TAPBPR mediates peptide dissociation from MHC class I using a leucine lever.
eLife Sciences Publications, Ltd
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Ilca, F. T., Neerincx, A., Hermann, C., Marcu, A., Stevanović, S., Deane, J., & Boyle, L. (2018). TAPBPR mediates peptide dissociation from MHC class I using a leucine lever.. Elife, 7 https://doi.org/10.7554/eLife.40126
Tapasin and TAPBPR are known to perform peptide editing on major histocompatibility complex class I (MHC I) molecules; however, the precise molecular mechanism(s) involved in this process remain largely enigmatic. Here, using immunopeptidomics in combination with novel cell-based assays that assess TAPBPR-mediated peptide exchange, we reveal a critical role for the K22-D35 loop of TAPBPR in mediating peptide exchange on MHC I. We identify a specific leucine within this loop that enables TAPBPR to facilitate peptide dissociation from MHC I. Moreover, we delineate the molecular features of the MHC I F pocket required for TAPBPR to promote peptide dissociation in a loop-dependent manner. These data reveal that chaperone-mediated peptide editing on MHC I can occur by different mechanisms dependent on the C-terminal residue that the MHC I accommodates in its F pocket and provide novel insights that may inform the therapeutic potential of TAPBPR manipulation to increase tumour immunogenicity.
Hela Cells, Humans, Leucine, Peptides, Immunoglobulins, Membrane Proteins, Histocompatibility Antigens Class I, HLA-A Antigens, Antigen Presentation, Binding Sites, Amino Acid Sequence, Protein Binding, Mutation, Molecular Docking Simulation, Protein Domains
Wellcome PhD studentship (109076/Z/15/A). Wellcome Senior Research Fellowship (104647/Z/14/Z) South African Medical Research Council Bosch-Forschungsstiftung. Royal Society University Research Fellowship (UF100371).
Wellcome Trust (104647/Z/14/Z)
Royal Society (UF150682)
Wellcome Trust (109076/Z/15/Z)
External DOI: https://doi.org/10.7554/eLife.40126
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287215