ArticleJournal of immunology (Baltimore, Md. : 1950)2012
A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing.
Article in Journal of immunology (Baltimore, Md. : 1950), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 104 citations in OpenAlex.
- Methods and Guidelines for Analyzing the Conformational Dynamics of Proteins in the Antigen Presentation Pathway.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Deciphering genetic associations with blood pressure in peripheral blood mononuclear cells through single-cell transcriptomic profiling.Hypertension research : official journal of the Japanese Society of Hypertension · 2025Article
- Genetic Polymorphisms in MHC Classes I and II Predict Outcomes in Metastatic Colorectal Cancer.International journal of molecular sciences · 2025Article
- The important roles of ERAP1, ERAP2 genes polymorphisms and their DNA methylation levels in pulmonary tuberculosis.BMC infectious diseases · 2025Article
- Unveiling the impact of ERAP1 and ERAP2 on migration, angiogenesis and ER stress response.Frontiers in cell and developmental biology · 2025Review
- Unveiling the therapeutic potential ofHeliyon · 2024Article
- Integrating plasma proteomics with genome-wide association data to identify novel drug targets for inflammatory bowel disease.Scientific reports · 2024Article
- Epistatic interaction between ERAP2 and HLA modulates HIV-1 adaptation and disease outcome in an Australian population.PLoS pathogens · 2024Article
- Exploring the Pathogenesis of Spondylarthritis beyond HLA-B27: A Descriptive Review.International journal of molecular sciences · 2024Review
- Biology of HLA class I associated inflammatory diseases.Best practice & research. Clinical rheumatology · 2024Review
- Transcriptome-wide association studies associated with Crohn's disease: challenges and perspectives.Cell & bioscience · 2024Review
- Deciphering the molecular landscape of rheumatoid arthritis offers new insights into the stratified treatment for the condition.Frontiers in immunology · 2024Article
- Evolutionary immuno-genetics of endoplasmic reticulum aminopeptidase II (ERAP2).Genes and immunity · 2023Review
- A Comparative Review of Pregnancy and Cancer and Their Association with Endoplasmic Reticulum Aminopeptidase 1 and 2.International journal of molecular sciences · 2023Review
- Phenylsulfamoyl Benzoic Acid Inhibitor of ERAP2 with a Novel Mode of Inhibition.ACS chemical biology · 2022Article
- Searching for New Genetic Biomarkers of Axial Spondyloarthritis.Journal of clinical medicine · 2022Article
- Inhibitor-Dependent Usage of the S1' Specificity Pocket of ER Aminopeptidase 2.ACS medicinal chemistry letters · 2022Article
- Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation.Frontiers in immunology · 2022Article
- Overexpression of ERAP2N in Human Trophoblast Cells Promotes Cell Death.International journal of molecular sciences · 2021Article
- Interaction between ERAP Alleles and HLA Class I Types Support a Role of Antigen Presentation in Hodgkin Lymphoma Development.Cancers · 2021Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
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.
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