The recognition by cytotoxic lymphocytes of antigenic peptides presented by MHC class I molecules plays a crucial role in the cellular defences against viruses and cancer but also contributes to autoimmune disease. MHC class I molecules present peptides that are 8-9 residues long and are derived from peptides generated during degradation of proteins by the proteasome. These particles generally release longer precursors to the presented epitopes that are trimmed further by ER-resident aminopeptidases, primarily ERAP1. 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 that have hydrophobic C-termini to peptides of no more than 8 or 9 residues, the exact size and C-terminus requirements for loading onto most human MHC class I alleles. To further elucidate ERAP1 specificity we have screened a peptide library based on an antigenic epitope sequence template. We have discovered strong internal sequence preferences in peptide precursor degradation by ERAP1. These sequence preferences follow the binding preferences of MHC alleles, indicating an interesting correlation between ERAP1 peptide trimming and MHC binding. This finding suggests that the activity of ERAP1 on the antigenic peptide precursor pool will greatly bias the repertoire of peptides presented towards specific sequences, preferred by specific MHC alleles.
Speaker: Efstratios Stratikos, PhD
Researcher C
NCSR Demokritos
IRRP
Time: Monday, 3 December 2007, 13:00