Allosteric Mechanism of Membrane Fusion Activation in a Herpesvirus

Overview

Journal bioRxiv

Date 2024 Sep 30

PMID 39345478

Authors

Gonzalo L Gonzalez-Del Pino

Richard M Walsh Jr

Doina Atanasiu

Tina M Cairns

Wan Ting Saw

Gary H Cohen

Ekaterina E Heldwein

Affiliations

Soon will be listed here.

Abstract

infect nearly all humans for life, causing diseases that range from painful to life-threatening. These viruses penetrate cells by employing a complex apparatus composed of separate receptor-binding, signal-transmitting, and membrane-fusing components. 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 and points to a new target for subunit-based vaccines and treatment efforts.

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