{"doi":"10.1101/2022.02.08.479534","title":"FoxP3 can fold into two distinct dimerization states with divergent functional implications for T cell homeostasis","abstract":"Abstract FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrate that, unlike other known forkhead TFs, FoxP3 forms a head-to-head dimer using a unique linker (Runx1-binding region, RBR) preceding the forkhead domain. Head-to-head dimerization confers distinct DNA-binding specificity and creates a docking site for the cofactor Runx1. RBR is also important for proper folding of the forkhead domain, as truncation of RBR induces domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impairs FoxP3 function, as demonstrated with the disease-causing mutation R337Q, while a swap-suppressive mutation largely rescues R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap-dimerization with impaired functions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":305874,"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":0.9629,"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":999922,"name":"Wenxiang Zhang","orcid":"0000-0001-6528-7629","position":1,"is_corresponding":false},{"id":43276,"name":"Ricardo N. Ramírez","orcid":"0000-0002-1259-5406","position":2,"is_corresponding":false},{"id":552215,"name":"Juliette Léon","orcid":"0000-0001-5314-8154","position":3,"is_corresponding":false},{"id":999923,"name":"義夫 田中","orcid":"0000-0003-2294-0995","position":4,"is_corresponding":false},{"id":273567,"name":"Joris van der Veeken","orcid":"0000-0001-7299-2174","position":5,"is_corresponding":false},{"id":90403,"name":"Alexander Y. Rudensky","orcid":"0000-0003-1280-2898","position":6,"is_corresponding":false},{"id":18715,"name":"Christophe Benoıst","orcid":"0000-0003-1172-6555","position":7,"is_corresponding":false},{"id":274412,"name":"Sun Hur","orcid":"0000-0001-5005-5550","position":8,"is_corresponding":false},{"id":999921,"name":"Fangwei Leng","orcid":"0000-0001-8027-9387","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:44.983506Z","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":[]}