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PLoS Negl Trop Dis. 2011 Nov;5(11):e1395. doi: 10.1371/journal.pntd.0001395. Epub 2011 Nov 15.

Ebola virus glycoprotein needs an additional trigger, beyond proteolytic priming for membrane fusion.

Author information

1
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.

Abstract

BACKGROUND:

Ebolavirus belongs to the family filoviridae and causes severe hemorrhagic fever in humans with 50-90% lethality. Detailed understanding of how the viruses attach to and enter new host cells is critical to development of medical interventions. The virus displays a trimeric glycoprotein (GP(1,2)) on its surface that is solely responsible for membrane attachment, virus internalization and fusion. GP(1,2) is expressed as a single peptide and is cleaved by furin in the host cells to yield two disulphide-linked fragments termed GP1 and GP2 that remain associated in a GP(1,2) trimeric, viral surface spike. After entry into host endosomes, GP(1,2) is enzymatically cleaved by endosomal cathepsins B and L, a necessary step in infection. However, the functional effects of the cleavage on the glycoprotein are unknown.

PRINCIPAL FINDINGS:

We demonstrate by antibody binding and Hydrogen-Deuterium Exchange Mass Spectrometry (DXMS) of glycoproteins from two different ebolaviruses that although enzymatic priming of GP(1,2) is required for fusion, the priming itself does not initiate the required conformational changes in the ectodomain of GP(1,2). Further, ELISA binding data of primed GP(1,2) to conformational antibody KZ52 suggests that the low pH inside the endosomes also does not trigger dissociation of GP1 from GP2 to effect membrane fusion.

SIGNIFICANCE:

The results reveal that the ebolavirus GP(1,2) ectodomain remains in the prefusion conformation upon enzymatic cleavage in low pH and removal of the glycan cap. The results also suggest that an additional endosomal trigger is necessary to induce the conformational changes in GP(1,2) and effect fusion. Identification of this trigger will provide further mechanistic insights into ebolavirus infection.

PMID:
22102923
PMCID:
PMC3216919
DOI:
10.1371/journal.pntd.0001395
[Indexed for MEDLINE]
Free PMC Article

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