Abstract
Paramyxovirus (PMV) entry requires the coordinated action of two envelope glycoproteins, the receptor binding protein (RBP) and fusion protein (F). The sequence of events that occurs during the PMV entry process is tightly regulated. This regulation ensures entry will only initiate when the virion is in the vicinity of a target cell membrane. Here, we review recent structural and mechanistic studies to delineate the entry features that are shared and distinct amongst the Paramyxoviridae. In general, we observe overarching distinctions between the protein-using RBPs and the sialic acid- (SA-) using RBPs, including how their stalk domains differentially trigger F. Moreover, through sequence comparisons, we identify greater structural and functional conservation amongst the PMV fusion proteins, as compared to the RBPs. When examining the relative contributions to sequence conservation of the globular head versus stalk domains of the RBP, we observe that, for the protein-using PMVs, the stalk domains exhibit higher conservation and find the opposite trend is true for SA-using PMVs. A better understanding of conserved and distinct features that govern the entry of protein-using versus SA-using PMVs will inform the rational design of broader spectrum therapeutics that impede this process.
Highlights
The isolated transmembrane domain (TM) domains of HeV-F and parainfluenza virus 5 (PIV5)-F were found to associate in monomer-trimer equilibria [133]. Given these two PMVs are distantly related, these results suggest trimeric TM-TM interactions are a common phenomenon for PMV-F proteins, and these interactions could have functional relevance in entry
Co-expression of the isolated HeV-F TM domain with native, full-length HeV-F resulted in reduced expression of the native HeV-F and disrupted fusion activity, likely because interaction of the two forms leads to either protein misfolding during trafficking or premature triggering at the cell surface [135]
To avoid non-productive triggering events, the receptor binding protein (RBP) acts as a regulatory switch to ensure fusion protein activation occurs only when the target and viral membranes are in close proximity
Summary
The family Paramyxoviridae (Order: Mononegavirales, Class: Monjiviricetes, Subphylum: Haploviricotina, Phylum: Negarnaviricotina, Realm: Riboviria) comprises of enveloped, non-segmented negative-sense. Followingfusion receptor binding, undergoes a conformational change that protein, whichthe undergoes its own conformational cascade that allosterically triggers the metastable fusion protein, which undergoes its own conformational eventually facilitates the merging of the viral envelope with the host cell membrane. These findings inform the rational design of therapeutics that bind these targets and This particular review highlights the PMV entry pathway, focusing on the functional render thein virus unable to infect. 2. Modes of Receptor Binding binding protein (RBP) [1], to the host cell receptor is the first step in paramyxovirus (PMV) entry. (1) those thatReceptor bind to binding occurs on the globular head(e.g., domain of the which as a six-bladed β-propeller sialic acid-containing surface molecules viruses that RBP, comprise the folds. Avula-, respiro-, rubula-, ferla- and aquaparamyxo- viruses express RBPs that recognize sialic acids
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