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Phenylalanines at positions 88 and 159 of Ebolavirus envelope glycoprotein differentially impact envelope function
Wu Ou1, Harlan King, Josie Delisle
1Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, FDA, Bethesda, MD 20892, USA.
Abstract:
The envelope glycoprotein (GP) of Ebolavirus (EBOV) mediates viral entry into host cells. Through mutagenesis, we and other groups reported that two phenylalanines at positions 88 and 159 of GP are critical for viral entry. However, it remains elusive which steps of viral entry are impaired by F88 or F159 mutations and how. In this study, we further characterized these two phenylalanines through mutagenesis and examined the impact on GP expression, function, and structure. Our data suggest that F159 plays an indirect role in viral entry by maintaining EBOV GP's overall structure. In contrast, we did not detect any evidence for conformational differences in GP with F88 mutations. The data suggest that F88 influences viral entry during a step after cathepsin processing, presumably impacting viral fusion.
Insights
Phenylalanines 88 and 159 in the Ebolavirus glycoprotein are crucial for viral entry. F159 maintains glycoprotein structure, while F88 impacts fusion after cathepsin processing.
Area of Science:
- Virology
- Molecular Biology
- Structural Biology
Background:
- The Ebolavirus envelope glycoprotein (GP) is essential for mediating viral entry into host cells.
- Previous studies identified two critical phenylalanines (F88 and F159) in GP for viral entry, but the precise mechanisms remain unclear.
Purpose of the Study:
- To elucidate the specific roles of F88 and F159 in Ebolavirus GP-mediated viral entry.
- To investigate the impact of mutations at these positions on GP expression, function, and structure.
Main Methods:
- Site-directed mutagenesis of Ebolavirus GP at positions 88 and 159.
- Analysis of GP expression levels.
- Functional assays to assess viral entry efficiency.
- Structural characterization of mutant GPs.
Main Results:
- Mutation of F159 did not cause detectable conformational changes but impaired viral entry, suggesting an indirect role in maintaining GP structure.
- Mutations at F88 did not alter GP conformation but affected viral entry at a post-cathepsin processing step, likely impacting viral fusion.
- F88 appears to be directly involved in the fusion process, while F159's role is structural.
Conclusions:
- F159 is critical for maintaining the overall structural integrity of Ebolavirus GP.
- F88 plays a distinct role in the viral entry pathway, specifically influencing the fusion step after cathepsin-mediated processing.
- Understanding these distinct roles can inform the development of antiviral strategies targeting Ebolavirus entry.
