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Phosphorylation barcodes encoded by CXCR3 agonists direct biased chemokine signaling

ABSTRACT: Chemokine receptors (CKRs), a class of G protein-coupled receptors (GPCRs), interact with transducers like G proteins and β-arrestins. Many chemokines act as “biased agonists” that activate certain transducers over others. There has been limited success in pharmacologically targeting CKRs, with little evidence that differential receptor phosphorylation, or “phosphorylation barcodes,” direct biased responses. Here, we used mass spectrometry to demonstrate that CXCR3 chemokines generate different phosphorylation barcodes associated with differential activation of transducers. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of CXCR3 phosphosites altered β-arrestin conformation and activation in molecular dynamics simulations. T-cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles not completely explained by engagement of G proteins and β-arrestins. Our results demonstrate that CXCR3 chemokines act as biased agonists through differential encoding of phosphorylation barcodes, and highlight the limitations of assessing GPCR physiology with proximal effector activity alone.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Sudarshan Rajagopal

PROVIDER: PXD034033 | JPOST Repository | Wed May 24 00:00:00 BST 2023

REPOSITORIES: jPOST

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			Action	DRS
	CXCR3_TMT_04_Phos_31Oct18_Polaroid_AQ-18-10-01.raw	Raw
	CXCR3_TMT_05_Lumos_Re-Run_1Dec18_Polaroid_18-11-01.raw	Raw
	CXCR3_TMT_05_Phos_31Oct18_Polaroid_AQ-18-10-01.raw	Raw
	CXCR3_TMT_06_Lumos_Re-Run_1Dec18_Polaroid_18-11-01.raw	Raw
	CXCR3_TMT_06_Phos_31Oct18_Polaroid_AQ-18-10-01.raw	Raw

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