Cryo-Electron Microscopy Structure and Interactions of the Human Cytomegalovirus gHgLgO Trimer with Platelet-Derived Growth Factor Receptor Alpha

Liu, Jing; Vanarsdall, Adam L.; Chen, Donghua; Chin, Andrea; Johnson, David C.; Jardetzky, Theodore S.

doi:10.1128/mbio.02625-21

Cited by 2 publications

(2 citation statements)

References 59 publications

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“…Fig 9 shows the positions of peptides 19, 20, 32 and 33 in our recently acquired structure of the HCMV trimer (AD169 gH/gL with TR gO) bound to PDGFRα [40]. gO forms a globular structure attached to gL that interacts with three N-terminal domains of PDGFRα (DI-DIII), similar to the structure described by Kschonsak et al [36].…”

Section: Plos Pathogenssupporting

confidence: 63%

“…Their mutational screen of conserved gO sequences described a mutant form of gO involving a.a. 249-254 that exhibited highly reduced entry of cell-free virus, as well as mutations nearer the N-terminus of gO that reduced entry [32,39]. Recently, while this manuscript was being written, two detailed structures of the HCMV trimer in contact with PDGFRα were reported, including one from our group [36,40].…”

Section: Introductionmentioning

confidence: 99%

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Identification of functionally important domains of human cytomegalovirus gO that act after trimer binding to receptors

et al. 2022

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Human cytomegalovirus (HCMV) entry involves trimer (gH/gL/gO) that interacts with PDGFRα in fibroblasts. Entry into epithelial and endothelial cells requires trimer, which binds unidentified receptors, and pentamer (gH/gL/UL128-131), which binds neuropilin-2. To identify functionally important domains in trimer, we screened an overlapping 20-mer gO peptide library and identified two sets of peptides: 19/20 (a.a. 235–267) and 32/33 (a.a. 404–436) that could block virus entry. Soluble trimer containing wild type gO blocked HCMV entry, whereas soluble trimers with the 19/20 or 32/33 sequences mutated did not block entry. Interestingly, the mutant trimers retained the capacity to bind to cellular receptors including PDGFRα. Peptide 19/20 and 32/33 sequences formed a lobe extending from the surface of gO and an adjacent concave structure, respectively. Neither of these sets of sequences contacted PDGFRα. Instead, our data support a model in which the 19/20 and 32/33 trimer sequences function downstream of receptor binding, e.g. trafficking of HCMV into endosomes or binding to gB for entry fusion. We also screened for peptides that bound antibodies (Abs) in human sera, observing that peptides 20 and 26 bound Abs. These peptides engendered neutralizing Abs (NAbs) after immunization of rabbits and could pull out NAbs from human sera. Peptides 20 and 26 sequences represent the first NAb epitopes identified in trimer. These studies describe two important surfaces on gO defined by: i) peptides 19/20 and 32/33, which apparently act downstream of receptor binding and ii) peptide 26 that interacts with PDGFRα. Both these surfaces are targets of NAbs.

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Section: Plos Pathogenssupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Identification of functionally important domains of human cytomegalovirus gO that act after trimer binding to receptors

et al. 2022

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Well Put Together—A Guide to Accessorizing with the Herpesvirus gH/gL Complexes

Pino

Heldwein

2022

Viruses

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Herpesviruses are enveloped, double-stranded DNA viruses that infect a variety of hosts across the animal kingdom. Nine of these establish lifelong infections in humans, for which there are no cures and few vaccine or treatment options. Like all enveloped viruses, herpesviruses enter cells by fusing their lipid envelopes with a host cell membrane. Uniquely, herpesviruses distribute the functions of receptor engagement and membrane fusion across a diverse cast of glycoproteins. Two glycoprotein complexes are conserved throughout the three herpesvirus subfamilies: the trimeric gB that functions as a membrane fusogen and the heterodimeric gH/gL, the role of which is less clearly defined. Here, we highlight the conserved and divergent functions of gH/gL across the three subfamilies of human herpesviruses by comparing its interactions with a broad range of accessory viral proteins, host cell receptors, and neutralizing or inhibitory antibodies. We propose that the intrinsic structural plasticity of gH/gL enables it to function as a signal integration machine that can accept diverse regulatory inputs and convert them into a “trigger” signal that activates the fusogenic ability of gB.

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Cryo-Electron Microscopy Structure and Interactions of the Human Cytomegalovirus gHgLgO Trimer with Platelet-Derived Growth Factor Receptor Alpha

Cited by 2 publications

References 59 publications

Identification of functionally important domains of human cytomegalovirus gO that act after trimer binding to receptors

Identification of functionally important domains of human cytomegalovirus gO that act after trimer binding to receptors

Well Put Together—A Guide to Accessorizing with the Herpesvirus gH/gL Complexes

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