A possible model of how the F activation


  • Regions of the fusion protein involved in attachment protein interactions offer insights into the F-triggering process
    A number of regions on various paramyxovirus F proteins have been found to potentially interact with the HN, H or G proteins. Many of these regions harbor histone demethylase  residues and are surface exposed, suggesting a protein–protein interaction interface with the hydrophobic F-interacting region on the central part of the attachment protein stalks, discussed above (Apte-Sengupta et al., 2012; Avila et al., 2014; Bose et al., 2013; Lee et al., 2007) (Fig. 3F). A number of such residues identified on the PIV5 F protein and the MeV F protein appear to be localized near an immunoglobulin-like (Ig-like domain) fold of domain II and also within an adjacent hydrophobic cavity (Apte-Sengupta et al., 2012; Bose et al., 2013) (Fig. 2G). This cavity is created by residues from two adjacent protomers of F (Apte-Sengupta et al., 2012; Avila et al., 2014; Bose et al., 2013), that juxtapose next to two long β-strands forming a ‘strap’ that connects the HRA domains of the F protein head (Fig. 2H). Mutations of residues in these three adjacent regions – the Ig-like domain, the hydrophobic cavity and the ‘strap’ regions of different paramyxovirus F proteins haimageve many effects including, transfer of HN specificity among different F proteins (Tsurudome et al., 2011, 2013), complete abrogation of F-activation or destabilization of the F protein, making F less reliant on the attachment protein trigger (Avila et al., 2014; Bose et al., 2013; Plattet et al., 2009). Through a more recent dynamic view of PIV5 F refolding it was observed that only the outer loop of the Ig like domain shows conformational mobility, while the rest of the Ig-like domain remains unchanged. In contrast, the ‘strap’ regions underwent some of the largest conformational changes as F protein converted from its prefusion to its post-fusion form (Poor et al., 2014). Based on these data an attractive hypothesis for F triggering could be that HN, H or G interactions through the structurally well defined Ig-like domain could dock the attachment protein stalk into the adjacent hydrophobic cavity, which in turn destabilizes the F protein by initiating structural rearrangements in the adjoining ‘strap’ regions and ultimately culminating in the sequential cascade of refolding events that convert F into its postfusion form. Further studies are required to tease out more of the details as to how HN interaction with F leads to F destabilization and eventual membrane merger (Fig. 2G–H).


    Molecular cooperation between the different domains of the attachment protein ensures timing of F-activation and membrane fusion
    In silico models of MeV F and H proteins (Lee et al., 2008b; Paal et al., 2009) suggested that prior to fusion activation, the MeV prefusion F and H protein heads are positioned at different levels to each other (‘staggered heads’ arrangement), where the H protein head rises above that of the F protein. However, conflicting results from electron micrograph studies of virions suggested that the glycoprotein spikes appear to be of the same height (“parallel-head” model) (Jain et al., 2008). Recently obtained atomic structures of HN proteins of PIV5 (Welch et al., 2013; Yuan et al., 2005) and NDV (Yuan et al., 2011) and electron microscopy data of purified proteins (Bose et al., 2012; Yuan et al., 2008) have suggested that the attachment protein globular heads can attain various different conformational arrangements. Of these, a ‘four heads down’ structure observed for NDV HN has the globular head dimers folded back and making contacts with the 4HB stalk domains (Yuan et al., 2011) thus lowering the height of HN. This, or a similar arrangement could represent the “parallel head” model observed by EM on virions. On the other hand, the ‘four heads up’ arrangement of PIV5 HN globular heads forming a dimer-of-dimer interface (Yuan et al., 2005) represents a taller form of the HN protein as proposed by the ‘staggered head’ model. Interestingly, PIV5 HN was also crystallized in a third arrangement, which showed a shifted dimer-of dimer interface and appeared to represe

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