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Structure-Function Analysis of Herpesvirus Glycoprotein H

Subject Area Virology
Term from 2011 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 203064123
 
Final Report Year 2020

Final Report Abstract

Herpesvirus infection requires a species-specific receptor binding protein and the conserved fusion machinery consisting of glycoprotein B (gB) and the heterodimeric gH/gL complex. gB specifies all features of a class III fusion protein. However, in contrast to other class III fusogens gB alone is not fusion active but depends on presence of gH/gL. It is hypothesized that structural rearrangements after receptor binding activate the gH/gL complex, which then triggers gB fusogenic activity. However, many molecular details and especially the role of gH/gL remained unknown. The crystal structures of gH or gH/gL from several herpesviruses including the porcine alphaherpesvirus Pseudorabiesvirus (PrV), uncovered four highly conserved domains despite only low amino acid sequence identity. We speculated that distinct rearrangements between these domains triggers gB-mediated membrane fusion. Targeted deletion or introduction of specific mutations at various sites within gH, which prohibited the intramolecular movement supported our hypothesis. In a parallel approach, we assessed gH function by selecting for PrV revertants after repeated co-seeding of infected and non-infected cells which were capable to infect cells without gL. The identified compensatory mutations not only shed light on gH/gL function in membrane fusion but also uncovered a finely tuned but also highly flexible interplay between the different entry glycoproteins. Then, we concentrated on PrV gB by elucidating its 3D-structure and finally succeeded in isolating an autonomously fusogenic herpesvirus gB.

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