Differential Features of Fusion Activation within the Paramyxoviridae

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.

Genome-wide transposon mutagenesis of paramyxoviruses reveals constraints on genomic plasticity

“…Despite using overlapping receptors, orthomyxoviruses (including influenza viruses) and paramyxoviruses have significantly different entry strategies: while the influenza virus HA glycoprotein coordinates both receptor binding and fusion in a single protein, it requires a separate protein (NA, neuraminidase) to release virions from infected cells. Paramyxoviruses, in contrast, contain neuraminidase (when needed) and receptor binding activities in a single protein (RBD), while using a separate protein (F) to initiate membrane fusion, and there is a tightly co-ordinated series of interactions between the RBD and F proteins during virus entry that likely varies among different paramyxovirus genera [ 20 ]. This co-ordinated interaction process likely introduces stringent constraints on both proteins to preserve interactions and capacity for structural rearrangements that are not present in influenza virus glycoproteins.…”

Cellular CARD11 Inhibits the Fusogenic Activity of Newcastle Disease Virus via CBM Signalosome-Mediated Furin Reduction in Chicken Fibroblasts

“…Then the syncytia died and were exfoliated to produce plaques on cell monolayers. To achieve the fusogenic activity of NDV, F , and HN are two transmembrane glycoproteins responsible for viral envelope fusion with host cell membranes, allowing viral entry into the cytoplasm of target cells to cause viral spread and cell-cell membrane fusion ( Gravel et al, 2011 ; Wang et al, 2017 ; Azarm and Lee, 2020 ). Both precursor F 0 and cleaved F (F 1 + F 2 ) are present on NDV virions ( Chambers and Samson, 1980 ; Yoshida et al, 1989 ).…”

Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes

“…The homologous leucine is conserved amongst all major paramyxoviruses (Fig 5A), as demonstrated by our alignment of the fusion peptide region from the indicated viruses. We chose an overrepresentation of F proteins from morbilliviruses and henipaviruses as paramyxoviruses that use protein-based receptors may have differential features for fusion activation 34 . Nonetheless, a phylogenetic tree shows that we chose prototypical viruses that span the diversity within the Paramyxoviridae (Fig 5B).…”