Affinage

ERAP1

Endoplasmic reticulum aminopeptidase 1 · UniProt Q9NZ08

Length
941 aa
Mass
107.2 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERAP1 is an endoplasmic reticulum-resident M1-family zinc metallopeptidase that trims N-terminally extended peptide precursors to optimal 8–10-mer lengths for loading onto MHC class I molecules, thereby shaping the immunopeptidome and controlling CD8+ T cell immunodominance hierarchies and NK cell recognition (PMID:16754858, PMID:31222486). It operates via a conformational open-to-closed catalytic cycle triggered by long-peptide binding, with the internal cavity acting as a molecular ruler that senses substrate length; disease-associated polymorphisms such as K528R impair this interdomain mechanism (PMID:21478864, PMID:34489420). ERAP1 forms allosterically enhanced heterodimers with ERAP2 that improve substrate-binding affinity and generate mature epitopes more efficiently, and these heterodimers can also trim MHC I-bound precursors (PMID:24928998, PMID:27514473). Beyond antigen processing, ERAP1 promotes TNFR1 and IL-6Rα ectodomain shedding through direct receptor binding (PMID:12189246, PMID:12748171), enhances Hedgehog signaling by binding USP47 and destabilizing βTrCP (PMID:31341163), and acts as a hepatokine that impairs skeletal muscle insulin sensitivity by binding ADRB2 and inhibiting USP33-mediated deubiquitination (PMID:35192681).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    Identification of ERAP1 as a signal-peptide-bearing M1 zinc metallopeptidase with leucine-preferring aminopeptidase activity established its catalytic identity and vesicular localization, setting the stage for functional studies.

    Evidence cDNA cloning, recombinant enzyme assays with aminoacyl β-naphthylamide substrates, and GFP-fusion localization in COS-7/BHK cells

    PMID:10824104

    Open questions at the time
    • Physiological substrates in vivo unknown
    • No structural information available
    • Precise ER versus other vesicular compartment localization not distinguished
  2. 2002 High

    Discovery that ERAP1 physically binds TNFR1 and promotes its ectodomain shedding revealed an unexpected non-peptide-trimming function — receptor processing at the cell surface — and showed that this shedding role was independent of ERAP1's own proteolytic activity.

    Evidence Yeast two-hybrid, co-IP, overexpression and antisense knockdown in pulmonary epithelial/endothelial cells

    PMID:12189246

    Open questions at the time
    • Identity of the actual sheddase recruited by ERAP1 unknown
    • Whether ERAP1 exits the ER to reach TNFR1 at the surface not resolved
  3. 2003 High

    Demonstration that ERAP1 binds IL-6Rα and is required for its constitutive shedding — and that this shedding requires ERAP1 catalytic activity — distinguished mechanistically between ERAP1's enzymatic and non-enzymatic receptor-shedding roles.

    Evidence Reciprocal co-IP, ERAP1-null cells showing loss of basal shedding, catalytic-dead mutant analysis

    PMID:12748171

    Open questions at the time
    • Whether ERAP1 directly cleaves IL-6Rα or activates another sheddase not determined
    • Structural basis of the ERAP1–IL-6Rα interaction unknown
  4. 2005 High

    Discovery that ERAP1 and ERAP2 form ER-resident heterodimers performing concerted peptide trimming — with ERAP2 cleaving N-terminal residues refractory to ERAP1 — explained how the full range of MHC I precursors are processed.

    Evidence Co-IP, co-localization, in vitro peptide digestion, cellular antigen presentation assays

    PMID:15908954

    Open questions at the time
    • Stoichiometry and structural architecture of the heterodimer not resolved
    • Allosteric regulation between subunits not yet characterized
  5. 2006 High

    Genetic knockout of ERAP1 in mice proved it is the major ER peptide trimming enzyme in vivo, directly controlling peptide–MHC I complex abundance and shifting CD8+ T cell immunodominance hierarchies during viral infection.

    Evidence ERAP1 knockout mouse, viral infection models, CD8+ T cell immunodominance assays across multiple epitopes

    PMID:16754858

    Open questions at the time
    • Contribution of ERAP2 versus ERAP1 in vivo not separated (mice lack ERAP2)
    • Whether ERAP1 loss also affects non-classical MHC I presentation not examined
  6. 2006 High

    Characterization of the K528R disease-associated polymorphism as catalytically impaired, with K528 positioned near the substrate pocket, provided the first genotype-to-enzymatic-activity link and a rationale for disease associations.

    Evidence Site-directed mutagenesis panel, in vitro aminopeptidase assays, molecular modeling

    PMID:16513116

    Open questions at the time
    • No crystal structure to confirm K528 positioning
    • Effect on peptide trimming in cells not tested
  7. 2008 High

    Systematic substrate profiling revealed that ERAP1 trimming rates depend on internal peptide sequence (up to 40,000-fold variation), consistent with a large internal cavity sensing full peptide length — the 'molecular ruler' concept.

    Evidence In vitro trimming of systematically varied peptide collections, modeling of internal cavity

    PMID:18987748

    Open questions at the time
    • No direct structural evidence for cavity–peptide contacts
    • Molecular ruler mechanism not validated in a cellular context
  8. 2011 High

    Crystal structures of ERAP1 in open and closed conformations, and bound to bestatin, revealed the structural basis for length-dependent trimming: long-substrate binding induces domain closure that repositions a catalytic residue, explaining how the enzyme preferentially trims long precursors and how K528R disrupts interdomain interactions.

    Evidence X-ray crystallography (multiple conformations, bestatin-bound), enzymatic assays with K528R mutant

    PMID:21478864 PMID:21508329

    Open questions at the time
    • No structure of ERAP1 bound to a native peptide substrate
    • Conformational dynamics during the catalytic cycle not captured in crystals
  9. 2011 High

    HCMV miR-US4-1 was shown to specifically target ERAP1 mRNA, reducing peptide trimming and CTL killing of infected cells — establishing viral immune evasion through ERAP1 suppression as a pathogenically relevant strategy.

    Evidence miRNA functional assays, ERAP1 expression measurement, viral peptide trimming and CTL cytotoxicity assays

    PMID:21892175

    Open questions at the time
    • Whether other herpesviruses use analogous miRNA strategies unknown
    • Contribution relative to other HCMV immune evasion genes not quantified
  10. 2014 High

    Reconstitution of stabilized ERAP1–ERAP2 heterodimers demonstrated allosteric enhancement: physical interaction with ERAP2 improved ERAP1 substrate-binding affinity and produced mature epitopes more efficiently than a non-dimerizing enzyme mixture.

    Evidence Stabilized heterodimer production, comparative enzyme kinetics, in vitro epitope trimming

    PMID:24928998

    Open questions at the time
    • Structural basis of allosteric communication between ERAP1 and ERAP2 not resolved
    • In vivo relevance of allosteric enhancement not yet demonstrated
  11. 2015 High

    ERAP1 activity was shown to control HLA-B27 free heavy chain surface expression, KIR3DL2 engagement, and Th17 expansion in ankylosing spondylitis, providing a direct mechanistic link between ERAP1 peptide trimming and autoimmune pathology.

    Evidence siRNA knockdown and pharmacological ERAP1 inhibition in antigen-presenting cells, KIR3DL2 reporter assays, Th17 cytokine measurements from AS patient cells

    PMID:26130142

    Open questions at the time
    • Which specific peptides drive HLA-B27 FHC formation not identified
    • Whether ERAP1 inhibition is therapeutic in vivo for AS not tested
  12. 2016 High

    Demonstration that ERAP1–ERAP2 heterodimers trim MHC I-bound precursor peptides (not only free peptides) and improve pMHC stability expanded the functional scope of ERAP1 trimming beyond the free-peptide pool.

    Evidence In vitro trimming of HLA-B*0801-bound N-terminally extended peptides, conformational stability assays

    PMID:27514473

    Open questions at the time
    • Physiological relevance of MHC-bound trimming versus free-peptide trimming not quantified in cells
    • Whether tapasin or other PLC components modulate on-MHC trimming unknown
  13. 2019 High

    ERAP1 was found to bind USP47, displacing βTrCP from USP47 and promoting βTrCP degradation, thereby upregulating Gli transcription factors and Hedgehog signaling — revealing a non-canonical signaling role outside the antigen-processing pathway.

    Evidence Reciprocal co-IP, genetic knockdown/knockout, pharmacological inhibition, Gli reporter assays, in vivo tumor xenograft model

    PMID:31341163

    Open questions at the time
    • Whether ERAP1's aminopeptidase activity is required for USP47 binding not determined
    • Structural basis of ERAP1–USP47 interaction unknown
  14. 2019 High

    Immunopeptidomics upon pharmacological ERAP1 inhibition revealed that baseline ERAP1 activity is destructive for many potential epitopes, not only generative — shifting the view from ERAP1 as a simple epitope producer to a dual editor of the immunopeptidome.

    Evidence ERAP1 inhibitor treatment of A375 melanoma, LC-MS/MS immunopeptidome profiling of ~3204 peptides

    PMID:31222486

    Open questions at the time
    • Whether destructive trimming is cell-type or allele dependent not addressed
    • Functional immunogenicity of the altered peptidome not tested with T cells
  15. 2021 High

    Solution SAXS and crystallography confirmed that open-to-closed conformational transitions occur during catalysis in solution, are driven by long-peptide binding, and are modulated by allosteric activators/inhibitors — unifying the structural and biochemical molecular-ruler model.

    Evidence SAXS, X-ray crystallography, chemical crosslinking, enzymatic assays with allosteric modulators

    PMID:34489420

    Open questions at the time
    • Full catalytic cycle dynamics at single-molecule resolution not captured
    • How heterodimer formation with ERAP2 modulates conformational dynamics unknown
  16. 2021 High

    In psoriasis, ERAP1 was shown to generate the causative melanocyte autoantigen by trimming precursors for HLA-C*06:02 presentation, with a risk haplotype producing the autoantigen more efficiently — directly connecting ERAP1 genotype to autoimmune epitope generation.

    Evidence ERAP1 KO and genetically defined cell lines, autoreactive psoriatic TCR activation assay, in vitro peptide trimming, flow cytometry

    PMID:34580106

    Open questions at the time
    • Whether ERAP1 inhibition is therapeutic in psoriasis in vivo unknown
    • Full set of ERAP1-dependent autoantigens in psoriasis not mapped
  17. 2022 High

    Discovery of ERAP1 as a secreted hepatokine that binds ADRB2 in skeletal muscle and impairs insulin signaling by inhibiting USP33-mediated deubiquitination of ADRB2 revealed a systemic metabolic role entirely independent of antigen processing.

    Evidence Hepatic overexpression/knockdown in HFD mice, serum ERAP1 measurement, co-IP of ERAP1–ADRB2, ubiquitination/deubiquitination assays, insulin signaling readouts in skeletal muscle

    PMID:35192681

    Open questions at the time
    • How ERAP1 is secreted from the ER lumen to serum not elucidated
    • Whether the hepatokine function requires ERAP1 aminopeptidase activity unknown
    • Relevance in human metabolic disease not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of ERAP1–ERAP2 heterodimer allostery, how ERAP1 exits the ER for its receptor-shedding and hepatokine roles, whether aminopeptidase activity is required for all non-canonical functions (Hedgehog, ADRB2), and whether ERAP1 inhibition can be therapeutically exploited in autoimmunity or cancer.
  • No structure of ERAP1–ERAP2 heterodimer available
  • ER-exit or secretion mechanism undefined
  • Therapeutic efficacy of ERAP1 modulation not tested in clinical studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005576 extracellular region 1
Pathway
R-HSA-168256 Immune System 9 R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3
Partners
ADRB2ERAP2IL6RNUCB2RBMXTNFRSF1AUSP47
Complex memberships
ERAP1–ERAP2 heterodimerNUCB2–ERAP1–TNFR1 complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 ERAP1 and ERAP2 physically associate as heterodimeric complexes in the endoplasmic reticulum and perform concerted trimming of peptide precursors for HLA class I presentation; ERAP1 alone cannot remove certain N-terminal amino acids that ERAP2 trims efficiently, requiring the combined action of both enzymes. Co-localization in vivo, physical co-immunoprecipitation, in vitro peptide digestion assays, cellular antigen presentation assays Nature immunology High 15908954
2002 ERAP1 (ARTS-1) binds to the extracellular domain of TNFR1 via yeast two-hybrid and co-immunoprecipitation, and promotes TNFR1 ectodomain shedding; overexpression increases shedding while antisense knockdown decreases it. ARTS-1 displays selective aminopeptidase activity toward nonpolar amino acids but does not itself act as the TNFR1 sheddase. Yeast two-hybrid, co-immunoprecipitation, overexpression and antisense knockdown in human pulmonary epithelial and endothelial cells, in vitro aminopeptidase activity assay The Journal of clinical investigation High 12189246
2003 ERAP1 (ARTS-1) directly binds membrane-associated IL-6Rα and is required for its constitutive shedding; this regulation requires ARTS-1 catalytic activity, distinguishing it from its non-enzymatic role in TNFR1 shedding. Reciprocal co-immunoprecipitation, overexpression, ARTS-1 knockout cells (absence of basal shedding), catalytic mutant analysis The Journal of biological chemistry High 12748171
2006 ERAP1 is the major enzyme trimming peptide precursors in the endoplasmic reticulum in vivo; genetic knockout in mice shifts the immunodominance hierarchy of viral CD8+ T cell responses by generating or destroying antigenic peptides, demonstrating that ERAP1 trimming activity directly controls peptide-MHC class I complex abundance. ERAP1 knockout mouse, viral infection model, CD8+ T cell immunodominance assay Proceedings of the National Academy of Sciences of the United States of America High 16754858
2006 The hypertension-associated Lys528Arg polymorphism of ERAP1 significantly reduces enzymatic aminopeptidase activity; site-directed mutagenesis of Lys528 to various amino acids (Ala, Met, His, Arg) all reduce activity, and molecular modeling places Lys528 near the substrate pocket entrance. Site-directed mutagenesis, in vitro aminopeptidase activity assay with aminoacyl β-naphthylamide substrates, molecular modeling FEBS letters High 16513116
2006 NUCB2 (nucleobindin 2) binds the ARTS-1 (ERAP1) extracellular domain via a calcium-dependent interaction identified by yeast two-hybrid and co-immunoprecipitation; the NUCB2–ARTS-1 complex associates with TNFR1 and is required for both constitutive release of TNFR1 exosome-like vesicles and inducible proteolytic cleavage of soluble TNFR1 ectodomains. Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, RNA interference knockdown of NUCB2 and ARTS-1 The Journal of biological chemistry High 16407280
2008 ERAP1 trimming of peptide N-termini is strongly influenced by the internal sequence of the substrate; positively charged or hydrophobic residues at positions distal to the N-terminus alter trimming rates by up to 100-fold for single substitutions and >40,000-fold for multiple substitutions, consistent with ERAP1 recognizing full peptide length via a large negatively charged internal cavity. Systematic in vitro peptide substrate analysis with collections of peptide variants, molecular modeling of internal cavity PloS one High 18987748
2008 RBMX (a heterogeneous nuclear ribonucleoprotein) associates with ERAP1 (ARTS-1) by co-immunoprecipitation, and RNAi knockdown of RBMX reduces both constitutive TNFR1 exosome-like vesicle release and IL-1β-mediated inducible proteolytic cleavage of TNFR1 ectodomains. Co-immunoprecipitation, RNA interference Biochemical and biophysical research communications Medium 18445477
2011 X-ray crystal structures of human ERAP1 in open and closed conformations reveal a zinc-metallopeptidase with HEXXH-(X)18-E and GAMEN motifs; structures show extensive domain movements including active-site closure, and the disease-associated K528R mutant shows significantly altered peptide-processing characteristics attributable to impaired interdomain interactions. X-ray crystallography (open and closed conformations), in vitro peptide-processing assays of K528R mutant Proceedings of the National Academy of Sciences of the United States of America High 21508329
2011 X-ray crystal structure of human ERAP1 bound to bestatin reveals an open conformation with a large interior compartment and an extended groove from the catalytic center that accommodates long peptides; structural and biochemical analyses show that binding of long (but not short) substrates induces conformational change reorienting a key catalytic residue toward the active site, explaining length-dependent trimming activity. X-ray crystallography (bestatin-bound), biochemical substrate trimming assays Nature structural & molecular biology High 21478864
2011 Human cytomegalovirus miR-US4-1 specifically targets and downregulates ERAP1 expression during infection, inhibiting trimming of HCMV-derived peptides and reducing susceptibility of infected cells to HCMV-specific cytotoxic T lymphocytes. miRNA functional assays, ERAP1 expression measurement, viral peptide trimming assay, CTL cytotoxicity assay Nature immunology High 21892175
2013 p53 upregulates ERAP1 expression by binding to a cognate p53 response element in the ERAP1 gene, increasing MHC class I surface expression; this mechanism operates in cancer cells and in influenza-infected cells where H1N1 activates p53 leading to ERAP1 upregulation. ChIP-seq, gene expression analysis, p53 silencing, ERAP1 silencing, MHC class I surface expression measurement Nature communications High 23965983
2014 ERAP1 and ERAP2 form stabilized heterodimers in which physical interaction with ERAP2 changes basic enzymatic parameters of ERAP1, improving its substrate-binding affinity; the heterodimer produces mature MHC class I epitopes more efficiently than a mixture of the two enzymes unable to dimerize. Stabilized heterodimer production, in vitro epitope trimming assays comparing heterodimers vs. non-dimerizing enzyme mix, enzymatic kinetics Journal of immunology High 24928998
2015 ERAP1 activity controls the surface expression of HLA-B27 free heavy chains (FHCs) on antigen-presenting cells; silencing or pharmacological inhibition of ERAP1 reduces HLA-B27 FHC surface expression, reduces KIR3DL2 engagement, and suppresses Th17 expansion and IL-17A secretion by ankylosing spondylitis CD4+ T cells. siRNA knockdown, pharmacological ERAP1 inhibition, flow cytometry, KIR3DL2-reporter cell assay, Th17 intracellular cytokine staining and ELISA Annals of the rheumatic diseases High 26130142
2015 Genetic or pharmacological inhibition of ERAP1 perturbs tumor cell engagement of inhibitory NK cell receptors (KIR by pMHC-I; CD94-NKG2A by nonclassical pMHC-I), reducing protection from NK cell killing; the protective effect can be restored by adding high-affinity peptides, indicating ERAP1 is required to generate high-affinity natural peptide ligands. ERAP1 inhibition (genetic and pharmacological), NK cell cytotoxicity assay, inhibitory receptor–ligand interaction measurement, high-affinity peptide add-back Cancer research High 25592150
2016 ERAP1-ERAP2 heterodimers can trim MHC I-bound precursor peptides to their correct and final lengths (albeit more slowly than free precursors); trimming of MHC I-bound precursors by the heterodimer increases the conformational stability of MHC I/peptide complexes. ERAP1/ERAP2 heterodimer production, in vitro trimming assays of free and HLA-B*0801-bound N-terminally extended peptides, conformational stability assessment Scientific reports High 27514473
2016 ERAP1 knockdown in monocytic U937 cells expressing HLA-B27 specifically increases cell surface accumulation of HLA-B27 (including disulfide-linked dimers) but has no effect on HLA-B18 or HLA-B51, indicating that ERAP1 activity selectively controls HLA-B27 surface expression and aberrant heavy-chain dimer formation. ERAP1 siRNA knockdown, immunoprecipitation, isoelectric focusing, immunoblotting, flow cytometry with subtype-specific antibodies, non-reducing PAGE for disulfide-linked dimers Molecular immunology High 27107845
2017 HCMV miR-UL112-5p targets the ERAP1 3′ UTR (A variant), reducing ERAP1 expression at RNA and protein levels and inhibiting processing and presentation of the HCMV pp65495–503 peptide to CTLs; a naturally occurring rs17481334 G variant in the ERAP1 3′ UTR prevents miR-UL112-5p binding, preserving ERAP1 expression and CTL killing. miRNA–3′UTR binding assay, ERAP1 expression measurement (RNA and protein), CTL cytotoxicity assay, genotype analysis of human fibroblasts Cell reports High 28746870
2019 ERAP1 binds the deubiquitylase USP47, displaces USP47-associated βTrCP (the substrate receptor of SCFβTrCP ubiquitin ligase), and promotes βTrCP degradation; this leads to upregulation of Gli transcription factors and enhancement of Hedgehog signaling pathway activity, and genetic or pharmacological ERAP1 inhibition suppresses Hedgehog-dependent tumor growth in vitro and in vivo. Co-immunoprecipitation (ERAP1–USP47 and USP47–βTrCP interaction), genetic knockdown/knockout, pharmacological inhibition, Gli reporter assay, in vivo tumor model Nature communications High 31341163
2019 Pharmacological inhibition of ERAP1 in A375 melanoma cells alters the qualitative and quantitative composition of the MHC-I immunopeptidome (affecting ~half of 3204 identified peptides) without reducing surface MHC-I expression; inhibition reduces presentation of suboptimal long peptides and increases presentation of high-affinity 9–12-mers, suggesting baseline ERAP1 activity is destructive for many potential epitopes in this line. ERAP1 inhibitor treatment, MHC-I peptide isolation, LC-MS/MS mass spectrometry of eluted peptides, MHC-I affinity prediction Cancer immunology, immunotherapy High 31222486
2019 X-ray crystallographic structures of HLA-B*0801 bound to N-terminally extended 10–20-mer precursor peptides show that residue extensions protrude out of the A pocket while the peptide core adopts a canonical conformation; ERAP1-mediated trimming of MHC I-bound peptides requires a minimal length of 14 amino acids, and HLA-B*0801 residue 62 is critical for opening the A pocket to accommodate the extension. X-ray crystallography (1.40–1.65 Å resolution), thermostability assays, in vitro ERAP1 trimming assay of MHC I-bound peptides The Journal of biological chemistry High 31601650
2021 ERAP1 conformational states in solution (open and closed) occur during the catalytic cycle and are promoted by binding of long peptide substrates; allosteric activators shift the enzyme toward closed conformation, inhibitors toward open; structural reconfigurations of the active site are physically linked to domain closure, providing the mechanistic basis for allosteric regulation and explaining the Lys/Arg528 polymorphism disease association. Small-angle X-ray scattering (SAXS) in solution, X-ray crystallography, chemical crosslinking to localize C-terminal binding sites, enzymatic assays with substrates/allosteric modulators/inhibitors Nature communications High 34489420
2021 In psoriasis, ERAP1 generates the causative melanocyte autoantigen by trimming N-terminally extended peptide precursors to the length required for presentation by HLA-C*06:02; an ERAP1 risk haplotype produces the autoantigen more efficiently and increases HLA-C expression and stimulation of a psoriatic autoreactive TCR. ERAP1 knockout significantly reduces cell-surface HLA-C expression more than total HLA class I. Genetically modified cell lines, TCR activation assay with autoreactive psoriatic TCR, ERAP1 knockout, in vitro peptide trimming assays, flow cytometry for HLA-C surface expression Journal of immunology High 34580106
2022 ERAP1 functions as an inflammation-induced hepatokine; hepatically secreted ERAP1 interacts with β2 adrenergic receptor (ADRB2) in skeletal muscle, reduces ADRB2 expression by decreasing USP33-mediated deubiquitination, and thereby impairs ADRB2-stimulated insulin signaling, attenuating skeletal muscle insulin sensitivity. Hepatic overexpression and knockdown in vivo (HFD mice), serum ERAP1 measurement, co-immunoprecipitation (ERAP1–ADRB2 interaction), ubiquitination assay (USP33-mediated deubiquitination), insulin signaling assays in skeletal muscle Diabetes High 35192681
2000 ERAP1 (PILS-AP) contains the HEXXH(X)18E zinc-binding motif characteristic of M1 family aminopeptidases and a signal sequence directing it to intracellular vesicles; recombinant protein shows leucine-specific (and lesser methionine) aminopeptidase activity inhibited by metal chelators, but insensitive to puromycin. cDNA cloning, GFP fusion protein localization in COS-7 and BHK cells, recombinant expression in Sf9 insect cells, aminoacyl β-naphthylamide substrate hydrolysis assays, inhibitor profiling European journal of biochemistry High 10824104

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nature genetics 424 23291587
2005 Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nature immunology 382 15908954
2011 Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proceedings of the National Academy of Sciences of the United States of America 202 21508329
2002 Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. The Journal of clinical investigation 177 12189246
2011 Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nature structural & molecular biology 168 21478864
2011 Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1. Nature immunology 157 21892175
2006 Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance. Proceedings of the National Academy of Sciences of the United States of America 157 16754858
2018 How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins. Frontiers in immunology 134 30425713
2013 p53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1. Nature communications 132 23965983
2013 Naturally occurring ERAP1 haplotypes encode functionally distinct alleles with fine substrate specificity. Journal of immunology (Baltimore, Md. : 1950) 126 23733883
2009 Investigating the genetic association between ERAP1 and ankylosing spondylitis. Human molecular genetics 119 19692350
2009 Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis and rheumatism 117 19877036
2003 An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding. The Journal of biological chemistry 117 12748171
2006 Reduced activity of the hypertension-associated Lys528Arg mutant of human adipocyte-derived leucine aminopeptidase (A-LAP)/ER-aminopeptidase-1. FEBS letters 95 16513116
2009 Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Annals of the rheumatic diseases 90 19433412
2009 Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis. Arthritis and rheumatism 88 19404951
2014 Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis. Proceedings of the National Academy of Sciences of the United States of America 87 25422414
2004 Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. British journal of cancer 87 14710229
2016 ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. Scientific reports 82 27514473
2008 Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues. Journal of cellular physiology 81 18393273
2012 Endoplasmic reticulum aminopeptidase 1 (ERAP1) exhibits functionally significant interaction with HLA-B27 and relates to subtype specificity in ankylosing spondylitis. Annals of the rheumatic diseases 77 22355039
2009 Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma. Genes, chromosomes & cancer 76 19202550
2008 The internal sequence of the peptide-substrate determines its N-terminus trimming by ERAP1. PloS one 76 18987748
2006 Extracellular TNFR1 release requires the calcium-dependent formation of a nucleobindin 2-ARTS-1 complex. The Journal of biological chemistry 76 16407280
2015 Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis. Annals of the rheumatic diseases 74 26130142
2014 ERAP1-ERAP2 dimerization increases peptide-trimming efficiency. Journal of immunology (Baltimore, Md. : 1950) 70 24928998
2013 ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases. Molecular immunology 68 23916068
2015 ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors. Cancer research 62 25592150
2017 The Behçet's disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B*51 peptidome by differential subpeptidome processing. The Journal of biological chemistry 54 28446606
2020 The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity: New insights and perspective. Molecular immunology 53 32135401
2012 Genetic association with ERAP1 in psoriasis is confined to disease onset after puberty and not dependent on HLA-C*06. The Journal of investigative dermatology 52 22931917
2000 Molecular characterization of a puromycin-insensitive leucyl-specific aminopeptidase, PILS-AP. European journal of biochemistry 52 10824104
2011 CD39+ regulatory T cells suppress generation and differentiation of Th17 cells in human malignant pleural effusion via a LAP-dependent mechanism. Respiratory research 51 21663645
2019 Regulation of ERAP1 and ERAP2 genes and their disfunction in human cancer. Human immunology 50 30825518
2017 Separate effects of the ankylosing spondylitis associated ERAP1 and ERAP2 aminopeptidases determine the influence of their combined phenotype on the HLA-B*27 peptidome. Journal of autoimmunity 50 28063628
2017 The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis. Clinical and experimental immunology 50 28759104
2015 Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen. Molecular & cellular proteomics : MCP 50 25892735
2019 ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP. Nature communications 49 31341163
2017 The Human Leukocyte Antigen (HLA)-B27 Peptidome in Vivo, in Spondyloarthritis-susceptible HLA-B27 Transgenic Rats and the Effect of Erap1 Deletion. Molecular & cellular proteomics : MCP 49 28188227
2018 Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis. Human molecular genetics 47 30215709
2019 Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations. Human immunology 46 30797823
2012 ERAP1 genetic variations associated with HLA-B27 interaction and disease severity of syndesmophytes formation in Taiwanese ankylosing spondylitis. Arthritis research & therapy 45 22632381
2018 The role of polymorphic ERAP1 in autoinflammatory disease. Bioscience reports 44 30054427
2012 A functional variant in ERAP1 predisposes to multiple sclerosis. PloS one 44 22253828
2019 Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1). Cancer immunology, immunotherapy : CII 43 31222486
2011 ERAP1 polymorphisms and haplotypes are associated with ankylosing spondylitis susceptibility and functional severity in a Spanish population. Rheumatology (Oxford, England) 42 21865284
2021 ERAP1 Controls the Autoimmune Response against Melanocytes in Psoriasis by Generating the Melanocyte Autoantigen and Regulating Its Amount for HLA-C*06:02 Presentation. Journal of immunology (Baltimore, Md. : 1950) 41 34580106
2011 Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis. Arthritis research & therapy 39 21281511
2015 Dominant role of the ERAP1 polymorphism R528K in shaping the HLA-B27 Peptidome through differential processing determined by multiple peptide residues. Arthritis & rheumatology (Hoboken, N.J.) 37 25469497
2020 ERAP1: a potential therapeutic target for a myriad of diseases. Expert opinion on therapeutic targets 36 32249641
2012 Association between endoplasmic reticulum aminopeptidase-1 (ERAP-1) and susceptibility to ankylosing spondylitis in Iran. Iranian journal of allergy, asthma, and immunology 36 23264405
2010 Genetic studies of ankylosing spondylitis in Koreans confirm associations with ERAP1 and 2p15 reported in white patients. The Journal of rheumatology 35 21041274
2020 The Multifaceted Nature of Aminopeptidases ERAP1, ERAP2, and LNPEP: From Evolution to Disease. Frontiers in immunology 34 32793222
2011 Expression of MHC class I dimers and ERAP1 in an ankylosing spondylitis patient cohort. Immunology 34 21574996
2017 Identification of a Genetic Variation in ERAP1 Aminopeptidase that Prevents Human Cytomegalovirus miR-UL112-5p-Mediated Immunoevasion. Cell reports 33 28746870
2012 Exploring ankylosing spondylitis-associated ERAP1, IL23R and IL12B gene polymorphisms in subphenotypes of psoriatic arthritis. Rheumatology (Oxford, England) 32 23093722
2018 An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes. Scientific reports 31 29991817
2019 ERAP1 enzyme-mediated trimming and structural analyses of MHC I-bound precursor peptides yield novel insights into antigen processing and presentation. The Journal of biological chemistry 30 31601650
2012 Investigating the genetic association between ERAP1 and spondyloarthritis. Annals of the rheumatic diseases 30 22896742
2021 Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism. Nature communications 29 34489420
2019 ERAP1 shapes just part of the immunopeptidome. Human immunology 29 30849449
2014 Epistatic interaction of ERAP1 and HLA-B in Behçet disease: a replication study in the Spanish population. PloS one 29 25019531
2022 Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity. Annals of the rheumatic diseases 28 35922122
2019 HPV Epitope Processing Differences Correlate with ERAP1 Allotype and Extent of CD8+ T-cell Tumor Infiltration in OPSCC. Cancer immunology research 28 31151965
2018 ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis. Scientific reports 28 30127455
2014 Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis. Genes and immunity 28 25354578
2017 ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism. Oncoimmunology 27 28811980
2010 ERAP1 is associated with ankylosing spondylitis in Han Chinese. The Journal of rheumatology 27 21078719
2014 ERAP1 in the pathogenesis of ankylosing spondylitis. Immunologic research 26 25434650
2008 An association between RBMX, a heterogeneous nuclear ribonucleoprotein, and ARTS-1 regulates extracellular TNFR1 release. Biochemical and biophysical research communications 25 18445477
2020 The Differential Expression of ERAP1/ERAP2 and Immune Cell Activation in Pre-eclampsia. Frontiers in immunology 24 32210971
2017 ERAP1 and ERAP2 Gene Variations Influence the Risk of Psoriatic Arthritis in Romanian Population. Archivum immunologiae et therapiae experimentalis 24 28083616
2013 ERAP1 and ankylosing spondylitis. Current opinion in immunology 24 23452840
2011 The association between seven ERAP1 polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis involving 8,530 cases and 12,449 controls. Rheumatology international 24 21229357
2017 ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population. Innate immunity 23 28651467
2021 ERAP1 and ERAP2 Enzymes: A Protective Shield for RAS against COVID-19? International journal of molecular sciences 22 33567739
2019 The role of ERAP1 in autoinflammation and autoimmunity. Human immunology 22 30817945
2019 Redundancy and Complementarity between ERAP1 and ERAP2 Revealed by their Effects on the Behcet's Disease-associated HLA-B*51 Peptidome. Molecular & cellular proteomics : MCP 22 31092671
2018 Ranking the Contribution of Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphisms to Shaping the HLA-B*27 Peptidome. Molecular & cellular proteomics : MCP 22 29632046
2016 Discovery of potent and selective inhibitors of human aminopeptidases ERAP1 and ERAP2 by screening libraries of phosphorus-containing amino acid and dipeptide analogues. Bioorganic & medicinal chemistry letters 21 27390066
2015 Association of ERAP1 Gene Polymorphisms With Behçet's Disease in Han Chinese. Investigative ophthalmology & visual science 21 26393469
2013 Concerted in vitro trimming of viral HLA-B27-restricted ligands by human ERAP1 and ERAP2 aminopeptidases. PloS one 21 24223975
2019 ERAP1-ERAP2 haplotypes are associated with ankylosing spondylitis in Polish patients. Human immunology 20 30794838
2017 Single Nucleotide Polymorphisms of the ERAP1 Gene and Risk of NSCLC: A Comparison of Genetically Distant Populations, Chinese and Caucasian. Archivum immunologiae et therapiae experimentalis 20 28083613
2017 Associations of ERAP1 coding variants and domain specific interaction with HLA-C∗06 in the early onset psoriasis patients of India. Human immunology 20 28867178
2019 ERAP1 allotypes shape the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection. Journal of hepatology 19 30769005
2016 ERAP1 reduces accumulation of aberrant and disulfide-linked forms of HLA-B27 on the cell surface. Molecular immunology 19 27107845
2013 A polymorphism in ERAP1 is associated with susceptibility to ankylosing spondylitis in a Turkish population. Rheumatology international 19 23864143
2021 ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers. Investigative ophthalmology & visual science 18 34727153
2022 Hepatokine ERAP1 Disturbs Skeletal Muscle Insulin Sensitivity Via Inhibiting USP33-Mediated ADRB2 Deubiquitination. Diabetes 17 35192681
2022 The emerging multifunctional roles of ERAP1, ERAP2 and IRAP between antigen processing and renin-angiotensin system modulation. Frontiers in immunology 17 36203608
2021 Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival. Cancer immunology, immunotherapy : CII 17 33651148
2018 Association analysis of ERAP1 gene single nucleotide polymorphism in susceptibility to ankylosing spondylitis in Iranian population. Immunology letters 17 30412714
2014 ERAP1 functions override the intrinsic selection of specific antigens as immunodominant peptides, thereby altering the potency of antigen-specific cytolytic and effector memory T-cell responses. International immunology 17 25087231
2021 Genetic association of ERAP1 and ERAP2 with eclampsia and preeclampsia in northeastern Brazilian women. Scientific reports 16 33762660
2018 ERAP1/ERAP2 and RUNX3 polymorphisms are not associated with ankylosing spondylitis susceptibility in Chinese Han. Clinical and experimental immunology 16 29480940
2013 Functional variants of ERAP1 gene are associated with HLA-B27 positive spondyloarthritis. Tissue antigens 16 23800305
2012 Association of ankylosing spondylitis with HLA-B27 and ERAP1: pathogenic role of antigenic peptide. Medical hypotheses 16 23123136
2011 Susceptibility to ankylosing spondylitis: evidence for the role of ERAP1, TGFb1 and TLR9 gene polymorphisms. Rheumatology international 16 21833528
2017 Association of polymorphisms in ERAP1 and risk of ankylosing spondylitis in a Chinese population. Gene 15 29278768