The Roles of Histidines and Charged Residues as Potential Triggers of a Conformational Change in the Fusion Loop of Ebola Virus Glycoprotein

• Published in: PloS one Vol. 11; no. 3; p. e0152527
• Main Authors: Lee, Jinwoo, Gregory, Sonia M, Nelson, Elizabeth A, White, Judith M, Tamm, Lukas K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.03.2016; Public Library of Science (PLoS)
• Subjects: Amino Acid Sequence; Biochemistry; Biology and Life Sciences; Cell fusion; Circular Dichroism; Crystal structure; Ebola virus; Ebolavirus; Ebolavirus - metabolism; Endosomes; Genetic aspects; Glycoproteins; Histidine - metabolism; Hydrogen ions; Hydrogen-Ion Concentration; Influenza; Insertion; Lipids; Lysosomes; Magnetic Resonance Spectroscopy; Membrane fusion; Membranes; Molecular Sequence Data; Mutagenesis; NMR; Nuclear magnetic resonance; pH effects; Physical Sciences; Physics; Physiological aspects; Physiology; Protein Structure, Secondary; Proteins; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Research and analysis methods; Residues; Sequence Alignment; Structure-Activity Relationship; Studies; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism; Viral proteins; Virus-like particles; Viruses; United States; United States > US; Virginia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152527

Ebola virus (EBOV) enters cells from late endosomes/lysosomes under mildly acidic conditions. Entry by fusion with the endosomal membrane requires the fusion loop (FL, residues 507-560) of the EBOV surface glycoprotein to undergo a pH-dependent conformational change. To find the pH trigger for this reaction we mutated multiple conserved histidines and charged and uncharged hydrophilic residues in the FL and measured their activity by liposome fusion and cell entry of virus-like particles. The FL location in the membrane was assessed by NMR using soluble and lipid-bound paramagnetic relaxation agents. While we could not identify a single residue to be alone responsible for pH triggering, we propose that a distributed pH effect over multiple residues induces the conformational change that enhances membrane insertion and triggers the fusion activity of the EBOV FL.