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.
