Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
Liu, Aijun (Guangdong Medical University)
Liu, Yezhou (The Chinese University of Hong Kong)
Llinas del Torrent, Claudia (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Zhang, Weijia (The Chinese University of Hong Kong)
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Unitat de Bioestadística)
Ye, Richard D. (The Chinese University of Hong Kong)

Data:	2024
Resum:	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.
Ajuts:	Science, Technology and Innovation Commission of Shenzhen Municipality ((深圳市科技创新委员会) GXWD20201231105722002-20200831175432002 Shenzhen Municipal Science and Technology Innovation Council | Shenzhen Science and Technology Innovation Program (深圳市科技创新计划) RCBS20221008093330067 MOST | National Natural Science Foundation of China (NSFC) 32070950 China Postdoctoral Science Foundation (China Postdoctoral Foundation Project) 2022M713049
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Kaposi's sarcoma ; Chemokine ; KSHV-GPCR ; CXCL1 ; cryo-EM structure
Publicat a:	Proceedings of the National Academy of Sciences of the United States of America, Vol. 121 (october 2024) , ISSN 1091-6490

DOI: 10.1073/pnas.2403217121
PMID: 39378089

11 p, 7.3 MB

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