{"doi":"10.1016/j.cell.2024.08.036","title":"Dynamic allostery drives autocrine and paracrine TGF-β signaling","abstract":"TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.","journal":"Cell","year":2024,"id":418734,"datarank":0.5837730447165941,"base_score":3.8918202981106265,"endowment":3.8918202981106265,"self_citation_contribution":0.5837730447165941,"citation_network_contribution":0.0,"self_endowment_contribution":0.5837730447165941,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"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":249424,"name":"Robert Seed","orcid":"0000-0002-7588-9903","position":1,"is_corresponding":false},{"id":1207236,"name":"Guoqing Cai","orcid":"0000-0001-8305-2196","position":2,"is_corresponding":false},{"id":1207923,"name":"Tiffany Shing","orcid":null,"position":3,"is_corresponding":false},{"id":383321,"name":"Liping Wang","orcid":"0000-0001-6893-3809","position":4,"is_corresponding":false},{"id":249423,"name":"Saburo Ito","orcid":"0000-0001-6619-4950","position":5,"is_corresponding":false},{"id":249422,"name":"Anthony Cormier","orcid":"0000-0002-2848-9536","position":6,"is_corresponding":false},{"id":103672,"name":"Stephanie A. Wankowicz","orcid":"0000-0002-4225-7459","position":7,"is_corresponding":false},{"id":699505,"name":"Jillian M. Jespersen","orcid":"0000-0002-8231-6978","position":8,"is_corresponding":false},{"id":249427,"name":"Jody L. Baron","orcid":"0000-0003-2799-9099","position":9,"is_corresponding":false},{"id":965890,"name":"Nicholas D. Carey","orcid":"0000-0001-5859-7549","position":10,"is_corresponding":false},{"id":108121,"name":"Melody G. Campbell","orcid":"0000-0003-1909-5751","position":11,"is_corresponding":false},{"id":227712,"name":"Zanlin Yu","orcid":"0000-0001-8381-8788","position":12,"is_corresponding":false},{"id":521363,"name":"Phu K. Tang","orcid":null,"position":13,"is_corresponding":false},{"id":1207237,"name":"Pilar Cossio","orcid":"0000-0002-5404-9948","position":14,"is_corresponding":false},{"id":961713,"name":"Weihua Wen","orcid":null,"position":15,"is_corresponding":false},{"id":249425,"name":"Jianlong Lou","orcid":"0000-0001-6455-692X","position":16,"is_corresponding":false},{"id":249426,"name":"James D. Marks","orcid":"0000-0003-0562-3517","position":17,"is_corresponding":false},{"id":249428,"name":"Stephen L. Nishimura","orcid":"0000-0003-2312-4113","position":18,"is_corresponding":false},{"id":98188,"name":"Yifan Cheng","orcid":"0000-0001-9535-0369","position":19,"is_corresponding":false},{"id":108150,"name":"Mingliang Jin","orcid":"0000-0003-4961-7143","position":0,"is_corresponding":true}],"reference_count":118,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:57:09.067930Z","pmid":"39288764","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":[]}