ERAP1 · Structural basis and specificity of antigenic peptide trimming by the newly discoverd ER aminopeptidases ERAP1 and ERAP2
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-01-01 → 2007-12-31
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
Final Activity Report Summary - ERAP1 (Structural basis and specificity of antigenic peptide trimming by the newly discoverd ER aminopeptidases ERAP1 and ERAP2)
The immune system is responsible to fighting external pathogens in humans as well as cancer. For immune system cells to be able to differentiate between healthy and sick human cells an intricate pathway of recognition through the generation of antigenic peptides has evolved. Antigenic peptides are pieces of healthy or sick cells or invading pathogens. Antigenic peptide generation has to be tightly regulated, and aberrant regulation can lead to pathogen escape or autoimmunity. The last few years a novel layer of immune response regulation has emerged in the pathway of antigen presentation. Enzymes called aminopeptidases exist in cells and appear to be necessary for the final steps of antigenic peptide generation as well as determining the variability of peptides generated. This project's goal was to contribute to our understanding on the mechanism of function of those aminopeptidases and their role in antigenic peptide generation. Significant progress was done in determining the three-dimensional structure of ERAP1, the most important of those aminopeptidases, a step necessary for understanding its function. Systematic analysis of ERAP1's specificity has led to surprising results that suggest that this enzyme has strong preferences for some peptides versus others. This finding can help us understand the in vivo effects of ERAP1 down-regulation seen in mouse models. Overall, the findings from this project appear to provide a molecular framework for understanding a new and crucial layer of regulation of immune response that is involved to predisposition to autoimmunity and cancer.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- NATIONAL CENTER FOR SCIENTIFIC RESEARCH DEMOKRITOS"" · AGHIA PARASKEVICoordinatorGreece
Links
Data: CORDIS, © European Union