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bioRxiv · 10.1101/2024.09.20.610514

Allosteric mechanism of membrane fusion activation in a herpesvirus

Gonzalez-Del Pino, G. L.·Walsh, R. M.·Atanasiu, D.·Cairns, T. M.·Saw, W. T.·Cohen, G. H.·Heldwein, E. E.
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Abstract

ABSTRACT/SUMMARYHerpesviridae infect nearly all humans for life, causing diseases that range from painful to life-threatening1. These viruses penetrate cells by employing a complex apparatus composed of separate receptor-binding, signal-transmitting, and membrane-fusing components2. But how these components coordinate their functions is unknown. Here, we determined the 4.19-angstrom cryoEM reconstruction of the central signal-transmitting component from herpes simplex virus 2, the gH/gL complex, in its elusive pre-activation state. Analysis of the continuum of conformational ensembles observed in cryoEM data revealed a series of structural rearrangements in gH/gL that allosterically transmit the fusion-triggering signal from the receptor-binding glycoprotein gD to the membrane fusogen gB. Furthermore, we identified a structural "switch" element in gH/gL that refolds and flips 180 degrees during the transition from pre-activation to activated form. Conservation of this "switch" in gH/gL homologs suggests that the proposed fusion triggering mechanism may apply to all Herpesviridae and points to a new target for subunit-based vaccines and treatment efforts.

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Gonzalez-Del Pino, G. L., Walsh, R. M., Atanasiu, D., Cairns, T. M., Saw, W. T., Cohen, G. H., Heldwein, E. E.. 2024-09-21. Allosteric mechanism of membrane fusion activation in a herpesvirus. https://doi.org/10.1101/2024.09.20.610514

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