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 Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM), Barcelona, 08003, 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., Zheng K; Trinity College, Duke University, Durham, NC, 27710, 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 Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM), Barcelona, 08003, 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.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 14. Date of Electronic Publication: 2023 Mar 14.
DOI:	10.1101/2023.03.14.532634
Abstrakt:	G protein-coupled receptor (GPCR) biased agonism, the activation of some signaling pathways over others, is thought to largely be due to differential receptor phosphorylation, or "phosphorylation barcodes." At chemokine receptors, ligands act as "biased agonists" with complex signaling profiles, which contributes to the limited success in 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 phosphoproteomic studies. Mutation of CXCR3 phosphosites altered β-arrestin conformation in cellular assays and was confirmed by 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 and lead to distinct physiological processes. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Databáze:	MEDLINE
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