Substrate specificity of human ERAP1 haplotypes in vivo identify three functional classes and multiple fine specificity

Reeves, Emma, Edwards, Christopher, Elliott, Tim and James, Edward (2013) Substrate specificity of human ERAP1 haplotypes in vivo identify three functional classes and multiple fine specificity. Journal of Immunology, 190 (S1), [P5034].

Abstract

Recent genome wide association studies have identified single nucleotide polymorphisms within Endoplasmic Reticulum Aminopeptidase1 (ERAP1) as being associated with autoimmune diseases, cervical carcinoma and hypertension. ERAP1 performs a key final step in antigen processing, trimming N-terminally extended peptides to the final epitope for presentation by MHC I molecules. Here we show that ERAP1 sequenced from individuals is polymorphic, with multiple haplotypes identified. Characterization of the amino acid trimming capacity of the identified haplotypes reveal distinct profiles that correlate with the SNPs they possess. In addition, the properties of the amino acids preferentially trimmed vary between haplotypes. RP-HPLC and mass spectrometry analysis allows classification of the ERAP1 haplotypes into three functional groups; those that have a predominantly i) Normal, ii) Hypo or iii) Hyper-functional activity. These results indicate that the repertoire of peptides presented at the cell surface depends, not only on the MHC I, but also on the ERAP1 expressed within an individual. This therefore has important implications for predisposition to disease, the ability to combat cancer and infection, and also vaccine efficacy.

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Contributors

Author: Edward James

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