TAPBPR mediates peptide dissociation from MHC class I using a leucine lever

  1. Florin Tudor Ilca
  2. Andreas Neerincx
  3. Clemens Hermann
  4. Ana Marcu
  5. Stefan Stefvanovic
  6. Janet E Deane
  7. Louise H Boyle  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Cape Town, South Africa
  3. University of Tübingen, Germany

Abstract

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-mediate 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 of 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files regarding the lists of peptides presented on MHC class I have been provided for Figures 5

The following data sets were generated

Article and author information

Author details

  1. Florin Tudor Ilca

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Florin Tudor Ilca, Some aspects of the work included in this manuscript form part of a recent patent application. Applicant: Cambridge Enterprise Limited. Application number: 1801323.5, Status: Pending.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6582-8007
  2. Andreas Neerincx

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Andreas Neerincx, Some aspects of the work included in this manuscript form part of a recent patent application. Applicant: Cambridge Enterprise Limited. Application number: 1801323.5, Status: Pending.
  3. Clemens Hermann

    Department of Integrative Biomedical Sciences, Division of Chemical and Systems Biology, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
    Competing interests
    No competing interests declared.
  4. Ana Marcu

    Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0808-8097
  5. Stefan Stefvanovic

    Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
  6. Janet E Deane

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4863-0330
  7. Louise H Boyle

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    lhb22@cam.ac.uk
    Competing interests
    Louise H Boyle, Some aspects of the work included in this manuscript form part of a recent patent application. Applicant: Cambridge Enterprise Limited. Application number: 1801323.5, Status: Pending.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3105-6555

Funding

Wellcome (104647/Z/14/Z)

  • Andreas Neerincx
  • Louise H Boyle

South African Medical Research Council

  • Clemens Hermann

Royal Society (UF100371)

  • Janet E Deane

Bosch-Forschungsstiftung

  • Ana Marcu
  • Stefan Stefvanovic

Wellcome (109076/Z/15/A)

  • Florin Tudor Ilca

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kai Wucherpfennig

Publication history

  1. Received: July 15, 2018
  2. Accepted: November 28, 2018
  3. Accepted Manuscript published: November 28, 2018 (version 1)
  4. Version of Record published: December 27, 2018 (version 2)

Copyright

© 2018, Ilca et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Florin Tudor Ilca
  2. Andreas Neerincx
  3. Clemens Hermann
  4. Ana Marcu
  5. Stefan Stefvanovic
  6. Janet E Deane
  7. Louise H Boyle
(2018)
TAPBPR mediates peptide dissociation from MHC class I using a leucine lever
eLife 7:e40126.
https://doi.org/10.7554/eLife.40126

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