title: A Micropolymorphism Altering the Residue Triad 97/114/156 Determines the Relative Levels of Tapasin Independence and Distinct Peptide Profiles for HLA-A(*)24 Allotypes.
abstract: While many HLA class I molecules interact directly with the peptide loading complex (PLC) for conventional loading of peptides certain class I molecules are able to present peptides in a way that circumvents the PLC components. We investigated micropolymorphisms at position 156 of HLA-A(*)24 allotypes and their effects on PLC dependence for assembly and peptide binding specificities. HLA-A(*)24:06(156Trp) and HLA-A(*)24:13(156Leu) showed high levels of cell surface expression while HLA-A(*)24:02(156Gln) was expressed at low levels in tapasin deficient cells. Peptides presented by these allelic variants showed distinct differences in features and repertoire. Immunoprecipitation experiments demonstrated all the HLA-A(*)24/156 variants to associate at similar levels with tapasin when present. Structurally, HLA-A(*)24:02 contains the residue triad Met97/His114/Gln156 and a Trp156 or Leu156 polymorphism provides tapasin independence by stabilizing these triad residues, thus generating an energetically stable and a more peptide receptive environment. Micropolymorphisms at position 156 can influence the generic peptide loading pathway for HLA-A(*)24 by altering their tapasin dependence for peptide selection. The trade-off for this tapasin independence could be the presentation of unusual ligands by these alleles, imposing significant risk following hematopoietic stem cell transplantation (HSCT).
authors: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor Lynen Street 21, 30625 Hannover, Germany.
authors: Soumya
authors: S
authors: Badrinath
authors: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor Lynen Street 21, 30625 Hannover, Germany.
authors: Heike
authors: 0000-0002-7416-6180
authors: H
authors: Kunze-Schumacher
authors: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor Lynen Street 21, 30625 Hannover, Germany.
authors: Rainer
authors: R
authors: Blasczyk
authors: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor Lynen Street 21, 30625 Hannover, Germany.
authors: Trevor
authors: T
authors: Huyton
authors: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor Lynen Street 21, 30625 Hannover, Germany.
authors: Christina
authors: C
authors: Bade-Doeding
mesh_terms: D000596:Amino Acids / Q000235:genetics*; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism*; D002460:Cell Line; D055785:Gene Knockdown Techniques; D059871:HLA-A24 Antigen / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D055550:Protein Stability; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000941:Antigens; D059871:HLA-A24 Antigen; D026901:Membrane Transport Proteins; D010446:Peptide Fragments; C107762:tapasin