruses (Basak
et al.
et al
., 2001; Stieneke-
Grober
., 1992). Recently, ubiquitous type II transmembrane serine proteases,
MSPL and its splice variant TMPRSS13, have been proposed as novel candidates
for proteases processing HA proteins of HPAI (Okumura
et al
,2010).
Is it interesting to note that viral receptors can also be modified by
proprotein convertase. Indeed, PCSK9 impedes hepatitis C virus infection
in vitro
et al.
, modulates liver CD81 expression, and enhances the degradation of the
low-density lipoprotein receptor (LDLR) (Labonte
, 2009), bestowing on
the proprotein convertase an additional role in controlling the fusogenicity of
the envelope glycoprotein.
et al.
2. Fusion peptide
The exhibition and insertion of a hydrophobic fragment of 10-30 residues in the
membrane, named “fusion peptide” or “fusion loop” is a crucial step of the fusion
process (Epand, 2003). The fusion peptides in an N-terminal position (such as for
the retrovirus or the influenza virus) is liberated for most viruses after envelope
glycoprotein cleavage, and it can insert into the external layer of the membrane
in an oblique manner, whereas the fusion loop (for the class II and III viruses)
remains probably more superficial (see Table 4.3). The fusion peptide of the class
I and II proteins is initially buried in the envelope glycoprotein trimer or dimer,
respectively. For the class III, the fusion loop is present outside of the structure,
most likely because the fusion peptide of class III fusion proteins is weakly
hydrophobic and probably requires a cooperation between several loops to be
functional and efficient. The simple picture of a viral fusion protein acting on
cell and viral membranes by means of only two restricted segments, that is to say,
the fusion peptide and the transmembrane domain, is too simplistic. Instead, a
more complex concerted action of different membranotropic segments of the
fusion proteins is necessary. More conformational changes are required to
achieve a complete fusion of the two lipid bilayers. As described previously,
the class I-III fusion proteins roughly share common refolding processes and
formation of intermediates. Several regions of the fusion protein complex indi-
rectly aid the fusion process, as for example, the “stem” regions (see below).
