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with interactions of the cytosolic tail of E2 with the nucleocapsid. Budding
results in the formation of icosahedral-enveloped particles of triangulation
4,
containing 80 trimeric E2/E1 spikes.
By contrast, flavivirus particles bud into the endoplasmic reticulum as
immature virions formed by 60 trimers of prM-E. The immature particles have
an organization similar to that of mature alphaviruses, with each trimer forming a
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 step 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 third and final
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. Three
different classes of fusion have been identified so far based on common structural
motives. (A) The class I fusion proteins are characterized by trimers of hairpins contain-
ing a central alpha-helical coiled-coil structure. For retroviruses, receptor binding
induces the movement of the SU, allowing a loop-to-helix transition of a polypeptide
segment of TM that was previously buried underneath the SU heads, projecting the
fusion peptide
100 ˚ toward the target membrane, where it inserts irreversibly. This
occurs by a “spring-loaded” mechanism. The HR2 C-terminal end (green) of the long
TM
-helix jackknifes back, reversing the direction of the viral-membrane-proximal
segment of TM, which then interacts in an antiparallel fashion with the groove formed
by the N-terminal HR1 (blue) trimeric coiled coil. The final postfusion conformation of
TM is, therefore, a highly stable rod with the TM and fusion-peptide segments together
at the same end of the molecule, a structure termed a “trimer of hairpins” or helix buddle
(HB). (B) Class II fusion proteins are characterized by trimers of hairpins composed of
beta structures. The red, yellow, and blue parts of each subunit correspond, respectively,
to domains I, II, and III of the ectodomain. The fusion loop is at the tip of domain II.
Monomeric transition between the prefusion dimer and the trimeric-extended interme-
diate is shown. After exposure to the low pH of the endosomes, domains I and II swing
outward, while domain III and the stem remain oriented against the membrane roughly
similar to the prefusion state. The fusion loop, at the top of the diagram, interacts with
the target bilayer. Domains I and II associate into the trimeric core of the postfusion
conformation, and domain III must then zip back along the trimer core, thus reorientat-
ing the domain III. (C) A third class of fusion proteins has been described recently,
which also forms trimers of hairpins by combining the two structural elements alpha-
helix and beta-sheet structures. Class III fusion proteins are composed of five domains
that give rise to a molecular architecture very distinct from any reported class I or class II
fusion proteins. Interestingly, the ectodomain of G has been crystallized in its pre and
postfusion (low-pH) state. During the conformational change that occurs upon low pH
exposure, the domains of G radically change their position and orientation as a result of
rearrangements that occur in the linker regions. Domain I (yellow), carrying the fusion
loops, and the transmembrane domain move 16 nm from one end of the molecule to the
opposite (Backovic and Jardetzky, 2009). Only domain III (blue) undergoes significant
refolding with extension of the central helix F. To complete the process, the C-terminal
helices of domain IV (red) insert into crevices formed by two other protomers in the
postfusion form, reminiscent of the structural changes observed during refolding events
of class I fusion proteins with HB formation.
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