{"doi":"10.1126/scisignal.adk5736","title":"Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways","abstract":"Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or β-arrestin. These different active conformations are thought to engage distinct intracellular transducers because of differential phosphorylation patterns in the receptor C-terminal tail (the \"barcode\" hypothesis). Here, we identified the AT1R barcodes for the endogenous agonist AngII, which stimulates both G protein activation and β-arrestin recruitment, and for a synthetic biased agonist that only stimulates β-arrestin recruitment. The endogenous and β-arrestin-biased agonists induced two different ensembles of phosphorylation sites along the C-terminal tail. The phosphorylation of eight serine and threonine residues in the proximal and middle portions of the tail was required for full β-arrestin functionality, whereas phosphorylation of the serine and threonine residues in the distal portion of the tail had little influence on β-arrestin function. Similarly, molecular dynamics simulations showed that the proximal and middle clusters of phosphorylated residues were critical for stable β-arrestin-receptor interactions. These findings demonstrate that ligands that stabilize different receptor conformations induce different phosphorylation clusters in the C-terminal tail as barcodes to evoke distinct receptor-transducer engagement, receptor trafficking, and signaling.","journal":"Science Signaling","year":2024,"id":434291,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":900573,"name":"Conrad T. Pfeiffer","orcid":"0000-0002-6768-4326","position":1,"is_corresponding":false},{"id":1240446,"name":"Xue Jiang","orcid":"0009-0008-1098-7204","position":2,"is_corresponding":false},{"id":136624,"name":"Joao A. Paulo","orcid":"0000-0002-4291-413X","position":3,"is_corresponding":false},{"id":107041,"name":"Steven P. Gygi","orcid":"0000-0001-7626-0034","position":4,"is_corresponding":false},{"id":705241,"name":"Uyen Pham","orcid":"0000-0002-2038-6794","position":5,"is_corresponding":false},{"id":1002445,"name":"Anand Chundi","orcid":"0000-0001-8148-7479","position":6,"is_corresponding":false},{"id":239844,"name":"Laura M. Wingler","orcid":"0000-0002-3688-5088","position":7,"is_corresponding":false},{"id":243477,"name":"Dean P. Staus","orcid":null,"position":8,"is_corresponding":false},{"id":424254,"name":"Tomasz Maciej Stępniewski","orcid":"0000-0002-6828-9192","position":9,"is_corresponding":false},{"id":424256,"name":"Jana Selent","orcid":"0000-0002-1844-4449","position":10,"is_corresponding":false},{"id":670517,"name":"Emilio Y. Lucero Garcia-Rojas","orcid":"0000-0001-5056-7126","position":11,"is_corresponding":false},{"id":406533,"name":"Alyssa Grogan","orcid":"0000-0002-1505-3311","position":12,"is_corresponding":false},{"id":354436,"name":"Sudarshan Rajagopal","orcid":"0000-0002-3443-5040","position":13,"is_corresponding":false},{"id":317677,"name":"Howard A. Rockman","orcid":"0000-0003-2921-1584","position":14,"is_corresponding":false},{"id":1240445,"name":"Clarice Gareri","orcid":"0000-0002-4859-8780","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T01:59:53.957667Z","pmid":"39137246","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}