Monomeric ephrinB2 binding induces allosteric changes in Nipah virus G that precede its full activation

• Published in: Nature communications 2017-10, Vol.8 (1), p.781-11, Article 781
• Main Authors: Wong, Joyce J. W., Young, Tracy A., Zhang, Jiayan, Liu, Shiheng, Leser, George P., Komives, Elizabeth A., Lamb, Robert A., Zhou, Z. Hong, Salafsky, Joshua, Jardetzky, Theodore S.
• Format: Article
• Language: English
• Subjects: 631/45; 631/57; Allosteric properties; Allosteric Regulation; Antibodies, Monoclonal - metabolism; Binding; Cell fusion; Cell surface; Change detection; Deuterium; Deuterium Exchange Measurement; Electron microscopy; Encephalitis; Ephrin-B2 - metabolism; F protein; Fusion protein; Glycoproteins; HEK293 Cells; Humanities and Social Sciences; Humans; Infections; Mass Spectrometry; Membrane fusion; Membrane proteins; Monoclonal antibodies; multidisciplinary; Mutant Proteins - metabolism; Mutant Proteins - ultrastructure; Negative Staining; Nipah virus; Nipah Virus - metabolism; Protein Binding; Protein folding; Protein G; Protein Multimerization; Proteins; Receptors; Science; Science (multidisciplinary); Second harmonic generation; Viral Envelope Proteins - metabolism; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00863-3

Nipah virus is an emergent paramyxovirus that causes deadly encephalitis and respiratory infections in humans. Two glycoproteins coordinate the infection of host cells, an attachment protein (G), which binds to cell surface receptors, and a fusion (F) protein, which carries out the process of virus-cell membrane fusion. The G protein binds to ephrin B2/3 receptors, inducing G conformational changes that trigger F protein refolding. Using an optical approach based on second harmonic generation, we show that monomeric and dimeric receptors activate distinct conformational changes in G. The monomeric receptor-induced changes are not detected by conformation-sensitive monoclonal antibodies or through electron microscopy analysis of G:ephrinB2 complexes. However, hydrogen/deuterium exchange experiments confirm the second harmonic generation observations and reveal allosteric changes in the G receptor binding and F-activating stalk domains, providing insights into the pathway of receptor-activated virus entry. Nipah virus causes encephalitis in humans. Here the authors use a multidisciplinary approach to study the binding of the viral attachment protein G to its host receptor ephrinB2 and show that monomeric and dimeric receptors activate distinct conformational changes in G and discuss implications for receptor-activated virus entry.