TY - JOUR
T1 - Phosphorylation barcodes direct biased chemokine signaling at CXCR3
AU - Eiger, Dylan S.
AU - Smith, Jeffrey S.
AU - Shi, Tujin
AU - Stepniewski, Tomasz Maciej
AU - Tsai, Chia Feng
AU - Honeycutt, Christopher
AU - Boldizsar, Noelia
AU - Gardner, Julia
AU - Nicora, Carrie D.
AU - Moghieb, Ahmed M.
AU - Kawakami, Kouki
AU - Choi, Issac
AU - Hicks, Chloe
AU - Zheng, Kevin
AU - Warman, Anmol
AU - Alagesan, Priya
AU - Knape, Nicole M.
AU - Huang, Ouwen
AU - Silverman, Justin D.
AU - Smith, Richard D.
AU - Inoue, Asuka
AU - Selent, Jana
AU - Jacobs, Jon M.
AU - Rajagopal, Sudarshan
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/4/20
Y1 - 2023/4/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chembiol.2023.03.006
DO - 10.1016/j.chembiol.2023.03.006
M3 - Article
C2 - 37030291
AN - SCOPUS:85152733478
SN - 2451-9456
VL - 30
SP - 362-382.e8
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 4
ER -