Phosphorylation barcodes direct biased chemokine signaling at CXCR3.

Autor:	Eiger DS; Department of Biochemistry, Duke University, Durham, NC 27710, USA., Smith JS; Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Dermatology Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA., Shi T; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Stepniewski TM; Research Program on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF), 08003 Barcelona, Spain., Tsai CF; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Honeycutt C; Trinity College, Duke University, Durham, NC 27710, USA., Boldizsar N; Trinity College, Duke University, Durham, NC 27710, USA., Gardner J; Trinity College, Duke University, Durham, NC 27710, USA., Nicora CD; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Moghieb AM; R&D Research, GlaxoSmithKline, Collegeville, PA 19426, USA., Kawakami K; Department of Pharmaceutical Sciences, Tohoku University, Sendai 980-8577, Japan., Choi I; Department of Medicine, Duke University, Durham, NC 27710, USA., Hicks C; Trinity College, Duke University, Durham, NC 27710, USA., Zheng K; Harvard Medical School, Boston, MA 02115, USA., Warman A; Trinity College, Duke University, Durham, NC 27710, USA., Alagesan P; Department of Biochemistry, Duke University, Durham, NC 27710, USA., Knape NM; Department of Biochemistry, Duke University, Durham, NC 27710, USA., Huang O; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA., Silverman JD; College of Information Sciences and Technology, The Pennsylvania State University, University Park, PA 16802, USA., Smith RD; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Inoue A; Department of Pharmaceutical Sciences, Tohoku University, Sendai 980-8577, Japan., Selent J; Research Program on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF), 08003 Barcelona, Spain., Jacobs JM; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., Rajagopal S; Department of Biochemistry, Duke University, Durham, NC 27710, USA; Department of Pharmaceutical Sciences, Tohoku University, Sendai 980-8577, Japan. Electronic address: sudarshan.rajagopal@duke.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2023 Apr 20; Vol. 30 (4), pp. 362-382.e8. Date of Electronic Publication: 2023 Apr 07.
DOI:	10.1016/j.chembiol.2023.03.006
Abstrakt:	G protein-coupled receptor (GPCR)-biased agonism, selective activation of certain signaling pathways relative to others, is thought to be directed by differential GPCR phosphorylation "barcodes." At chemokine receptors, endogenous chemokines can act as "biased agonists", which may contribute to the limited success when pharmacologically targeting these receptors. Here, mass spectrometry-based global phosphoproteomics revealed that CXCR3 chemokines generate different phosphorylation barcodes associated with differential transducer activation. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomics studies. Mutation of CXCR3 phosphosites altered β-arrestin 2 conformation in cellular assays and was consistent with conformational changes observed in molecular dynamics simulations. T cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles. Our results demonstrate that CXCR3 chemokines are non-redundant and act as biased agonists through differential encoding of phosphorylation barcodes, leading to distinct physiological processes. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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