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post-translational modification provides a source of altered self-antigens that can stimulate immune responses in autoimmunity, inflammation, and cancer. In recent years, phosphorylated peptides have emerged as a group of tumour-associated antigens presented by MHC molecules and recognised by T cells, and represent promising candidates for cancer immunotherapy. However, the impact of phosphorylation on the antigenic identity of phosphopeptide epitopes is unclear. Here we examined this by determining structures of MHC-bound phosphopeptides bearing canonical position 4-phosphorylations in the presence and absence of their phosphate moiety, and examining phosphopeptide recognition by the T cell receptor (TCR). Strikingly, two peptides exhibited major conformational changes upon phosphorylation, involving a similar molecular mechanism, which focussed changes on the central peptide region most critical for T cell recognition. In contrast, a third epitope displayed little conformational alteration upon phosphorylation. In addition, binding studies demonstrated TCR interaction with an MHC-bound phosphopeptide was both epitope-specific and absolutely dependent upon phosphorylation status. These results highlight the critical influence of phosphorylation on the antigenic identity of naturally processed class I MHC epitopes. In doing so they provide a molecular framework for understanding phosphopeptide-specific immune responses, and have implications for the development of phosphopeptide antigen-specific cancer immunotherapy approaches.","bibjson":{"author":[{"initials":"F","lastname":"Mohammed","name":"Mohammed F"},{"initials":"DH","lastname":"Stones","name":"Stones DH"},{"initials":"AL","lastname":"Zarling","name":"Zarling AL"},{"initials":"CR","lastname":"Willcox","name":"Willcox CR"},{"initials":"J","lastname":"Shabanowitz","name":"Shabanowitz J"},{"initials":"KL","lastname":"Cummings","name":"Cummings KL"},{"initials":"DF","lastname":"Hunt","name":"Hunt DF"},{"initials":"M","lastname":"Cobbold","name":"Cobbold M"},{"initials":"VH","lastname":"Engelhard","name":"Engelhard VH"},{"initials":"BE","lastname":"Willcox","name":"Willcox BE"}],"identifier":[{"id":"10.18632/oncotarget.16952","type":"doi"},{"id":"28903331","type":"pubmed"}],"issue":["33"],"journal":{"iso_abbreviation":"Oncotarget","name":""},"pages":["54160-54172"],"title":"The antigenic identity of human class I MHC phosphopeptides is critically dependent upon phosphorylation status.","type":"article","url":"https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.16952","volume":["8"],"year":[2017]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"2.00","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/4no2"},"rcsb":{"url":"https://www.rcsb.org/structure/4no2"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-A*02:01 binding \"RQASIELPSMAV\" at 2.00Å resolution","unique_chain_count":3}}