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is mounting that the major histocompatibility complex (MHC) molecule HLA-F (human leukocyte antigen\u00a0F) regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK\u00a0cell receptors (NKRs). We present structural, biochemical, and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OCs), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes, suggesting peptide-dependent engagement. Our in\u00a0vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded \u03b2<sub>2</sub>m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as \u03b2<sub>2</sub>m, thus precluding binding to HLA-F OCs. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.","bibjson":{"author":[{"initials":"CL","lastname":"Dulberger","name":"Dulberger CL"},{"initials":"CP","lastname":"McMurtrey","name":"McMurtrey CP"},{"initials":"A","lastname":"H\u00f6lzemer","name":"H\u00f6lzemer A"},{"initials":"KE","lastname":"Neu","name":"Neu KE"},{"initials":"V","lastname":"Liu","name":"Liu V"},{"initials":"AM","lastname":"Steinbach","name":"Steinbach AM"},{"initials":"WF","lastname":"Garcia-Beltran","name":"Garcia-Beltran WF"},{"initials":"M","lastname":"Sulak","name":"Sulak M"},{"initials":"B","lastname":"Jabri","name":"Jabri B"},{"initials":"VJ","lastname":"Lynch","name":"Lynch VJ"},{"initials":"M","lastname":"Altfeld","name":"Altfeld M"},{"initials":"WH","lastname":"Hildebrand","name":"Hildebrand WH"},{"initials":"EJ","lastname":"Adams","name":"Adams EJ"}],"identifier":[{"id":"10.1016/j.immuni.2017.06.002","type":"doi"},{"id":"28636952","type":"pubmed"}],"issue":["6"],"journal":{"iso_abbreviation":"Immunity","name":""},"pages":["1018-1029.e7"],"title":"Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors.","type":"article","url":"https://www.sciencedirect.com/science/article/abs/pii/S1074761317302297","volume":["46"],"year":[2017]},"in_pmc":"N","in_pmce":"Y","open_access":"N"},"resolution":"3.30","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/5knm"},"rcsb":{"url":"https://www.rcsb.org/structure/5knm"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-F*01:01 binding \"ILRWEQ\" with LIR-1 NK receptor at 3.30&#8491; resolution","unique_chain_count":4}}
