{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Chen Q"],"funding":["NIAID NIH HHS","NHLBI NIH HHS","NCI NIH HHS","NIGMS NIH HHS"],"pagination":["280-287"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12445016"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["643(8070)"],"pubmed_abstract":["Unique phosphorylation 'barcodes' installed in different regions of an active seven-transmembrane receptor by different G-protein-coupled receptor (GPCR) kinases (GRKs) have been proposed to promote distinct cellular outcomes<sup>1</sup>, but it is unclear whether or how arrestins differentially engage these barcodes. Here, to address this, we developed an antigen-binding fragment (Fab7) that recognizes both active arrestin2 (β-arrestin1) and arrestin3 (β-arrestin2) without interacting with bound receptor polypeptides. We used Fab7 to determine the structures of both arrestins in complex with atypical chemokine receptor 3 (ACKR3) phosphorylated in different regions of its C-terminal tail by either GRK2 or GRK5 (ref. <sup>2</sup>). The GRK2-phosphorylated ACKR3 resulted in more heterogeneous 'tail-mode' assemblies, whereas phosphorylation by GRK5 resulted in more rigid 'ACKR3-adjacent' assemblies. Unexpectedly, the finger loops of both arrestins engaged the micelle surface rather than the receptor intracellular pocket, with arrestin3 being more dynamic, partly because of its lack of a membrane-anchoring motif. Thus, both the region of the barcode and the arrestin isoform involved can alter the structure and dynamics of GPCR-arrestin complexes, providing a possible mechanistic basis for unique downstream cellular effects, such as the efficiency of chemokine scavenging and the robustness of arrestin binding in ACKR3."],"journal":["Nature"],"pubmed_title":["Effect of phosphorylation barcodes on arrestin binding to a chemokine receptor."],"pmcid":["PMC12445016"],"funding_grant_id":["F32 GM137505","P30 CA023168","R01 GM117372","R01 GM133840","R01 AI161880","R01 HL071818","R01 CA254402","R35 GM151033","R01 CA221289"],"pubmed_authors":["Kihara D","Chen Q","Fuller JR","Lamme TD","Terashi G","Handel TM","Schafer CT","Tesmer JJG","Aydin Y","Wang K","Gustavsson M","Kossiakoff AA","Mukherjee S","Tepper K","Yao XQ","Agrawal P"],"additional_accession":[]},"is_claimable":false,"name":"Effect of phosphorylation barcodes on arrestin binding to a chemokine receptor.","description":"Unique phosphorylation 'barcodes' installed in different regions of an active seven-transmembrane receptor by different G-protein-coupled receptor (GPCR) kinases (GRKs) have been proposed to promote distinct cellular outcomes<sup>1</sup>, but it is unclear whether or how arrestins differentially engage these barcodes. Here, to address this, we developed an antigen-binding fragment (Fab7) that recognizes both active arrestin2 (β-arrestin1) and arrestin3 (β-arrestin2) without interacting with bound receptor polypeptides. We used Fab7 to determine the structures of both arrestins in complex with atypical chemokine receptor 3 (ACKR3) phosphorylated in different regions of its C-terminal tail by either GRK2 or GRK5 (ref. <sup>2</sup>). The GRK2-phosphorylated ACKR3 resulted in more heterogeneous 'tail-mode' assemblies, whereas phosphorylation by GRK5 resulted in more rigid 'ACKR3-adjacent' assemblies. Unexpectedly, the finger loops of both arrestins engaged the micelle surface rather than the receptor intracellular pocket, with arrestin3 being more dynamic, partly because of its lack of a membrane-anchoring motif. Thus, both the region of the barcode and the arrestin isoform involved can alter the structure and dynamics of GPCR-arrestin complexes, providing a possible mechanistic basis for unique downstream cellular effects, such as the efficiency of chemokine scavenging and the robustness of arrestin binding in ACKR3.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Jul","modification":"2026-07-05T03:13:03.63Z","creation":"2026-07-05T03:08:31.878Z"},"accession":"S-EPMC12445016","cross_references":{"pubmed":["40399676"],"doi":["10.1038/s41586-025-09024-9"]}}