A structure-based rationale for sialic acid independent host-cell entry of Sosuga virus

Abstract

The bat-borne paramyxovirus, Sosuga virus (SosV), is one of many paramyxoviruses recently identified and classified within the newly established genus Pararubulavirus, family Paramyxoviridae. The envelope surface of SosV presents a receptor-binding protein (RBP), SosV-RBP, which facilitates host-cell attachment and entry. Unlike closely related hemagglutinin neuraminidase RBPs from other genera of the Paramyxoviridae, SosV-RBP and other pararubulavirus RBPs lack many of the stringently conserved residues required for sialic acid recognition and hydrolysis. We determined the crystal structure of the globular head region of SosV-RBP, revealing that while the glycoprotein presents a classical paramyxoviral six-bladed β-propeller fold and structurally classifies in close proximity to paramyxoviral RBPs with hemagglutininneuraminidase (HN) functionality, it presents a receptor-binding face incongruent with sialic acid recognition. Hemadsorption and neuraminidase activity analysis confirms the limited capacity of SosV-RBP to interact with sialic acid in vitro and indicates that SosV-RBP undergoes a nonclassical route of host-cell entry. The close overall structural conservation of SosV-RBP with other classical HN RBPs supports a model by which pararubulaviruses only recently diverged from sialic acid binding functionality.virus-host interaction | viral attachment | paramyxovirus | structure | glycoprotein

Unraveling virus relationships by structure-based phylogenetic classification

“…It seems likely that SBPA will continue to play an important role in characterizing and rationalizing the pathobiological features of newly emerging viruses. Indeed, we have shown that this is possible for emerging paramyxoviruses, where the receptor-binding domain, an important determinant of host cell tropism, structurally classifies according to receptor specificity (Rissanen et al 2017;Stelfox and Bowden 2019;Pryce et al 2020) (Fig. 2B).…”

“…HN RBPs bind and hydrolyze sialic acid (Villar and Barroso 2006), H RBPs are presented by morbilliviruses and recognize SLAMF1 and nectin-4 receptors (Bieringer et al 2013;Birch et al 2013;Noyce, Delpeut, and Richardson 2013;Sakai et al 2013;Melia et al 2014;Ader-Ebert et al 2015;Alves et al 2015;Feng et al 2016;Khosravi et al 2016), and most henipaviral G RBPs are specific to ephrin receptors (Bonaparte et al 2005;Negrete et al 2005;Bowden, Jones, and Stuart 2011;Pernet, Wang, and Lee 2012;Rissanen et al 2017). SBPA of known paramyxoviral HN, H, and G RBP structures has shown that these viral proteins segregate according to receptor-specificity (Bowden et al 2008;Lee et al 2015;Rissanen et al 2017;Stelfox and Bowden 2019;Pryce et al 2020) (Fig. 2B).…”

“…Similarly, the zoonotic paramyxovirus, Sosuga virus (SosV) (Albarino et al 2014), also displays a distinct RBP structure, despite presenting some of the conserved residues known to be integral for sialic acid binding and hydrolysis. Indeed, unlike the HN RBPs of Newcastle disease virus (NDV) and mumps virus (MuV), for example, SosV-RBP presents a putative receptor-binding site incompatible with known modes of HN functionality (Stelfox and Bowden 2019). SBPA reflects the relatively close structural relationship, yet functional difference of SosV-RBP from HN RBPs (Fig.…”

“…b-propellerstructures known to bind sialic acid are highlighted with a light blue background, while b-propeller structures that bind proteinaceous receptors are highlighted with a light red background. Note, the RBP of SosV is annotated as an HN glycoprotein, however, the receptor is currently unknown(Bowden et al 2001;Chua et al 2002;Johnson et al 2019;Stelfox and Bowden 2019). Calculated evolutionary distances are indicated beside the branches.W.…”

Differential Features of Fusion Activation within the Paramyxoviridae

“…Finally, remaining members of the Orthoparamyxovirinae, that do not express HN or H proteins, possess G proteins that are either experimentally confirmed or predicted to bind proteinaceous receptors [28][29][30][31][32][33]. More recently, the RBP from members of the Pararubulavirus genera (e.g., Sosuga virus), presumed to contain HN activity, has been shown to not use SA-based receptors [34] (Figure 2 and below for more detailed discussion). The RBP binds the host receptor on the target cell.…”