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

Yili Li, Florence R. Depontieu, John Sidney, Theresa M. Salay, Victor H. Engelhard, Donald F. Hunt, Alessandro Sette, Suzanne L. Topalian, Roy A. Mariuzza

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)596-603
Number of pages8
JournalJournal of molecular biology
Volume399
Issue number4
DOIs
StatePublished - Jun 2010

Keywords

  • Crystal structure
  • MHC class II
  • Melanoma
  • Phosphopeptide
  • T-cell receptor

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Li, Y., Depontieu, F. R., Sidney, J., Salay, T. M., Engelhard, V. H., Hunt, D. F., Sette, A., Topalian, S. L., & Mariuzza, R. A. (2010). Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells. Journal of molecular biology, 399(4), 596-603. https://doi.org/10.1016/j.jmb.2010.04.037