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J Mol Biol. 2010 Jun 18;399(4):596-603. doi: 10.1016/j.jmb.2010.04.037. Epub 2010 Apr 24.

Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells.

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1
University of Maryland Institute for Bioscience and Biotechnology Research, W. M. Keck Laboratory for Structural Biology, Rockville, MD 20850, USA.

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.

PMID:
20417641
PMCID:
PMC2904831
DOI:
10.1016/j.jmb.2010.04.037
[Indexed for MEDLINE]
Free PMC Article

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