Research Article 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

Copyright © 2014 Soumya Badrinath et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 ofHLA-A∗24 allotypes and their effects on PLC dependence for assembly and peptide binding specificities. HLA-A∗24:06156Trp and HLA-A∗24:13156Leu showed high levels of cell surface expression while HLA-A∗24:02156Gln 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 amore 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). 1