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...

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Autores: Liu, Aijun, Liu, Yezhou|||0000-0001-7575-8260, Llinas del Torrent, Claudia|||0000-0002-6772-6856, Zhang, Weijia, Pardo Carrasco, Leonardo|||0000-0003-1778-7420, Ye, Richard D.|||0000-0002-2164-5620
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
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spelling Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognitionLiu, AijunLiu, Yezhou|||0000-0001-7575-8260Llinas del Torrent, Claudia|||0000-0002-6772-6856Zhang, WeijiaPardo Carrasco, Leonardo|||0000-0003-1778-7420Ye, Richard D.|||0000-0002-2164-5620Kaposi's sarcomaChemokineKSHV-GPCRCXCL1cryo-EM structureKSHV-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. 22024-01-0120242024-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/322325https://dx.doi.org/urn:doi:10.1073/pnas.2403217121reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengScience, Technology and Innovation Commission of Shenzhen Municipality ((深圳市科技创新委员会) 501100010877 GXWD20201231105722002-20200831175432002Shenzhen Municipal Science and Technology Innovation Council | Shenzhen Science and Technology Innovation Program (深圳市科技创新计划) 501100017610 RCBS20221008093330067MOST | National Natural Science Foundation of China (NSFC) 501100001809 32070950China Postdoctoral Science Foundation (China Postdoctoral Foundation Project) 501100002858 2022M713049open accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3223252026-06-06T12:50:31Z
dc.title.none.fl_str_mv Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
title Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
spellingShingle Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
Liu, Aijun
Kaposi's sarcoma
Chemokine
KSHV-GPCR
CXCL1
cryo-EM structure
title_short Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
title_full Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
title_fullStr Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
title_full_unstemmed Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
title_sort Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition
dc.creator.none.fl_str_mv Liu, Aijun
Liu, Yezhou|||0000-0001-7575-8260
Llinas del Torrent, Claudia|||0000-0002-6772-6856
Zhang, Weijia
Pardo Carrasco, Leonardo|||0000-0003-1778-7420
Ye, Richard D.|||0000-0002-2164-5620
author Liu, Aijun
author_facet Liu, Aijun
Liu, Yezhou|||0000-0001-7575-8260
Llinas del Torrent, Claudia|||0000-0002-6772-6856
Zhang, Weijia
Pardo Carrasco, Leonardo|||0000-0003-1778-7420
Ye, Richard D.|||0000-0002-2164-5620
author_role author
author2 Liu, Yezhou|||0000-0001-7575-8260
Llinas del Torrent, Claudia|||0000-0002-6772-6856
Zhang, Weijia
Pardo Carrasco, Leonardo|||0000-0003-1778-7420
Ye, Richard D.|||0000-0002-2164-5620
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Kaposi's sarcoma
Chemokine
KSHV-GPCR
CXCL1
cryo-EM structure
topic Kaposi's sarcoma
Chemokine
KSHV-GPCR
CXCL1
cryo-EM structure
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2
2024-01-01
2024
2024-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/322325
https://dx.doi.org/urn:doi:10.1073/pnas.2403217121
url https://ddd.uab.cat/record/322325
https://dx.doi.org/urn:doi:10.1073/pnas.2403217121
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Science, Technology and Innovation Commission of Shenzhen Municipality ((深圳市科技创新委员会) 501100010877 GXWD20201231105722002-20200831175432002
Shenzhen Municipal Science and Technology Innovation Council | Shenzhen Science and Technology Innovation Program (深圳市科技创新计划) 501100017610 RCBS20221008093330067
MOST | National Natural Science Foundation of China (NSFC) 501100001809 32070950
China Postdoctoral Science Foundation (China Postdoctoral Foundation Project) 501100002858 2022M713049
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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