{"doi":"10.1073/pnas.2416992122","title":"CryoEM structure of an MHC-I/TAPBPR peptide-bound intermediate reveals the mechanism of antigen proofreading","abstract":"Class I major histocompatibility complex (MHC-I) proteins play a pivotal role in adaptive immunity by displaying epitopic peptides to CD8+ T cells. The chaperones tapasin and TAPBPR promote the selection of immunogenic antigens from a large pool of intracellular peptides. Interactions of chaperoned MHC-I molecules with incoming peptides are transient in nature, and as a result, the precise antigen proofreading mechanism remains elusive. Here, we leverage a high-fidelity TAPBPR variant and conformationally stabilized MHC-I, to determine the solution structure of the human antigen editing complex bound to a peptide decoy by cryogenic electron microscopy (cryo-EM) at an average resolution of 3.0 Å. Antigen proofreading is mediated by transient interactions formed between the nascent peptide binding groove with the P2/P3 peptide anchors, where conserved MHC-I residues stabilize incoming peptides through backbone-focused contacts. Finally, using our high-fidelity chaperone, we demonstrate robust peptide exchange on the cell surface across multiple clinically relevant human MHC-I allomorphs. Our work has important ramifications for understanding the selection of immunogenic epitopes for T cell screening and vaccine design applications.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":516317,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"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":301037,"name":"Ruth A. Pumroy","orcid":"0000-0002-6200-6083","position":1,"is_corresponding":false},{"id":555406,"name":"Leena Mallik","orcid":"0000-0002-5979-7494","position":2,"is_corresponding":false},{"id":471631,"name":"Apala Chaudhuri","orcid":"0000-0003-2669-850X","position":3,"is_corresponding":false},{"id":887881,"name":"Chloe Wang","orcid":"0009-0009-5193-9601","position":4,"is_corresponding":false},{"id":281019,"name":"Daniel Hwang","orcid":"0000-0002-6071-8271","position":5,"is_corresponding":false},{"id":1038174,"name":"Julia N. Danon","orcid":"0000-0001-6971-6582","position":6,"is_corresponding":false},{"id":924971,"name":"Kimia Dasteh Goli","orcid":"0009-0005-6921-655X","position":7,"is_corresponding":false},{"id":301040,"name":"Vera Y. Moiseenkova‐Bell","orcid":"0000-0002-0589-4053","position":8,"is_corresponding":false},{"id":314926,"name":"Nikolaos G. Sgourakis","orcid":"0000-0003-3655-3902","position":9,"is_corresponding":false},{"id":1038172,"name":"Yi Sun","orcid":"0000-0002-7821-4346","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"39786927","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":[]}