title: 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 structure-function 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 receptor-induced 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.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; thomas.bowden@strubi.ox.ac.uk benhur.lee@mssm.edu.
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;
authors.forename: Olivier
authors.initials: O
authors.lastname: Pernet
authors.affiliation: Division of Infectious Disease, Boston Children's Hospital, Boston, MA 02115; and.
authors.forename: Asim A
authors.initials: AA
authors.lastname: Ahmed
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Antra
authors.initials: A
authors.lastname: Zeltina
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Beaty
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom thomas.bowden@strubi.ox.ac.uk benhur.lee@mssm.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bowden
mesh_terms: D036388:Ephrin-B2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D036389:Ephrin-B3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D045403:Henipavirus / Q000737:chemistry / Q000502:physiology; D045464:Henipavirus Infections / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D036388:Ephrin-B2; D036389:Ephrin-B3; D014764:Viral Proteins
keywords: emerging virus; glycoprotein; henipavirus; structure; viral attachment
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