Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self.
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, UK.
Fiyaz
F
Mohammed
Mark
M
Cobbold
Angela L
AL
Zarling
Mahboob
M
Salim
Gregory A
GA
Barrett-Wilt
Jeffrey
J
Shabanowitz
Donald F
DF
Hunt
Victor H
VH
Engelhard
Benjamin E
BE
Willcox
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015234:HLA-A Antigens / Q000737:chemistry / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000951:Antigens, Neoplasm; D001324:Autoantigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010748:Phosphopeptides; D011994:Recombinant Proteins