spacer Structure of MHC class II molecule HLA-DR1 complexed with phosphopeptide MART-1
Primary citation
Title Structural Basis for the Presentation of Tumor-Associated MHC Class II-Restricted Phosphopeptides to CD4(+) T Cells.
Authors Li,; Depontieu,; Sidney,; Salay,; Engelhard,; Hunt,; Sette,; Topalian,; Mariuzza,
Journal vol:399, pag:596-603 (2010), Identifiers: PubMed ID (20417641)search DOI (10.1016/j.jmb.2010.04.037)
Abstract Dysregulated protein phosphorylation is a hallmark of malignant transformation. Transformation can generate major histocompatibility complex (MHC)-bound phosphopeptides that are differentially displayed on tumor cells for specific recognition by T cells. To understand how phosphorylation alters the antigenic identity of self-peptides and how MHC class II molecules present phosphopeptides for CD4(+) T-cell recognition, we determined the crystal structure of a phosphopeptide derived from melanoma antigen recognized by T cells-1 (pMART-1), selectively expressed by human melanomas, in complex with HLA-DR1. The structure revealed that the phosphate moiety attached to the serine residue at position P5 of pMART-1 is available for direct interactions with T-cell receptor (TCR) and that the peptide N-terminus adopts an unusual conformation orienting it toward TCR. This structure, combined with measurements of peptide affinity for HLA-DR1 and of peptide-MHC recognition by pMART-1-specific T cells, suggests that TCR recognition is focused on the N-terminal portion of pMART-1. This recognition mode appears to be distinct from that of foreign antigen complexes but is remarkably reminiscent of the way autoreactive TCRs engage self- or altered self-peptides, consistent with the tolerogenic nature of tumor-host immune interactions.
MeSH terms Amino Acid Sequencesearch, Antigen Presentationsearch, Antigenssearch, Neoplasmsearch, Binding Sitessearch, CD4-Positive T-Lymphocytessearch, Crystallographysearch, X-Raysearch, HLA-DR1 Antigensearch, Humanssearch, MART-1 Antigensearch, Melanomasearch, Modelssearch, Molecularsearch, Molecular Sequence Datasearch, Multiprotein Complexessearch, Neoplasm Proteinssearch, Peptide Fragmentssearch, Phosphopeptidessearch, Phosphorylationsearch, Protein Conformationsearch, Receptorssearch, Antigensearch, T-Cellsearch, Serinesearch