{"doi":"10.1101/2022.07.13.499031","title":"Structural basis of interdomain communication in PPARγ","abstract":"The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates transcription via two activation function (AF) regulatory domains: a ligand-dependent AF-2 coregulator interaction surface within the C-terminal ligand-binding domain (LBD), and an N-terminal disordered AF-1 domain (NTD or A/B region) that functions through poorly understood structural mechanisms. Here, we show the PPARγ AF-1 contains an evolutionary conserved Trp-Pro motif that undergoes cis/trans isomerization, populating two long-lived conformations that participate in intradomain AF-1 and interdomain interactions including two surfaces in the C-terminal LBD (β-sheet and the AF-2 surface), which are predicted in AlphaFold 3 models but not AlphaFold 2. NMR and chemical crosslinking mass spectrometry show that interdomain interactions occur for soluble isolated AF-1 and LBD proteins, as well as in full-length PPARγ in a phase separated state. Mutation of the region containing the Trp-Pro motif, which abrogates cis/trans isomerization of this region, impacts LBD interaction and reduces basal PPARγ transcription and agonist-dependent activation of PPARγ. Our findings provide structural insight into published in vitro and cellular studies that reported interdomain functional communication between the PPARγ AF-1 and LBD suggesting some of these effects may be mediated via AF-1/LBD interactions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298318,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":343815,"name":"Paola Munoz‐Tello","orcid":"0000-0002-5225-1907","position":1,"is_corresponding":false},{"id":97257,"name":"Kuan‐Ting Kuo","orcid":"0000-0002-3657-1652","position":2,"is_corresponding":false},{"id":987757,"name":"Brian S. MacTavish","orcid":null,"position":3,"is_corresponding":false},{"id":753719,"name":"Xiaoyu Yu","orcid":"0000-0003-0549-9560","position":4,"is_corresponding":false},{"id":732683,"name":"Daniel Scholl","orcid":"0000-0002-5242-2032","position":5,"is_corresponding":false},{"id":987758,"name":"Christopher C. Williams","orcid":null,"position":6,"is_corresponding":false},{"id":329382,"name":"Timothy S. Strutzenberg","orcid":"0000-0003-0598-534X","position":7,"is_corresponding":false},{"id":356211,"name":"Jess Li","orcid":"0000-0001-7708-8555","position":8,"is_corresponding":false},{"id":283800,"name":"Jared Bass","orcid":null,"position":9,"is_corresponding":false},{"id":282826,"name":"Richard Brust","orcid":"0000-0002-9200-1101","position":10,"is_corresponding":false},{"id":987759,"name":"E. Kalkhoven","orcid":null,"position":11,"is_corresponding":false},{"id":438032,"name":"Ashok A. Deniz","orcid":"0000-0003-2819-4049","position":12,"is_corresponding":false},{"id":282828,"name":"Patrick R. Griffin","orcid":"0000-0002-3404-690X","position":13,"is_corresponding":false},{"id":282829,"name":"Douglas J. Kojetin","orcid":"0000-0001-8058-6168","position":14,"is_corresponding":false},{"id":282824,"name":"Sarah A. Mosure","orcid":"0000-0003-4477-5396","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T00:31:36.269611Z","pmid":null,"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":[]}