5eu5
HLA Class I antigen
Structural highlights
FunctionPMEL_HUMAN Plays a central role in the biogenesis of melanosomes. Involved in the maturation of melanosomes from stage I to II. The transition from stage I melanosomes to stage II melanosomes involves an elongation of the vesicle, and the appearance within of distinct fibrillar structures. Release of the soluble form, ME20-S, could protect tumor cells from antibody mediated immunity.[1] Publication Abstract from PubMedHuman CD8+ cytotoxic T lymphocytes (CTLs) can mediate tumour regression in melanoma through the speci fi c recognition of human leukocyte antigen (HLA)-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCR), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumour immunity capable of breaking tolerance towards these self-antigens. Previous studies have shown that these immunogenic designer peptides are not always effective and detailed structural analyses will be required in order to improve future success rates. The melanocyte differentiation protein, glycoprotein (gp)100, 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 through knock-on effects. 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. A molecular switch abrogates gp100 TCR-targeting of a human melanoma antigen.,Bianchi V, Bulek A, Fuller A, Lloyd A, Attaf M, Rizkallah PJ, Dolton G, Sewell AK, Cole DK J Biol Chem. 2016 Feb 25. pii: jbc.M115.707414. PMID:26917722[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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