4NO2

Crystal structure of RQA_V phosphopeptide bound to HLA-A2

Summary for 4NO2

• Entry DOI: 10.2210/pdb4no2/pdb
• Related: 4NNX 4NNY 4NO0 4NO3 4NO5
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Lymphocyte-specific protein 1, ... (6 entities in total)
• Functional Keywords: phosphoserine, phosphopeptide, peptide-mhc complex, mhc, tumor immunology, peptide conformation, post translational modification, tumor antigen, neoepitope, immune system-antigen complex, immune system/antigen
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 45064.94

Authors

Mohammed, F.,Stones, D.H.,Willcox, B.E. (deposition date: 2013-11-19, release date: 2014-11-19, Last modification date: 2024-11-06)

Primary citation

Mohammed, F.,Stones, D.H.,Zarling, A.L.,Willcox, C.R.,Shabanowitz, J.,Cummings, K.L.,Hunt, D.F.,Cobbold, M.,Engelhard, V.H.,Willcox, B.E.
The antigenic identity of human class I MHC phosphopeptides is critically dependent upon phosphorylation status.
Oncotarget, 8:54160-54172, 2017

PubMed Abstract: Dysregulated post-translational modification provides a source of altered self-antigens that can stimulate immune responses in autoimmunity, inflammation, and cancer. In recent years, phosphorylated peptides have emerged as a group of tumour-associated antigens presented by MHC molecules and recognised by T cells, and represent promising candidates for cancer immunotherapy. However, the impact of phosphorylation on the antigenic identity of phosphopeptide epitopes is unclear. Here we examined this by determining structures of MHC-bound phosphopeptides bearing canonical position 4-phosphorylations in the presence and absence of their phosphate moiety, and examining phosphopeptide recognition by the T cell receptor (TCR). Strikingly, two peptides exhibited major conformational changes upon phosphorylation, involving a similar molecular mechanism, which focussed changes on the central peptide region most critical for T cell recognition. In contrast, a third epitope displayed little conformational alteration upon phosphorylation. In addition, binding studies demonstrated TCR interaction with an MHC-bound phosphopeptide was both epitope-specific and absolutely dependent upon phosphorylation status. These results highlight the critical influence of phosphorylation on the antigenic identity of naturally processed class I MHC epitopes. In doing so they provide a molecular framework for understanding phosphopeptide-specific immune responses, and have implications for the development of phosphopeptide antigen-specific cancer immunotherapy approaches.

PubMed: 28903331
DOI: 10.18632/oncotarget.16952

Experimental method

X-RAY DIFFRACTION (2 Å)