Cathepsin Cleavage Potentiates the Ebola Virus Glycoprotein To Undergo a Subsequent Fusion-Relevant Conformational Change
| Autor: | Sue E. Delos, Kathryn L. Schornberg, Erica Ollmann Saphire, Matthew Brecher, Marnie L. Fusco, Judith M. White |
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| Rok vydání: | 2011 |
| Předmět: |
Conformational change
Protein Conformation Endosome Cathepsin L Immunology Mutant Endosomes Biology medicine.disease_cause Membrane Fusion Microbiology Virus Cell Line Pseudovirion Viral Envelope Proteins Virology medicine Humans Cathepsin chemistry.chemical_classification Ebola virus Hemorrhagic Fever Ebola Ebolavirus Virus-Cell Interactions Cell biology Biochemistry chemistry Insect Science Glycoprotein Protein Processing Post-Translational |
| Zdroj: | Journal of Virology |
| ISSN: | 0022-538X |
| DOI: | 10.1128/jvi.05708-11 |
| Popis: | Cellular entry of Ebola virus (EBOV), a deadly hemorrhagic fever virus, is mediated by the viral glycoprotein (GP). The receptor-binding subunit of GP must be cleaved (by endosomal cathepsins) in order for entry and infection to proceed. Cleavage appears to proceed through 50-kDa and 20-kDa intermediates, ultimately generating a key 19-kDa core. How 19-kDa GP is subsequently triggered to bind membranes and induce fusion remains a mystery. Here we show that 50-kDa GP cannot be triggered to bind to liposomes in response to elevated temperature but that 20-kDa and 19-kDa GP can. Importantly, 19-kDa GP can be triggered at temperatures ∼10°C lower than 20-kDa GP, suggesting that it is the most fusion ready form. Triggering by heat (or urea) occurs only at pH 5, not pH 7.5, and involves the fusion loop, as a fusion loop mutant is defective in liposome binding. We further show that mild reduction (preferentially at low pH) triggers 19-kDa GP to bind to liposomes, with the wild-type protein being triggered to a greater extent than the fusion loop mutant. Moreover, mild reduction inactivates pseudovirion infection, suggesting that reduction can also trigger 19-kDa GP on virus particles. Our results support the hypothesis that priming of EBOV GP, specifically to the 19-kDa core, potentiates GP to undergo subsequent fusion-relevant conformational changes. Our findings also indicate that low pH and an additional endosomal factor (possibly reduction or possibly a process mimicked by reduction) act as fusion triggers. |
| Databáze: | OpenAIRE |
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