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

Authors :
Natasha D. Durham
Angela R. Howard
Ramesh Govindan
Fernando Senjobe
J. Maximilian Fels
William E. Diehl
Jeremy Luban
Kartik Chandran
James B. Munro
Source :
Viruses, Vol 12, Iss 1, p 103 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

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.

Details

Language :
English
ISSN :
19994915 and 12010103
Volume :
12
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Viruses
Publication Type :
Academic Journal
Accession number :
edsdoj.bcdb787ba87e49aa8b5f334b67dd47fe
Document Type :
article
Full Text :
https://doi.org/10.3390/v12010103