{"doi":"10.1073/pnas.2414606122","title":"A tethering mechanism underlies Pin1-catalyzed proline <i>cis–trans</i> isomerization at a noncanonical site","abstract":"The prolyl isomerase Pin1 catalyzes the cis – trans isomerization of proline peptide bonds, a noncovalent posttranslational modification that influences cellular and molecular processes, including protein–protein interactions. Pin1 is a two-domain enzyme containing a WW domain that recognizes phosphorylated serine/threonine-proline (pS/pT-P) canonical motifs and an enzymatic PPIase domain that catalyzes proline cis – trans isomerization of pS/pT-P motifs. Here, we show that Pin1 uses a tethering mechanism to bind and catalyze proline cis – trans isomerization of a noncanonical motif in the disordered N-terminal activation function-1 (AF-1) domain of the human nuclear receptor PPARγ. NMR reveals multiple Pin1 binding regions within the PPARγ AF-1, including a canonical motif (pS112-P113) that when phosphorylated by the kinase ERK2 binds the Pin1 WW domain with high affinity. NMR methods reveal that Pin1 also binds and accelerates cis – trans isomerization of a noncanonical motif containing a tryptophan-proline motif (W39-P40) previously shown to be involved in an interdomain interaction with the C-terminal ligand-binding domain (LBD) of PPARγ. Cellular transcription studies combined with mutagenesis and Pin1 inhibitor treatment reveal a functional role for Pin1-mediated acceleration of cis – trans isomerization of the PPARγ W39-P40 motif. Our data inform a refined model of the Pin1 catalytic mechanism where the WW domain can bind a canonical pS/T-P motif and tether Pin1 to a target, which enables the PPIase domain to exert catalytic cis – trans isomerization at a distal noncanonical site.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":566233,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1470355,"name":"Jonathan Chuck","orcid":null,"position":1,"is_corresponding":false},{"id":343815,"name":"Paola Munoz‐Tello","orcid":"0000-0002-5225-1907","position":2,"is_corresponding":false},{"id":282829,"name":"Douglas J. Kojetin","orcid":"0000-0001-8058-6168","position":3,"is_corresponding":false},{"id":987758,"name":"Christopher C. Williams","orcid":null,"position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:56:36.440192Z","pmid":"40388619","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":[]}