Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells.
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.
Li
Yili
Y
University of Maryland Institute for Bioscience and Biotechnology Research, W. M. Keck Laboratory for Structural Biology, Rockville, MD 20850, USA.
Depontieu
Florence R
FR
Sidney
John
J
Salay
Theresa M
TM
Engelhard
Victor H
VH
Hunt
Donald F
DF
Sette
Alessandro
A
Topalian
Suzanne L
SL
Mariuzza
Roy A
RA
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018360:Crystallography, X-Ray; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010748:Phosphopeptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012694:Serine / Q000737:chemistry
D000951:Antigens, Neoplasm; D015798:HLA-DR1 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010748:Phosphopeptides; D011948:Receptors, Antigen, T-Cell; D012694:Serine