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

DOI: 10.1073/pnas.1501690112
PMID: 25825759

Authors: Benhur Lee (Icahn School of Medicine at Mount Sinai) , Olivier Pernet (David Geffen School of Medicine at UCLA) , Asim A. Ahmed (Boston Children’s Hospital, Boston) , Antra Zeltina (University of Oxford) , Shannon M. Beaty (Icahn School of Medicine at Mount Sinai) , Thomas Bowden (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 112 (17) , PAGES E2156 - E2165

State: Published (Approved)
Published: April 2015
Diamond Proposal Number(s): 10627

Abstract: The discovery of African henipaviruses (HNVs) related to patho- genic 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 in- fection 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 sig- nificant 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 diver- gent 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 con- tributes 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.

Journal Keywords: Emerging Virus; Viral Attachment; Glycoprotein; Henipavirus; Structure

Diamond Keywords: Henipaviruses; Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 23/09/2015 12:13

Documents:
pnas.1501690112.pdf

Discipline Tags:

Vaccines Pathogens Infectious Diseases Disease in the Developing World Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)