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repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface is tailored by the ER-resident peptide loading complex (PLC), which contains the exchange catalyst tapasin. Tapasin stabilizes MHC-I molecules and promotes the formation of stable peptide-MHC-I (pMHC-I) complexes that serve as T cell antigens. Exchange of suboptimal by high-affinity ligands is catalyzed by tapasin, but the underlying mechanism is still elusive. Here we analyze the tapasin-induced changes in MHC-I dynamics, and find the catalyst to exploit two essential features of MHC-I. First, tapasin recognizes a conserved allosteric site underneath the \u03b1<sub>2-1</sub>-helix of MHC-I, 'loosening' the MHC-I F-pocket region that accomodates the C-terminus of the peptide. Second, the scoop loop<sub>11-20</sub> of tapasin relies on residue L18 to target the MHC-I F-pocket, enabling peptide exchange. Meanwhile, tapasin residue K16 plays an accessory role in catalysis of MHC-I allotypes bearing an acidic F-pocket. Thus, our results provide an explanation for the observed allele-specificity of catalyzed peptide exchange.","bibjson":{"author":[{"initials":"H","lastname":"Lan","name":"Lan H"},{"initials":"ET","lastname":"Abualrous","name":"Abualrous ET"},{"initials":"J","lastname":"Sticht","name":"Sticht J"},{"initials":"LMA","lastname":"Fernandez","name":"Fernandez LMA"},{"initials":"T","lastname":"Werk","name":"Werk T"},{"initials":"C","lastname":"Weise","name":"Weise C"},{"initials":"M","lastname":"Ballaschk","name":"Ballaschk M"},{"initials":"P","lastname":"Schmieder","name":"Schmieder P"},{"initials":"B","lastname":"Loll","name":"Loll B"},{"initials":"C","lastname":"Freund","name":"Freund C"}],"identifier":[{"id":"10.1038/s41467-021-24401-4","type":"doi"},{"id":"34244493","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Nat Commun","name":""},"pages":["4236"],"title":"Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules.","type":"article","url":"http://www.nature.com/articles/s41467-021-24401-4","volume":["12"],"year":[2021]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.80","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/7alo"},"rcsb":{"url":"https://www.rcsb.org/structure/7alo"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*27:09 binding \"RRKWRRWXL\" at 1.80&#8491; resolution","unique_chain_count":3}}
