10.1 Structure
Spike proteins S are present on surface of coronaviruses and facilitate
in viral entry for infection.76 The entry of
cronavirus into the host cells is mediated by spike glycoproteins (S)
that form homo-trimers that extend above the surface of
virus77 (Figure 8a). S consists of two functional
subunits which are present for attachment with the receptor of host cell
(S1 subunit) and fusion of the viral and cellular membranes (S2
subunit). For most CoVs, at the boundary between the S1 and S2 subunits,
S is cleaved which remain non-covalently bound in the prefusion
conformation.52,54,62,70,78-80 The diatal S1 unit
consists of receptor binding domains and participates in the stability
of the prefusion state of the membrane-anchored S2 subunit which
consists of the fusion machinery52,54,55,58,60,81,82(Figure 8b).
Trimers are being formed by spike molecules, which must be cleaved by
cellular proteases, so that fusion peptide can aid in fusion of viral
membrane with infected cells. The proteases produce two subunits S1 and
S2 from the spike molecule, and S1 subunit consists of critical RBD
receptor binding domains to bind with ACE2 of host cells. The receptor
binding motif which is present in receptor binding domain forms direct
contact with ACE2. Several others critical structures of spike proteins
including Central Helix (CH) and heptad repeat 1 and 2 (HR1 and HR2)
domains also help in fusion of virus with host cells51(Figure 9).
10.2 Spike proteins and conformational changes
For all CoVs, the so-called S2 site located immediately
upstream of the fusion peptide is being used for further cleavage of
S.62,83 This cleavage has been reported to trigger
conformational changes that activate the proteins for membrane fusion
via extensive irreversible changes.60-62,70Consequently, entry of coronavirus into susceptible cells is a
complicated activity that requires coherent action of receptor binding
and proteolytic processing of the S protein to enhance virus-cell
fusion. After getting entry into the host cell, usually through contact
with contaminated surfaces and aerosolized viral particles, the virus
needs to undergo biological cycle. Spike proteins which are encoded by S
gene on open reading frame on viral genome need to interact with viral
receptors on the surface of host cells. Coronavirus spike binds with
angiotensin-converting enzyme-2 (ACE-2), which are present in epithelial
cells of the lungs.84,85 This is one of the major
reasons why coronaviruses often cause respiratory disorders. ACE-2
receptors may also be highly expressed in intestinal tissues leading to
diarrhea, as detected in few cases of SARS COV-2
patients.86 After binding to ACE-2 receptors via the
RBD of the S1 and S2 domains of the spike protein, the viral envelope
fuses with the host cell membrane and is further internalized. Genetic
material approximately of the size 20-32 kb, is released into the
cytoplasm for replication51 (Figure 10).