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Open AccessArticle

Real-Time Analysis of Individual Ebola Virus Glycoproteins Reveals Pre-Fusion, Entry-Relevant Conformational Dynamics

1
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
2
Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, USA
3
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
4
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2020, 12(1), 103; https://doi.org/10.3390/v12010103
Received: 16 December 2019 / Revised: 9 January 2020 / Accepted: 10 January 2020 / Published: 15 January 2020
(This article belongs to the Special Issue Mechanisms of Viral Fusion and Applications in Antivirals)
The Ebola virus (EBOV) envelope glycoprotein (GP) mediates the fusion of the virion membrane with the membrane of susceptible target cells during infection. While proteolytic cleavage of GP by endosomal cathepsins and binding of the cellular receptor Niemann-Pick C1 protein (NPC1) are essential steps for virus entry, the detailed mechanisms by which these events promote membrane fusion remain unknown. Here, we applied single-molecule Förster resonance energy transfer (smFRET) imaging to investigate the structural dynamics of the EBOV GP trimeric ectodomain, and the functional transmembrane protein on the surface of pseudovirions. We show that in both contexts, pre-fusion GP is dynamic and samples multiple conformations. Removal of the glycan cap and NPC1 binding shift the conformational equilibrium, suggesting stabilization of conformations relevant to viral fusion. Furthermore, several neutralizing antibodies enrich alternative conformational states. This suggests that these antibodies neutralize EBOV by restricting access to GP conformations relevant to fusion. This work demonstrates previously unobserved dynamics of pre-fusion EBOV GP and presents a platform with heightened sensitivity to conformational changes for the study of GP function and antibody-mediated neutralization. View Full-Text
Keywords: Ebola virus; envelope glycoprotein; conformational dynamics; single-molecule FRET; virus entry Ebola virus; envelope glycoprotein; conformational dynamics; single-molecule FRET; virus entry
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Durham, N.D.; Howard, A.R.; Govindan, R.; Senjobe, F.; Fels, J.M.; Diehl, W.E.; Luban, J.; Chandran, K.; Munro, J.B. Real-Time Analysis of Individual Ebola Virus Glycoproteins Reveals Pre-Fusion, Entry-Relevant Conformational Dynamics. Viruses 2020, 12, 103.

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