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Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self

Nature Immunology volume 9, pages 12361243 (2008) | Download Citation

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Abstract

Protein phosphorylation generates a source of phosphopeptides that are presented by major histocompatibility complex class I molecules and recognized by T cells. As deregulated phosphorylation is a hallmark of malignant transformation, the differential display of phosphopeptides on cancer cells provides an immunological signature of 'transformed self'. Here we demonstrate that phosphorylation can considerably increase peptide binding affinity for HLA-A2. To understand this, we solved crystal structures of four phosphopeptide–HLA-A2 complexes. These identified a novel peptide-binding motif centered on a solvent-exposed phosphate anchor. Our findings indicate that deregulated phosphorylation can create neoantigens by promoting binding to major histocompatibility complex molecules or by affecting the antigenic identity of presented epitopes. These results highlight the potential of phosphopeptides as novel targets for cancer immunotherapy.

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Acknowledgements

We thank S. White and K. Fütterer for help with X-ray data collection, and P. Hornbeck (Cell Signaling Technology; PhosphoSites) and F. Diella (European Molecular Biology Laboratory, Heidelberg; Phospho.ELM) for data sets of identified human phosphorylation sites. Supported by US Public Health Service (AI20963 to V.H.E. and AI33993 to D.F.H.), the Medical Research Council (B.E.W. and M.C.), the Wellcome Trust (B.E.W.), the Biotechnology and Biological Sciences Research Council (F.M.) and the Sidney Kimmel Foundation (A.L.Z.).

Author information

Author notes

    • Fiyaz Mohammed
    •  & Mark Cobbold

    These authors contributed equally to this work.

Affiliations

  1. Cancer Research UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

    • Fiyaz Mohammed
    • , Mahboob Salim
    •  & Benjamin E Willcox
  2. Carter Immunology Center and Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.

    • Mark Cobbold
    • , Angela L Zarling
    •  & Victor H Engelhard
  3. School of Immunity, Infection and Inflammation, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

    • Mark Cobbold
  4. Department of Chemistry, University of Virginia, Charlottesville, Virginia 22908, USA.

    • Gregory A Barrett-Wilt
    • , Jeffrey Shabanowitz
    •  & Donald F Hunt

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Contributions

F.M., M.C., A.L.Z., M.S., V.H.E. and B.E.W. did the experiments and/or analyzed the data; G.A.B.-W., J.S. and D.F.H. contributed to the mass spectrometry data and analysis; B.E.W, M.C. and V.H.E. designed the study; and B.E.W. and V.H.E. prepared the manuscript.

Corresponding author

Correspondence to Victor H Engelhard.

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DOI

https://doi.org/10.1038/ni.1660

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