title: Tapasin discriminates peptide-human leukocyte antigen-A*02:01 complexes formed with natural ligands.
abstract: A plethora of peptides are generated intracellularly, and most peptide-human leukocyte antigen (HLA)-I interactions are of a transient, unproductive nature. Without a quality control mechanism, the HLA-I system would be stressed by futile attempts to present peptides not sufficient for the stable peptide-HLA-I complex formation required for long term presentation. Tapasin is thought to be central to this essential quality control, but the underlying mechanisms remain unknown. Here, we report that the N-terminal region of tapasin, Tpn(1-87), assisted folding of peptide-HLA-A*02:01 complexes according to the identity of the peptide. The facilitation was also specific for the identity of the HLA-I heavy chain, where it correlated to established tapasin dependence hierarchies. Two large sets of HLA-A*02:01 binding peptides, one extracted from natural HLA-I ligands from the SYFPEITHI database and one consisting of medium to high affinity non-SYFPEITHI ligands, were studied in the context of HLA-A*02:01 binding and stability. We show that the SYFPEITHI peptides induced more stable HLA-A*02:01 molecules than the other ligands, although affinities were similar. Remarkably, Tpn(1-87) could functionally discriminate the selected SYFPEITHI peptides from the other peptide binders with high sensitivity and specificity. We suggest that this HLA-I- and peptide-specific function, together with the functions exerted by the more C-terminal parts of tapasin, are major features of tapasin-mediated HLA-I quality control. These findings are important for understanding the biogenesis of HLA-I molecules, the selection of presented T-cell epitopes, and the identification of immunogenic targets in both basic research and vaccine design.
authors.affiliation: Laboratory of Experimental Immunology, Institute of International Health, Immunology and Microbiology, University of Copenhagen, Panum DK-2200 Copenhagen, Denmark.
authors.forename: Gustav
authors.initials: G
authors.lastname: Roder
authors.forename: Linda
authors.initials: L
authors.lastname: Geironson
authors.forename: Michael
authors.initials: M
authors.lastname: Rasmussen
authors.forename: Mikkel
authors.initials: M
authors.lastname: Harndahl
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Kajsa
authors.initials: K
authors.lastname: Paulsson
mesh_terms: D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006801:Humans; D008024:Ligands; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D055550:Protein Stability
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D008024:Ligands; D026901:Membrane Transport Proteins; D046912:Multiprotein Complexes; D010455:Peptides; C107762:tapasin