title: A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing.
abstract: Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules and help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 and ERAP2 have been linked with predisposition to human diseases ranging from viral and bacterial infections to autoimmunity and cancer. It has been hypothesized that altered Ag processing by these enzymes is a causal link to disease etiology, but the molecular mechanisms are obscure. We report in this article that the common ERAP2 single nucleotide polymorphism rs2549782 that codes for amino acid variation N392K leads to alterations in both the activity and the specificity of the enzyme. Specifically, the 392N allele excises hydrophobic N-terminal residues from epitope precursors up to 165-fold faster compared with the 392K allele, although both alleles are very similar in excising positively charged N-terminal amino acids. These effects are primarily due to changes in the catalytic turnover rate (k(cat)) and not in the affinity for the substrate. X-ray crystallographic analysis of the ERAP2 392K allele suggests that the polymorphism interferes with the stabilization of the N terminus of the peptide both directly and indirectly through interactions with key residues participating in catalysis. This specificity switch allows the 392N allele of ERAP2 to supplement ERAP1 activity for the removal of hydrophobic N-terminal residues. Our results provide mechanistic insight to the association of this ERAP2 polymorphism with disease and support the idea that polymorphic variation in Ag processing enzymes constitutes a component of immune response variability in humans.
authors: National Center for Scientific Research Demokritos, 15310 Athens, Greece.
authors: Irini
authors: I
authors: Evnouchidou
authors: James
authors: J
authors: Birtley
authors: Sergey
authors: S
authors: Seregin
authors: Athanasios
authors: A
authors: Papakyriakou
authors: Efthalia
authors: E
authors: Zervoudi
authors: Martina
authors: M
authors: Samiotaki
authors: George
authors: G
authors: Panayotou
authors: Petros
authors: P
authors: Giastas
authors: Olivia
authors: O
authors: Petrakis
authors: Dimitris
authors: D
authors: Georgiadis
authors: Andrea
authors: A
authors: Amalfitano
authors: Emmanuel
authors: E
authors: Saridakis
authors: Irene M
authors: IM
authors: Mavridis
authors: Efstratios
authors: E
authors: Stratikos
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000235:genetics*; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D018360:Crystallography, X-Ray; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D014644:Genetic Variation / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D013379:Substrate Specificity / Q000235:genetics / Q000276:immunology
chemical_list: D000626:Aminopeptidases; C503944:ERAP2 protein, human