ArticleThe Journal of biological chemistry
Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- Cancers modulate processing and presentation of p53 neoantigens to evade T cell detection.Immunity · 2026Article
- Review
- Exploring the Involvement ofLife (Basel, Switzerland) · 2026Review
- ERAP1 Allotypes 2 and 10 Differentially Regulate the Immunopeptidome of Melanocytes.Immunology · 2026Article
- The Impact of ERAP1 and ERAP2 Haplotype Combinations on Susceptibility and Severity of Birdshot Chorioretinitis.Investigative ophthalmology & visual science · 2026Article
- Methods and Guidelines for Analyzing the Conformational Dynamics of Proteins in the Antigen Presentation Pathway.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Transient Transfection and T Cell Activation in the Assessment of Endoplasmic Reticulum Aminopeptidase 1 and 2 Peptide Trimming Function.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Rare and common variants in ERAP1 and ERAP2 selected for in response to Yersinia pestis infection contribute to autoimmune disease including inflammatory bowel disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Rewiring tumor visibility: The immunopeptidome as a dynamic interface between antigen processing, microenvironmental stress, and immune recognition.Frontiers in oncology · 2025Review
- Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.ACS medicinal chemistry letters · 2024Article
- Epistatic interaction between ERAP2 and HLA modulates HIV-1 adaptation and disease outcome in an Australian population.PLoS pathogens · 2024Article
- A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs.Cell genomics · 2024Article
- Structure-guided discovery of aminopeptidase ERAP1 variants capable of processing antigens with novel PC anchor specificities.Immunology · 2024Article
- Polymorphic positions 349 and 725 of the autoimmunity-protective allotype 10 of ER aminopeptidase 1 are key in determining its unique enzymatic properties.Frontiers in immunology · 2024Article
- Evolutionary immuno-genetics of endoplasmic reticulum aminopeptidase II (ERAP2).Genes and immunity · 2023Review
- Review
- EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.Annals of the rheumatic diseases · 2023Review
- Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity.Annals of the rheumatic diseases · 2022Article
- Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation.Frontiers in immunology · 2022Article
- To Be or Not to Be: The Case of Endoplasmic Reticulum Aminopeptidase 2.Frontiers in immunology · 2022Review
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Polymorphic variation of immune system proteins can drive variability of individual immune responses. Endoplasmic reticulum aminopeptidase 1 (ERAP1) generates antigenic peptides for presentation by major histocompatibility complex class I molecules. Coding SNPs in ERAP1 have been associated with predisposition to inflammatory rheumatic disease and shown to affect functional properties of the enzyme, but the interplay between combinations of these SNPs as they exist in allotypes has not been thoroughly explored. We used phased genotype data to estimate ERAP1 allotype frequency in 2504 individuals across five major human populations, generated highly pure recombinant enzymes corresponding to the ten most common ERAP1 allotypes, and systematically characterized their in vitro enzymatic properties. We find that ERAP1 allotypes possess a wide range of enzymatic activities, up to 60-fold, whose ranking is substrate dependent. Strikingly, allotype 10, previously associated with Behçet's disease, is consistently a low-activity outlier, suggesting that a significant percentage of individuals carry a subactive ERAP1 gene. Enzymatic analysis revealed that ERAP1 allotypes can differ in both catalytic efficiency and substrate affinity, differences that can change intermediate accumulation in multistep trimming reactions. Alterations in efficacy of an allosteric inhibitor that targets the regulatory site suggest that allotypic variation influences the communication between the regulatory and the active site. Our work defines the wide landscape of ERAP1 activity in human populations and demonstrates how common allotypes can induce substrate-dependent variability in antigen processing, thus contributing, in synergy with major histocompatibility complex haplotypes, to immune response variability and predisposition to chronic inflammatory conditions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.