{"doi":"10.1101/2025.09.11.675682","title":"Weak SLP-76-PLC-γ1 interaction in the LAT-nucleated multi-protein complex fine-tunes TCR signal strength to optimize T cell responsiveness","abstract":"Upon TCR engagement several protein tyrosine kinases are recruited and activated, and adapter proteins and enzymes are phosphorylated on tyrosine residues, leading to further events characterizing activated T cells. Phosphorylation of the LAT adapter protein enables binding of the enzyme PLC-γ1 and of a dimer of two additional adapter proteins Gads and SLP-76, forming a tetrameric structure. Within this heterotetramer there is a weak interaction between SLP-76 and PLC-γ1, and the relevant binding sites of SLP-76 and PLC-γ1 are highly conserved in vertebrates. To address the biological relevance of this weak interaction, we introduced a mutation in the SLP-76 that enhanced its affinity for PLC-γ1 and found that this mutation increased PLC-γ1 activity and altered thymocyte development and peripheral T cell responses due to enhanced TCR signal strength. The conserved weak SLP-76-PLC-γ1 interaction is critical for the controlled activation of PLC-γ1, thus fine-tuning TCR signal strength to optimize T cell-mediated immunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":575078,"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":0.9586,"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":1428403,"name":"Junya Wada","orcid":null,"position":1,"is_corresponding":false},{"id":889772,"name":"Elizabeth Stassenko","orcid":null,"position":2,"is_corresponding":false},{"id":1483418,"name":"Natalie D. Convertino","orcid":null,"position":3,"is_corresponding":false},{"id":928577,"name":"Mariah Lee","orcid":"0000-0002-2059-5801","position":4,"is_corresponding":false},{"id":712677,"name":"Melanie S. Vacchio","orcid":"0000-0001-5407-6439","position":5,"is_corresponding":false},{"id":1483083,"name":"Wenmei Li","orcid":"0000-0002-1108-0507","position":6,"is_corresponding":false},{"id":1428402,"name":"Udumbara M. Rathnayake","orcid":null,"position":7,"is_corresponding":false},{"id":499195,"name":"Lakshmi Balagopalan","orcid":"0000-0002-6371-0101","position":8,"is_corresponding":false},{"id":260578,"name":"Raj Chari","orcid":"0000-0002-2216-313X","position":9,"is_corresponding":false},{"id":1483419,"name":"Herbert Hagenau","orcid":null,"position":10,"is_corresponding":false},{"id":262758,"name":"Parirokh Awasthi","orcid":"0000-0002-5831-9781","position":11,"is_corresponding":false},{"id":235863,"name":"Dorian B. McGavern","orcid":"0000-0001-9568-545X","position":12,"is_corresponding":false},{"id":299371,"name":"Rémy Bosselut","orcid":"0000-0003-2033-1790","position":13,"is_corresponding":false},{"id":499199,"name":"Lawrence E. Samelson","orcid":"0000-0002-5963-2112","position":14,"is_corresponding":false},{"id":232578,"name":"Hidehiro Yamane","orcid":"0009-0008-3282-2515","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:57:48.486077Z","pmid":"41000640","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":[]}