Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus

Abstract

The discovery of African henipaviruses (HNVs) related to pathogenic Hendra virus (HeV) and Nipah virus (NiV) from Southeast Asia and Australia presents an open-ended health risk. Cell receptor use by emerging African HNVs at the stage of host-cell entry is a key parameter when considering the potential for spillover and infection of human populations. The attachment glycoprotein from a Ghanaian bat isolate (GhV-G) exhibits <30% sequence identity with Asiatic NiV-G/HeV-G. Here, through functional and structural analysis of GhV-G, we show how this African HNV targets the same human cell-surface receptor (ephrinB2) as the Asiatic HNVs. We first characterized this virus−receptor interaction crystallographically. Compared with extant HNV-G-ephrinB2 structures, there was significant structural variation in the six-bladed β-propeller scaffold of the GhV-G receptor-binding domain, but not the Greek key fold of the bound ephrinB2. Analysis revealed a surprisingly conserved mode of ephrinB2 interaction that reflects an ongoing evolutionary constraint among geographically distal and phylogenetically divergent HNVs to maintain the functionality of ephrinB2 recognition during virus-host entry. Interestingly, unlike NiV-G/HeV-G, we could not detect binding of GhV-G to ephrinB3. Comparative structurefunction analysis further revealed several distinguishing features of HNV-G function: a secondary ephrinB2 interaction site that contributes to more efficient ephrinB2-mediated entry in NiV-G relative to GhV-G and cognate residues at the very C terminus of GhV-G (absent in Asiatic HNV-Gs) that are vital for efficient receptorinduced fusion, but not receptor binding per se. These data provide molecular-level details for evaluating the likelihood of African HNVs to spill over into human populations.emerging virus | viral attachment | glycoprotein | henipavirus | structure

Idiosyncratic Mòjiāng virus attachment glycoprotein directs a host-cell entry pathway distinct from genetically related henipaviruses

“…5). In contrast to established paramyxoviral host-recognition glycoproteins, which cluster according to respective genera and cellular receptor usage30, the distal placement of MojV-G from HNV-G, H and HN glycoproteins indicates the absence of a functional and evolutionary constraint for MojV-G to utilize known paramyxoviral receptors.…”

Structure of a phleboviral envelope glycoprotein reveals a consolidated model of membrane fusion

“…Indeed, unpaired cysteines, with no obvious functional roles, have also been observed in other virus families. For example, such a free cysteine motif has been observed on the attachment glycoprotein of an African henipavirus (30).…”

Paramyxovirus Glycoproteins and the Membrane Fusion Process

“…Henipavirus (e.g. NiV or HeV) G glycoproteins utilize protein receptors such as ephrinB2 and/or ephrinB3 (23, 50–57). Interestingly, there are some viruses that do not require the attachment protein to trigger fusion, such as the pneumoviruses, hMPV and RSV (20, 22, 48, 58–60).…”