Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
KSHV-GPCR is a cell surface receptor encoded by the genome of Kaposi's sarcoma-associated herpesvirus that, when expressed in host cells, causes angiogenic tumor of proliferative endothelial cells. The present study investigates the structural basis for constitutive activation of KSHV-GPCR and...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:322325 |
| Acceso en línea: | https://ddd.uab.cat/record/322325 https://dx.doi.org/urn:doi:10.1073/pnas.2403217121 |
| Access Level: | acceso abierto |
| Palabra clave: | Kaposi's sarcoma Chemokine KSHV-GPCR CXCL1 cryo-EM structure |
| Sumario: | KSHV-GPCR is a cell surface receptor encoded by the genome of Kaposi's sarcoma-associated herpesvirus that, when expressed in host cells, causes angiogenic tumor of proliferative endothelial cells. The present study investigates the structural basis for constitutive activation of KSHV-GPCR and its modulation by chemokines. Our structural models indicate that KSHV-GPCR uses its extracellular loop 2 for self-activation without ligand stimulation, but it retains the ability of binding and responding to the chemokine CXCL1 that further enhances its angiogenic activity. Our findings demonstrate structural features for the unique dual activation mechanism employed by this viral GPCR for immune evasion and angiogenic proliferation, that may be targeted for antiviral therapy. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi's sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. Like other herpesvirus-encoded GPCRs, KSHV-GPCR is characterized by its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent and constitutive activation of KSHV-GPCR, obtaining high-resolution cryo-EM structures of KSHV-GPCR-Gi complexes with and without the bound CXCL1 chemokine. Analysis of the apo-KSHV-GPCR-Gi structure (2.81 Å) unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. In comparison, the CXCL1-bound KSHV-GPCR-Gi structure (3.01 Å) showed a two-site binding mode and provided detailed information of CXCL1 binding to a chemokine receptor. The dual activation mechanism employed by KSHV-GPCR represents an evolutionary adaptation for immune evasion and contributes to the pathogenesis of Kaposi's sarcoma. Together with results from functional assays that confirmed the structural models, these findings may help to develop therapeutic strategies for KSHV infection. |
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