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Platelet-derived growth factor-? receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer.

ABSTRACT: Human cytomegalovirus encodes at least 25 membrane glycoproteins that are found in the viral envelope(1). While gB represents the fusion protein, two glycoprotein complexes control the tropism of the virus: the gHgLgO trimer is involved in the infection of fibroblasts, and the gHgLpUL128L pentamer is required for infection of endothelial, epithelial and myeloid cells(2-5). Two reports suggested that gB binds to ErbB1 and PDGFR? (refs 6,7); however, these results do not explain the tropism of the virus and were recently challenged(8,9). Here, we provide a 19?Å reconstruction for the gHgLgO trimer and show that it binds with high affinity through the gO subunit to PDGFR?, which is expressed on fibroblasts but not on epithelial cells. We also provide evidence that the trimer is essential for viral entry in both fibroblasts and epithelial cells. Furthermore, we identify the pentamer, which is essential for infection of epithelial cells, as a trigger for the ErbB pathway. These findings help explain the broad tropism of human cytomegalovirus and indicate that PDGFR? and the viral gO subunit could be targeted by novel anti-viral therapies.

SUBMITTER: Kabanova A

PROVIDER: S-EPMC4918640 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Platelet-derived growth factor-α receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer.

Kabanova Anna A Marcandalli Jessica J Zhou Tongqing T Bianchi Siro S Baxa Ulrich U Tsybovsky Yaroslav Y Lilleri Daniele D Silacci-Fregni Chiara C Foglierini Mathilde M Fernandez-Rodriguez Blanca Maria BM Druz Aliaksandr A Zhang Baoshan B Geiger Roger R Pagani Massimiliano M Sallusto Federica F Kwong Peter D PD Corti Davide D Lanzavecchia Antonio A Perez Laurent L

Nature microbiology 20160606 8

Human cytomegalovirus encodes at least 25 membrane glycoproteins that are found in the viral envelope(1). While gB represents the fusion protein, two glycoprotein complexes control the tropism of the virus: the gHgLgO trimer is involved in the infection of fibroblasts, and the gHgLpUL128L pentamer is required for infection of endothelial, epithelial and myeloid cells(2-5). Two reports suggested that gB binds to ErbB1 and PDGFRα (refs 6,7); however, these results do not explain the tropism of the ...[more]

PMID: 27573107

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Project description:Human cytomegalovirus (HCMV) is a herpesvirus that produces disease in transplant patients and newborn children. Entry of HCMV into cells relies on gH/gL trimer (gHgLgO) and pentamer (gHgLUL128-131) complexes that bind cellular receptors. Here, we studied the structure and interactions of the HCMV trimer, formed by AD169 strain gH and gL and TR strain gO proteins, with the human platelet-derived growth factor receptor alpha (PDGFRα). Three trimer surfaces make extensive contacts with three PDGFRα N-terminal domains, causing PDGFRα to wrap around gO in a structure similar to a human hand, explaining the high-affinity interaction. gO is among the least conserved HCMV proteins, with 8 distinct genotypes. We observed high conservation of residues mediating gO-gL interactions but more extensive gO variability in the PDGFRα interface. Comparisons between our trimer structure and a previously determined structure composed of different subunit genotypes indicate that gO variability is accommodated by adjustments in the gO-PDGFRα interface. We identified two loops within gO that were disordered and apparently glycosylated, which could be deleted without disrupting PDGFRα binding. We also identified four gO residues that contact PDGFRα, which when mutated produced markedly reduced receptor binding. These residues fall within conserved contact sites of gO with PDGFRα and may represent key targets for anti-trimer neutralizing antibodies and HCMV vaccines. Finally, we observe that gO mutations distant from the gL interaction site impact trimer expression, suggesting that the intrinsic folding or stability of gO can impact the efficiency of trimer assembly. IMPORTANCE HCMV is a herpesvirus that infects a large percentage of the adult population and causes significant levels of disease in immunocompromised individuals and birth defects in the developing fetus. The virus encodes a complex protein machinery that coordinates infection of different cell types in the body, including a trimer formed of gH, gL, and gO subunits. Here, we studied the interactions of the HCMV trimer with its receptor on cells, the platelet derived growth factor receptor α (PDGFRα), to better understand how HCMV coordinates virus entry into cells. Our results add to our understanding of HCMV strain-specific differences and identify sites on the trimer that represent potential targets for therapeutic antibodies or vaccine development.

Dataset Information

Platelet-derived growth factor-? receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer.

Publications

Platelet-derived growth factor-α receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer.

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