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. E., & Boyle, L. H. (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.
TAPBPR/TAPBPL, antigen presentation, antigen processing, human, immunology, inflammation, major histocompatibility complex, Amino Acid Sequence, Antigen Presentation, Binding Sites, HLA-A Antigens, HeLa Cells, Histocompatibility Antigens Class I, Humans, Immunoglobulins, Leucine, Membrane Proteins, Molecular Docking Simulation, Mutation, Peptides, Protein Binding, 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
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