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 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

Fingerprint

Phosphopeptides
Major Histocompatibility Complex
MART-1 Antigen
T-Lymphocytes
Peptides
T-Cell Antigen Receptor
HLA-DR1 Antigen
Neoplasms
Phosphorylation
Serine
Melanoma
Phosphates
Antigens
Proteins

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Li, Y., Depontieu, F. R., Sidney, J., Salay, T. M., Engelhard, V. H., Hunt, D. F., ... 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

Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells. / Li, Yili; Depontieu, Florence R.; Sidney, John; Salay, Theresa M.; Engelhard, Victor H.; Hunt, Donald F.; Sette, Alessandro; Topalian, Suzanne; Mariuzza, Roy A.

In: Journal of Molecular Biology, Vol. 399, No. 4, 06.2010, p. 596-603.

Research output: Contribution to journalArticle

Li, Y, Depontieu, FR, Sidney, J, Salay, TM, Engelhard, VH, Hunt, DF, Sette, A, Topalian, S & Mariuzza, RA 2010, 'Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells', Journal of Molecular Biology, vol. 399, no. 4, pp. 596-603. https://doi.org/10.1016/j.jmb.2010.04.037
Li, Yili ; Depontieu, Florence R. ; Sidney, John ; Salay, Theresa M. ; Engelhard, Victor H. ; Hunt, Donald F. ; Sette, Alessandro ; Topalian, Suzanne ; Mariuzza, Roy A. / Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells. In: Journal of Molecular Biology. 2010 ; Vol. 399, No. 4. pp. 596-603.
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