Intracellular cleavage of immature flaviviruses is a critical step in assembly that generates the membrane fusion potential of the E glycoprotein. With cryo-electron microscopy we show that the immature dengue particles undergo a reversible conformational change at low pH that renders them accessible to furin cleavage. At a pH of 6.0, the E proteins are arranged in a herringbone pattern with the pr peptides docked onto the fusion loops, a configuration similar to that of the mature virion. After cleavage, the dissociation of pr is pH-dependent, suggesting that in the acidic environment of the trans-Golgi network pr is retained on the virion to prevent membrane fusion. These results suggest a mechanism by which flaviviruses are processed and stabilized in the host cell secretory pathway.
"It has been reported that DENV glycoprotein prME undergoes a conformational change in the Golgi apparatus, possibly caused by luminal acidification, which leads to the formation of E homodimers (Li et al., 2008; Yu et al., 2008). RSP released by F&T showed that the percentage of E/E homodimers was 3-to 4-fold higher in cells expressing wild-type prME in comparison to Triple prME, which behaved in similar fashion to R6S (Figure 6F), corroborating immunofluorescence observations (Figures 6B–6D). "
"Next the Fig. 1. Possible hemifusion route to virus (upper)–host (lower) membrane fusion, illustrated through alignment of E protein to: a) dimeric, mature viral assembly (3C6R ); b) an intermediate structure during trimerization approximated by the two cryo-EM structures with exposed fusion loops, 3C6D  and 3IXY ; c) target, fused state with trimeric form (1OK8 ) as proposed in earlier works  , arbitrarily positioned to interact with a catenoid-shaped, zero mean curvature, membrane. Panels (b) and (d) are marked by * to illustrate the state defining the free energy barrier for this process. "
"Virus maturation occurs in the TGN, where a cellular protease, probably furin, cleaves prM, generating M protein (8 kDa) and the 'pr' peptide (Zhang et al., 2003a). The TGN acidic environment induces conformational changes in the prM:E heterodimer that expose the cleavage site (Randolph, Winkler and Stollar 1990; Yu et al., 2008). prM interacts and stabilizes E protein DII, as the pr sequence β-barrel structure shields the E protein fusion loop, preventing conformational changes that could activate its fusogenic activity during TGN secretory pathway (Zhang et al., 2003a; Li et al., 2008; Yu et al., 2008; Zheng, Umashankar and Kielian 2010). "
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