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

Mohammed F, Cobbold M, Zarling AL, Salim M, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Engelhard VH, Willcox BE
Nat Immunol 9 1236-43 (2008)
Related entries: 3bh8, 3bh9, 3bhb

Cited: 94 times
EuropePMC logo PMID: 18836451

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.

Articles - 3bgm mentioned but not cited (5)

  1. Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self. Mohammed F, Cobbold M, Zarling AL, Salim M, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Engelhard VH, Willcox BE. Nat. Immunol. 9 1236-1243 (2008)
  2. Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope. Song I, Gil A, Mishra R, Ghersi D, Selin LK, Stern LJ. Nat. Struct. Mol. Biol. 24 395-406 (2017)
  3. Molecular mechanism of phosphopeptide neoantigen immunogenicity. Patskovsky Y, Natarajan A, Patskovska L, Nyovanie S, Joshi B, Morin B, Brittsan C, Huber O, Gordon S, Michelet X, Schmitzberger F, Stein RB, Findeis MA, Hurwitz A, Van Dijk M, Buell JS, Underwood D, Krogsgaard M. Nat Commun 14 3763 (2023)
  4. Phosphosite-dependent presentation of dual phosphorylated peptides by MHC class I molecules. Zhao Y, Sun M, Zhang N, Liu X, Yue C, Feng L, Ji S, Liu X, Qi J, Wong CCL, Gao GF, Liu WJ. iScience 25 104013 (2022)
  5. Rosetta FlexPepDock to predict peptide-MHC binding: An approach for non-canonical amino acids. Bloodworth N, Barbaro NR, Moretti R, Harrison DG, Meiler J. PLoS One 17 e0275759 (2022)


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