Biology subjects

Cohen, G. H.

Publications and source records attributed to Cohen, G. H..

3 recordsLinked to original sources

bioRxiv2025

Unveiling the unique interaction mechanism of herpes simplex virus 2 glycoprotein C with C3b

AbstractThe complement cascade is part of the first line of defence against viral infections, and many viruses have evolved to block it. For example, glycoprotein C (gC) from Herpes Simplex Virus 1 and 2 (gC1 and gC2) facilitates infection by modulating the complement cascade through an interaction with C3b. gC is also involved in attachment and other viral processes. However, our understanding of the molecular mechanisms of gC have been limited due to the absence of a structure. AlphaFold predicts that gC contains a disordered N-terminus and three immunoglobulin-like domains. Here, we generated various gC2 constructs and demonstrated that gC2 domains 1 and 2 are necessary and sufficient to interact with C3b and block the alternative pathway. A gC2 construct lacking the N-terminus in complex with C3b was characterised by cryo-EM at 3.6 [A], providing the first structure for gC2, and revealing that the interaction is predominantly driven by gC2 domain 2 and the MG8 domain of C3b. This structure was confirmed by cross-linking mass spectrometry and by using C3b-blocking antibodies that recognised gC2 linear epitopes at the interface with C3b. Overall, the gC-C3b interaction is different from other C3b-interacting partners, providing a novel mechanism to regulate the complement cascade.

molecular biology↗

bioRxiv2025

Antibody Binding and Neutralizing Targets within the Predicted Structure of the Poxvirus Multiprotein Entry-Fusion Complex

The increased incidence of mpox emphasizes a need for new and improved vaccines. Poxviruses rely on a highly conserved but poorly characterized 11-protein entry-fusion complex (EFC), providing numerous potential targets. Here, we demonstrate that antibodies induced by six of 10 EFC proteins are neutralizing. Protein targets of the neutralizing and non-neutralizing antibodies are located within discrete regions of a model of the EFC predicted by AlphaFold3. Two newly identified targets, A16 and G9, at the apex of the EFC induced cross-neutralizing orthopoxvirus antibodies and protected female mice against a lethal VACV infection. Unexpectedly, antibodies to A16 and G9 were not detected following infection by attenuated or pathogenic VACV, likely due to physical sequestration of the proteins in the viral membrane. Our findings provide a model for the physical, immunogenic and antigenic structure of the EFC, new immunogens for incorporation into recombinant vaccines and suggest a novel poxvirus immune evasion strategy. 150 words.

microbiology↗

bioRxiv2024

Allosteric mechanism of membrane fusion activation in a herpesvirus

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.

microbiology↗