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bioRxiv · 10.1101/2022.03.14.484201

A surface pocket in the cytoplasmic domain of the herpes simplex virus fusogen gB controls membrane fusion

Pataki, Z.·Sanders, E. K.·Heldwein, E. E.
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Abstract

Membrane fusion during the entry of herpesviruses is carried out by the viral fusogen gB that is activated by its partner protein gH. Unusually, the fusogenic activity of gB is controlled by its cytoplasmic (or intraviral) domain (gBCTD) and, according to the current model, the gBCTD is a trimeric, inhibitory clamp that restrains gB in the prefusion conformation. But how the gBCTD clamp is released by gH is unclear. Here, we identified two new regulatory elements within gB and gH from the prototypical herpes simplex virus 1: a surface pocket within the gBCTD and residue V831 within the gH cytoplasmic tail. Mutagenesis and structural modeling suggest that gH V831 interacts with the gB pocket. The gB pocket is located above the "fault line" between adjacent protomers, and we hypothesize that insertion of the gH V831 wedge into the pocket serves to push the protomers apart. This releases the inhibitory clamp on the gB prefusion conformation and activates gB fusogenic activity. Both gB and gH are conserved across all herpesviruses, and this activation mechanism could be used by other gB homologs. Our proposed mechanism emphasizes a central role for the cytoplasmic regions in regulating the activity of a viral fusogen. AUTHOR SUMMARYHerpes simplex virus 1 (HSV-1) establishes lifelong infections in over a half of people and causes diseases ranging from oral or genital sores to blindness and brain inflammation. No vaccines or curative treatments are currently available. To infect cells, HSV-1 must first penetrate them by merging its lipid envelope with the membrane of the target cell. This process requires the collective actions of several viral and cellular proteins, notably, viral glycoproteins B and H (gB and gH). gH is thought to activate the fusogenic function of gB, but how the two proteins interact is unclear. Here, using mutational analysis, we have identified two new functional elements within the cytoplasmic regions of gB and gH: a surface pocket in gB and a single residue in gH, both of which are important for membrane fusion. Based on structural modeling, we propose that the gB pocket is the binding site for the gH residue, and that their interaction activates gB to cause membrane fusion. These findings extend our knowledge of the HSV-1 membrane fusion mechanism. Mechanistic understanding of HSV-1 entry is essential for understanding its pathogenesis and developing new strategies to prevent infections.

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Pataki, Z., Sanders, E. K., Heldwein, E. E.. 2022-03-14. A surface pocket in the cytoplasmic domain of the herpes simplex virus fusogen gB controls membrane fusion. https://doi.org/10.1101/2022.03.14.484201

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