Structural Basis for the Presentation of Tumor-Associated MHC Class II-Restricted Phosphopeptides to CD4+ T Cells

JOURNAL OF MOLECULAR BIOLOGY

卷:399

Article

Li, Yili^1,2  Depontieu, Florence R.^3,4  Sidney, John⁵  Salay, Theresa M.^3,4  Engelhard, Victor H.^6,7  Hunt, Donald F.^8,9  Sette, Alessandro⁵  Topalian, Suzanne L.^3,4  Mariuzza, Roy A.^1,2 

[1] Univ Maryland, Inst Biosci & Biotechnol Res, WM Keck Lab Struct Biol, Rockville, MD 20850 USA

[2] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA

[3] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[4] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21231 USA

[5] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA

[6] Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA

[7] Univ Virginia, Carter Immunol Ctr, Charlottesville, VA 22908 USA

[8] Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA

[9] Univ Virginia, Dept Pathol, Charlottesville, VA 22901 USA

关键词: crystal structure;    phosphopeptide;    MHC class II;    T-cell receptor;    melanoma;   

DOI  :  10.1016/j.jmb.2010.04.037

来源: Elsevier

【 摘 要 】

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. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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