Article abstract
Nature Immunology 9, 1236 - 1243 (2008)
Published online: 5 October 2008 | doi:10.1038/ni.1660
Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self
Fiyaz Mohammed1,5, Mark Cobbold2,3,5, Angela L Zarling2, Mahboob Salim1, Gregory A Barrett-Wilt4, Jeffrey Shabanowitz4, Donald F Hunt4, Victor H Engelhard2 & Benjamin E Willcox1
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.
- Cancer Research UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
- Carter Immunology Center and Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
- School of Immunity, Infection and Inflammation, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22908, USA.
- These authors contributed equally to this work.
Correspondence to: Victor H Engelhard2 e-mail: vhe@virginia.edu
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