Biology Reference
In-Depth Information
membrane fusion, which preserves the integrity of the cell membrane. The fusion
of two separate lipid bilayers in a nonaqueous environment first requires that they
come into close contact. This is followed by an intermediate stage characterized
by the merger of only the closest contacting monolayer, a process called hemifu-
sion. Third, the fully completed fusion results in whole bilayer merging, followed
by the opening of the pore. To achieve this process, the envelope glycoproteins
(EnvGP) have evolved in order to combine two features. On the one hand, they
acquired a domain to bind to a specific cellular protein, named “receptor.” On the
other hand, they developed in a different manner, according to the genus of the
virus, a function of fusion that allows the destabilization of the membrane and the
opening of a pore through which the genetic material will enter the cell.
Despite three different classes of fusion protein having been described so
far, three common main steps are described for achieving the pre- to post-
conformational changes. The first one, after EnvGP activation upon receptor
binding or acidification of the endosomal compartment, exposes the fusion
peptide that is projected toward the top of the glycoprotein, allowing the initial
interaction with the target membrane. The second one is the folding back of the
C-terminal region onto a trimeric N-terminal region that leads to the formation
of a postfusion protein structure. The final and third step also requires further
refolding of the membrane proximal and transmembrane regions in order to
obtain a full-length postfusion structure where both membrane anchors (fusion
peptide and tm domains) are present in the same membrane.
The viral glycoprotein-induced fusion must be controlled to allow
the virus to leave the cell, to prevent the aggregation of the viruses, and to release
genetic material next to a compartment that will permit the continuity of the
infectious cycle. This regulation is executed principally by the inactivation or
the masking of the fusion machinery that directly disorganizes the lipid bilayer.
On one hand, most of these EnvGP are synthesized as a precursor that requires a
cleavage by a cellular protease (like furin) and prepares the molecules for the
subsequent necessary changes of conformation for the fusion process. On the other
hand, the activation of the conformational changes is induced by interaction with
the receptor and/or the action of the pH (that protonates some amino acids),
modifying the interactions of the EnvGP and their structure. In addition, some
proteases or other enzymes are necessary to achieve some complementary priming
of the EnvGP to make it competent for fusion (such as cathepsin B and L).
Two types of fusion mechanisms can occur, namely, pH independent
and pH dependent. In the first case, the recognition between virus and receptor
directly triggers conformational changes in the EnvGP that leads to the direct
fusion between the two membranes (viral and plasma) and to the liberation of
the viral genetic material. This activation of EnvGP at neutral pH allows the
fusion
of EnvGP-expressing cells with receptor-expressing
cells. This fusion leads to the merging of cell cytoplasms and to the generation of
in vitro
and
in vivo
