To delineate the relative contribution of multiple HLA alleles to peptide editing by the intracellular MHC chaperone TAPBPR, Ilca et al. evaluated TAPBPR binding to HLA on beads and on cell surfaces, peptide editing on cellular surfaces, and binding/editing of targeted HLA mutations. HLA-A, in particular HLA-A2 and -A24 supertypes, were significantly more impacted by TAPBPR than HLA-B/C or other HLA-A family members. This preferential binding/editing was strongly associated with H114 and Y116 in the anchor residue binding F pocket of HLA. Allele-specific preferential editing may have implications for sensitivity to disease.
Understanding how peptide selection is controlled on different major histocompatibility complex class I (MHC I) molecules is pivotal for determining how variations in these proteins influence our predisposition to infectious diseases, cancer, and autoinflammatory conditions. Although the intracellular chaperone TAPBPR edits MHC I peptides, it is unclear which allotypes are subjected to TAPBPR-mediated peptide editing. Here, we examine the ability of 97 different human leukocyte antigen (HLA) class I allotypes to interact with TAPBPR. We reveal a striking preference of TAPBPR for HLA-A, particularly for supertypes A2 and A24, over HLA-B and -C molecules. We demonstrate that the increased propensity of these HLA-A molecules to undergo TAPBPR-mediated peptide editing is determined by molecular features of the HLA-A F pocket, specifically residues H114 and Y116. This work reveals that specific polymorphisms in MHC I strongly influence their susceptibility to chaperone-mediated peptide editing, which may play a significant role in disease predisposition.
Author Info: (1) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK. (2) Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104 Freiburg,
Author Info: (1) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK. (2) Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104 Freiburg, Germany. (3) Tissue Typing Laboratory, Box 209, Level 6 ATC, Cambridge University Hospitals, NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK. (4) Tissue Typing Laboratory, Box 209, Level 6 ATC, Cambridge University Hospitals, NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK. (5) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK. Electronic address: lhb22@cam.ac.uk.
