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Content archived on 2024-05-29

Structural basis and specificity of antigenic peptide trimming by the newly discoverd ER aminopeptidases ERAP1 and ERAP2


The recognition by cytotoxic lymphocytes of antigenic peptides presented by MHC class I molecules plays a crucial role in cellular defences against viruses and cancer. MHC class I molecules present peptides that are 8-9 residues long and are derived from p eptides generated during degradation of proteins by the proteasome. However, proteasomes generally release longer precursors to the presented epitopes. These precursors are trimmed further in the Endoplasmic Reticulum (ER) by the recently discovered aminop eptidases, ERAP1 and probably also ERAP2. Over-expression or depletion of ERAP1 has strong effects on the presentation of peptide epitopes in vivo. This enzyme has the novel property of trimming N-extended precursors to peptides of 8 or 9 residues, the siz e required for loading onto MHC class I molecules, and then stopping. A highly homologous aminopeptidase LRAP (ERAP2) is also find in the ER although its antigenic peptide trimming properties are still obscure. Unlike typical aminopeptidases, ERAP1 display s specificity for amino acids located away from the N-terminus of the peptide, raising the interesting possibility that its specificity correlates with the binding preferences of MHC-Class II molecules. Because of their importance in immunology and very un usual biochemical properties, greater information about their biochemical features is of major scientific and medical interest. To gain insights to the mechanism and specificity of these enzymes, I propose to solve the three dimensional structure of ERAP1 and ERAP2 by x-ray crystallography and to further characterize their peptide trimming specificity by enzymatic and biophysical methods. Such studies should help us understand the molecular basis of their unique properties and obtain insights on their spe cific roles in determining the nature of the antigens presented.

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