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A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen

Bianchi, Valentina, Bulek, Anna, Fuller, Anna, Lloyd, Angharad, Attaf, Meriem, Rizkallah, Pierre, Dolton, Garry, Sewell, Andrew K. and Cole, David 2016. A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen. Journal of Biological Chemistry 291 (17) , pp. 8951-8959. 10.1074/jbc.M115.707414

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Abstract

Human CD8+ cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu3 have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100280–288 peptide showed that Glu3 was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu3 → Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: ASBMB
ISSN: 00219258
Funders: Wellcome Trust
Date of First Compliant Deposit: 29 June 2016
Date of Acceptance: 9 February 2016
Last Modified: 25 Mar 2019 01:50
URI: http://orca-mwe.cf.ac.uk/id/eprint/92210

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