Affinage

ERAP1

Endoplasmic reticulum aminopeptidase 1 · UniProt Q9NZ08

Length
941 aa
Mass
107.2 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERAP1 is an endoplasmic-reticulum-resident, zinc-dependent M1/gluzincin aminopeptidase that shapes the MHC class I peptide repertoire by trimming N-terminally extended precursor peptides to their mature lengths for antigen presentation (PMID:15908954, PMID:16754858). Crystallographic and solution-scattering analyses define a multidomain enzyme bearing the HEXXH-(X)18-E zinc-binding and GAMEN motifs that cycles between open and closed conformations; binding of long peptide substrates or allosteric activators drives active-site closure and reorients a key catalytic residue, providing a structural basis for its length-dependent 'molecular ruler' trimming and for recognition of internal substrate residues via a large interior cavity (PMID:21508329, PMID:21478864, PMID:18987748, PMID:34489420). ERAP1 partners with ERAP2 to form ER heterodimers whose dimerization allosterically enhances substrate affinity and trimming efficacy beyond either enzyme alone, and it can edit precursor peptides while bound to MHC class I, requiring a minimum substrate length to engage MHC-bound peptides (PMID:15908954, PMID:24928998, PMID:27514473, PMID:31601650). Through this trimming activity ERAP1 establishes CD8+ T cell immunodominance hierarchies, sets surface levels and conformational stability of MHC class I (including disulfide-linked HLA-B27 free heavy chains), and tunes NK-cell inhibitory receptor engagement by modifying the affinity of natural MHC ligands (PMID:16754858, PMID:26130142, PMID:27107845, PMID:25592150); an ERAP1 risk haplotype efficiently generates an HLA-C*06:02-restricted melanocyte autoantigen in psoriasis (PMID:34580106). ERAP1 expression is directly induced by p53 and is suppressed by HCMV miRNAs (miR-US4-1 and miR-UL112-5p) as a CTL-evasion strategy (PMID:21892175, PMID:23965983, PMID:28746870). Beyond antigen processing, ERAP1 (originally identified as ARTS-1) binds the ectodomains of TNFR1 and IL-6Rα to promote their shedding (PMID:12189246, PMID:12748171), modulates Hedgehog signaling by displacing βTrCP from USP47 (PMID:31341163), and acts as a hepatokine that impairs skeletal-muscle insulin sensitivity by binding ADRB2 and reducing its USP33-mediated deubiquitination (PMID:35192681). ERAP1-deficient mice develop ankylosing-spondylitis-like skeletal disease and intestinal dysbiosis (PMID:30127455).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2000 Medium

    Established ERAP1's basic biochemical identity, answering whether the protein is an enzyme and where it acts.

    Evidence GFP-fusion live-cell imaging and in vitro aminopeptidase assays with inhibitor profiling

    PMID:10824104

    Open questions at the time
    • Vesicular localization in COS-7/BHK does not pinpoint the ER residence later established
    • Substrate specificity defined only with model aminoacyl substrates, not antigenic peptides
  2. 2002 High

    Revealed an antigen-processing-independent role by showing ERAP1 binds TNFR1 and promotes its ectodomain shedding, raising the question of how an aminopeptidase regulates receptor shedding.

    Evidence Yeast two-hybrid, reciprocal Co-IP in two cell types, gain/loss-of-function shedding assays

    PMID:12189246

    Open questions at the time
    • ERAP1 itself lacks sheddase activity, so the molecular link to the actual protease is unresolved
    • Selectivity for TNFR1 over TNFR2 mechanism not explained
  3. 2003 High

    Extended the shedding role to IL-6Rα and showed catalytic activity is required, distinguishing this function from passive receptor binding.

    Evidence Reciprocal Co-IP, KO cells, enzymatic inhibition of shedding

    PMID:12748171

    Open questions at the time
    • How aminopeptidase activity mechanistically enables shedding is undefined
    • Physiological substrates cleaved during shedding not identified
  4. 2005 High

    Defined ERAP1's central antigen-processing function by showing it forms ER heterodimers with ERAP2 to concertedly trim MHC I peptide precursors.

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

    PMID:15908954

    Open questions at the time
    • Structural basis of the heterodimer not resolved here
    • Quantitative contribution of each enzyme to the repertoire unclear
  5. 2006 High

    Demonstrated in vivo that ERAP1 trimming dominantly shapes CD8+ T cell immunodominance, establishing physiological consequence of trimming.

    Evidence ERAP1 knockout mice, influenza infection, tetramer staining and cytotoxicity

    PMID:16754858

    Open questions at the time
    • Does not address human allotype-specific effects
    • Mechanism of over-trimming/destruction not structurally resolved
  6. 2006 Medium

    Linked a disease-associated polymorphism to enzymatic function by showing Lys528 substitutions reduce aminopeptidase activity.

    Evidence Site-directed mutagenesis, fluorogenic substrate assays, molecular modeling

    PMID:16513116

    Open questions at the time
    • Structural explanation rests on modeling, not crystallography
    • Effect on physiological antigenic peptide trimming not tested
  7. 2006 Medium

    Identified NUCB2 as a calcium-dependent partner required for TNFR1 vesicular release, expanding the shedding machinery.

    Evidence Yeast two-hybrid, Co-IP in HUVEC, confocal, RNAi with TNFR1 release readout

    PMID:16407280

    Open questions at the time
    • Single lab; reciprocal validation of the ternary mechanism limited
    • How NUCB2 binding couples to proteolytic cleavage unclear
  8. 2008 Medium

    Showed that ERAP1 reads internal substrate residues, not just the N-terminus, refining the substrate-recognition model.

    Evidence Systematic in vitro trimming with substituted peptides plus cavity modeling

    PMID:18987748

    Open questions at the time
    • Structural cavity interpretation from modeling only
    • Single lab
  9. 2008 Low

    Proposed RBMX as an additional regulator of TNFR1 release, though on weaker evidence.

    Evidence Single Co-IP and RNAi/overexpression with TNFR1 release readout

    PMID:18445477

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Functional link to ERAP1 catalytic role undefined
    • Nuclear hnRNP partner is mechanistically unexpected and unexplained
  10. 2011 High

    Provided the structural foundation by solving ERAP1 open and closed crystal structures, defining it as a gluzincin protease with large catalytic domain movements.

    Evidence X-ray crystallography in two states with K528R mutagenesis

    PMID:21508329

    Open questions at the time
    • Conformational selection vs induced-fit not distinguished here
    • Allosteric activator binding sites not yet mapped
  11. 2011 High

    Established the length-dependent 'molecular ruler' mechanism by capturing ERAP1 with an extended groove and showing long substrates trigger a catalytic conformational change.

    Evidence ERAP1-bestatin crystal structure plus length-varied trimming assays

    PMID:21478864

    Open questions at the time
    • In-solution dynamics of closure not directly observed in this study
    • Behavior on MHC-bound substrates not addressed
  12. 2011 High

    Demonstrated viral immune evasion targeting ERAP1, showing HCMV miR-US4-1 downregulates ERAP1 to impair antigen trimming and CTL killing.

    Evidence Viral infection, miRNA gain/loss-of-function, trimming and CTL assays

    PMID:21892175

    Open questions at the time
    • Genome-wide miRNA target breadth not defined
    • In vivo relevance during natural infection not tested
  13. 2013 High

    Identified transcriptional control of ERAP1, showing p53 directly binds the locus to induce ERAP1 and raise MHC I expression.

    Evidence ChIP-seq, p53 siRNA, MHC I readouts, influenza infection model

    PMID:23965983

    Open questions at the time
    • Other transcriptional regulators not addressed
    • Quantitative impact on the presented repertoire not measured
  14. 2014 High

    Explained why heterodimerization matters by showing ERAP2 allosterically improves ERAP1 substrate affinity and trimming, beyond simple enzyme mixing.

    Evidence Stabilized heterodimers, head-to-head trimming, enzymatic kinetics

    PMID:24928998

    Open questions at the time
    • Structure of the heterodimer interface not resolved
    • Allosteric coupling mechanism not defined at atomic level
  15. 2015 Medium

    Connected ERAP1 to HLA-B27 biology and inflammatory T cell responses, linking trimming activity to ankylosing-spondylitis-relevant phenotypes.

    Evidence siRNA/pharmacological inhibition, FHC flow cytometry, KIR3DL2 reporter, Th17 readouts

    PMID:26130142

    Open questions at the time
    • Causal peptide species driving FHC reduction not identified
    • Single lab
  16. 2015 Medium

    Showed ERAP1 tunes NK-cell inhibitory receptor engagement by modifying MHC ligand affinity, extending its role beyond T cell immunity.

    Evidence siRNA/inhibition, NK cytotoxicity, MHC I flow cytometry, peptide rescue

    PMID:25592150

    Open questions at the time
    • Specific high-affinity ligands generated in vivo not enumerated
    • Single lab
  17. 2016 Medium

    Demonstrated ERAP1 specifically limits aberrant disulfide-linked HLA-B27 forms, sharpening the mechanistic link to spondyloarthritis.

    Evidence siRNA KD in HLA-B27 U937 cells, IP, isoelectric focusing, non-reducing immunoblot, flow cytometry

    PMID:27107845

    Open questions at the time
    • Why HLA-B27 but not HLA-B18/B51 is affected not explained
    • Single lab
  18. 2016 Medium

    Showed heterodimers can trim MHC-bound precursors and stabilize peptide-MHC, supporting a peptide-editor model on loaded molecules.

    Evidence In vitro trimming of HLA-B*0801-bound extended peptides, thermal stability

    PMID:27514473

    Open questions at the time
    • Slower MHC-bound trimming kinetics' physiological significance unclear
    • Single lab
  19. 2019 High

    Defined structural constraints of MHC-bound trimming, showing a minimum 14-residue length and how HLA-B*0801 accommodates extended N-termini.

    Evidence High-resolution crystallography of nested extended peptides, stability and trimming assays

    PMID:31601650

    Open questions at the time
    • Generalizability across HLA allotypes not established
    • ERAP1-MHC docking geometry not visualized
  20. 2019 Medium

    Uncovered a non-peptidase signaling role in which ERAP1 displaces βTrCP from USP47 to enhance Hedgehog/Gli activity and tumor growth.

    Evidence Co-IP of ternary complex, ubiquitination and Gli reporter assays, KD/inhibition, in vivo tumor models

    PMID:31341163

    Open questions at the time
    • Whether this requires aminopeptidase activity not resolved
    • Single lab
  21. 2021 High

    Unified the structural mechanism by showing in solution that long substrates and allosteric activators drive ERAP1 domain closure coupled to active-site reconfiguration, explaining K528R disease association.

    Evidence SAXS, crystallography, crosslinking-MS, enzymatic assays with allosteric modulators

    PMID:34489420

    Open questions at the time
    • Alternate C-terminal binding site occupancy under physiological conditions unclear
    • Dynamics of heterodimer closure not addressed
  22. 2021 Medium

    Linked an ERAP1 risk haplotype to autoimmune disease causation by showing efficient generation of an HLA-C*06:02-restricted psoriasis autoantigen.

    Evidence ERAP1-modified/KO cell lines, psoriatic autoreactive TCR activation, HLA-C flow cytometry, recombinant variant trimming

    PMID:34580106

    Open questions at the time
    • In vivo demonstration in patients not performed
    • Single lab
  23. 2021 Medium

    Confirmed a second viral evasion route via HCMV miR-UL112-5p targeting the ERAP1 3'UTR, with a host SNP that escapes targeting.

    Evidence 3'UTR reporter, genotyped fibroblasts, trimming and CTL assays, seropositivity analysis

    PMID:28746870

    Open questions at the time
    • Population-level impact of rs17481334 on HCMV control not established
    • Single lab
  24. 2022 Medium

    Identified a metabolic hepatokine function in which secreted ERAP1 binds ADRB2 and reduces USP33-mediated deubiquitination to impair muscle insulin sensitivity.

    Evidence Hepatic OE/KD in mice, serum ERAP1, ERAP1-ADRB2 Co-IP, ubiquitination and insulin signaling analysis

    PMID:35192681

    Open questions at the time
    • Whether secreted ERAP1's aminopeptidase activity is required not resolved
    • Single lab; human relevance untested
  25. 2018 Medium

    Showed ERAP1 loss produces ankylosing-spondylitis-like skeletal disease, dysbiosis, and regulatory T cell deficits, tying the enzyme to disease pathophysiology in vivo.

    Evidence ERAP1 KO mice, µCT, histology, microbiota cross-fostering, immune flow cytometry

    PMID:30127455

    Open questions at the time
    • Causal peptide/antigenic basis of skeletal phenotype undefined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ERAP1's multiple non-canonical functions (receptor shedding, Hedgehog modulation, ADRB2-directed metabolic signaling) mechanistically relate to its aminopeptidase activity and whether they share a common biochemical basis.
  • Catalytic dependence of the Hedgehog and ADRB2 functions untested
  • No structure of ERAP1 bound to TNFR1, ADRB2, or USP47
  • Mechanism linking aminopeptidase activity to ectodomain shedding undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005576 extracellular region 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Partners
ADRB2BTRCERAP2IL6RNUCB2TNFR1USP33USP47
Complex memberships
ERAP1-ERAP2 heterodimer

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 ERAP1 and ERAP2 form heterodimeric complexes in the endoplasmic reticulum and function concertedly to trim MHC class I peptide precursors; ERAP1 alone cannot remove certain N-terminal amino acids that ERAP2 trims efficiently, requiring the combined action of both enzymes for full trimming both in vitro and in vivo antigen presentation. Co-localization by immunofluorescence, physical association by co-immunoprecipitation, in vitro peptide digestion assays, cellular antigen presentation assays Nature immunology High 15908954
2011 X-ray crystal structures of human ERAP1 in open and closed conformations reveal it is a zinc-metallopeptidase with HEXXH-(X)18-E zinc-binding and GAMEN motifs characteristic of the gluzincin protease family; extensive domain movements including active-site closure are observed along the catalytic path, and the K528R disease-associated variant shows altered peptide processing characteristics possibly related to impaired interdomain interactions. X-ray crystallography (open and closed state structures); site-directed mutagenesis of K528R; in vitro peptide processing assays 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 demonstrate a length-dependent trimming mechanism whereby binding of long (but not short) substrates induces a conformational change reorienting a key catalytic residue toward the active site. X-ray crystallography (ERAP1–bestatin complex); biochemical trimming assays with peptides of varying length Nature structural & molecular biology High 21478864
2002 ERAP1 (ARTS-1) is a type II integral membrane aminopeptidase that physically binds the extracellular domain of TNFR1 and promotes TNFR1 ectodomain shedding; overexpression increases TNFR1 shedding while antisense knockdown decreases it; ARTS-1 does not bind TNFR2 and does not possess sheddase activity itself. Yeast two-hybrid screen; co-immunoprecipitation in human pulmonary epithelial and endothelial cells; overexpression and antisense knockdown with TNFR1 shedding quantification; in vitro aminopeptidase activity assay The Journal of clinical investigation High 12189246
2003 ERAP1 (ARTS-1) directly binds IL-6Rα and is required for constitutive IL-6Rα shedding; ARTS-1 catalytic activity is necessary for constitutive shedding; knockout cells lack basal IL-6Rα shedding, and overexpression increases it. Reciprocal co-immunoprecipitation; ARTS-1 overexpression and knockout cell lines; shedding quantification; catalytic activity requirement demonstrated by enzymatic inhibition The Journal of biological chemistry High 12748171
2006 In mice, ERAP1 is the major enzyme trimming precursor peptides in the endoplasmic reticulum; loss of ERAP1 markedly shifts the hierarchy of immunodominance in viral infections, generating some antigenic peptides while destroying others by over-trimming to sub-optimal lengths, demonstrating that ERAP1 trimming and resultant peptide-MHC abundance are dominant factors establishing immunodominance. ERAP1 knockout mice; viral infection model (influenza); CD8+ T cell response hierarchy measured by peptide-MHC tetramer staining and cytotoxicity assays Proceedings of the National Academy of Sciences of the United States of America High 16754858
2008 ERAP1 trimming efficiency is strongly influenced by internal (non-N-terminal) residues of the peptide substrate; positively charged or hydrophobic residues at internal positions increase trimming rates by up to 100-fold for single substitutions and >40,000-fold for multiple substitutions, indicating ERAP1 recognizes the full length of its substrate via a large negatively charged internal cavity adjacent to the active site. Systematic in vitro peptide trimming assays with collections of peptide substrates; molecular modeling of ERAP1 cavity PloS one Medium 18987748
2006 The Lys528Arg polymorphism of ERAP1 (A-LAP) significantly reduces enzymatic aminopeptidase activity; site-directed mutagenesis of Lys528 to multiple amino acids (Ala, Met, His, Arg) all caused decreased activity, and molecular modeling suggests Lys528 is near the substrate pocket entrance and maintains its optimal structure. Site-directed mutagenesis; in vitro aminopeptidase activity assays with fluorogenic substrates; molecular modeling FEBS letters Medium 16513116
2000 ERAP1 (PILS-AP) is a signal-sequence-bearing M1 family zinc-dependent aminopeptidase; when expressed as a GFP fusion protein it localizes to intracellular vesicles in COS-7 and BHK cells; it exhibits selective leucyl (and to a lesser extent methionyl) aminopeptidase activity that is inhibited by chelators of bivalent cations but, unusually, not by puromycin. GFP fusion protein live-cell imaging (subcellular localization); expression in Sf9 insect cells; in vitro enzymatic activity assay with aminoacyl β-naphthylamide substrates; inhibitor profiling European journal of biochemistry Medium 10824104
2006 ERAP1 (ARTS-1) forms a calcium-dependent complex with nucleobindin 2 (NUCB2) via NUCB2's helix-loop-helix domains binding the ARTS-1 extracellular domain; this NUCB2·ARTS-1 complex associates with a subset of cellular TNFR1 within intracytoplasmic vesicles, and both proteins are required for constitutive release of full-length TNFR1 in exosome-like vesicles and for inducible proteolytic cleavage of soluble TNFR1 ectodomains. Yeast two-hybrid screen; co-immunoprecipitation in HUVEC; confocal microscopy; RNA interference knockdown of NUCB2 and ARTS-1 with TNFR1 release quantification The Journal of biological chemistry Medium 16407280
2008 ERAP1 (ARTS-1) physically associates with RBMX (a heterogeneous nuclear ribonucleoprotein) as shown by co-immunoprecipitation; RNAi knockdown of RBMX reduces both constitutive TNFR1 exosome-like vesicle release and IL-1β-induced proteolytic cleavage of TNFR1 ectodomains, while RBMX overexpression has the opposite effect. Co-immunoprecipitation; RNA interference; overexpression with TNFR1 release quantification Biochemical and biophysical research communications Low 18445477
2011 HCMV miR-US4-1 specifically downregulates ERAP1 expression during viral infection, thereby inhibiting trimming of HCMV-derived peptide precursors and reducing susceptibility of infected cells to HCMV-specific cytotoxic T lymphocytes, constituting a viral miRNA-based CTL-evasion mechanism targeting the MHC class I antigen-processing pathway. Viral infection of cell lines; miRNA overexpression and knockdown; ERAP1 protein/mRNA quantification; peptide trimming assay; CTL killing assay Nature immunology High 21892175
2013 p53 directly upregulates ERAP1 expression by binding to a cognate response element in the ERAP1 gene, thereby increasing MHC class I surface expression; silencing p53 decreases ERAP1 protein and MHC class I expression; during H1N1 influenza infection, virus-activated p53 leads to ERAP1 upregulation and increased MHC class I expression. Chromatin immunoprecipitation sequencing (ChIP-seq) identifying p53 binding at ERAP1 locus; gene expression analysis; p53 siRNA knockdown; viral infection model Nature communications High 23965983
2014 Stabilized ERAP1-ERAP2 heterodimers produce mature MHC class I epitopes more efficiently than a mixture of the two enzymes unable to dimerize; physical interaction with ERAP2 allosterically changes basic enzymatic parameters of ERAP1 and improves its substrate-binding affinity, indicating that dimerization creates complexes with superior peptide-trimming efficacy. Production of stabilized ERAP1-ERAP2 heterodimers; in vitro peptide-trimming assays comparing heterodimer vs. non-dimerizing enzyme mixtures; enzymatic kinetics measurements (Km, kcat) Journal of immunology High 24928998
2016 ERAP1-ERAP2 heterodimers can trim MHC class I-bound precursor peptides to their correct final lengths (albeit more slowly than free precursors), and such trimming increases the conformational stability of MHC I/peptide complexes, supporting a model of ERAP1/2 as peptide editors acting on MHC I-bound substrates. In vitro trimming assay using ERAP1/2 heterodimers with free and HLA-B*0801-bound N-terminally extended peptides; thermal stability measurements of MHC I/peptide complexes Scientific reports Medium 27514473
2015 ERAP1 silencing or pharmacological inhibition in HLA-B27-expressing antigen-presenting cells downregulates surface HLA-B27 free heavy chain (FHC) expression, reduces IL-2 production by KIR3DL2-reporter cells, and suppresses Th17 expansion and IL-17A secretion by AS CD4+ T cells; AS-protective ERAP1 variants K528R and Q730E are associated with reduced FHC expression on patient monocytes. siRNA knockdown; pharmacological ERAP1 inhibition; flow cytometry (surface FHC and MHC I expression); KIR3DL2 reporter co-culture; Th17 intracellular cytokine staining; ELISA Annals of the rheumatic diseases Medium 26130142
2016 ERAP1 knockdown increases accumulation of HLA-B27 on the cell surface including disulfide-linked dimers but has no effect on HLA-B18 or HLA-B51, demonstrating that normal ERAP1 levels specifically reduce aberrant and disulfide-linked forms of HLA-B27 in monocytes. ERAP1 siRNA knockdown in HLA-B27-expressing U937 monocytic cells; immunoprecipitation; isoelectric focusing; immunoblotting (non-reducing gels); flow cytometry with HLA-B27-specific antibodies Molecular immunology Medium 27107845
2019 ERAP1 binds the deubiquitylase USP47, displaces USP47-associated βTrCP (the substrate-receptor subunit of SCFβTrCP ubiquitin ligase), and promotes βTrCP degradation; this results in modulation of Gli transcription factors and enhancement of Hedgehog pathway activity; genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo. Co-immunoprecipitation (ERAP1-USP47-βTrCP); ubiquitination assays; Gli reporter assays; ERAP1 genetic knockdown and pharmacological inhibition; in vivo tumor growth assays (mouse models) Nature communications Medium 31341163
2015 Genetic or pharmacological inhibition of ERAP1 on human tumor cell lines perturbs engagement of multiple classes of inhibitory NK cell receptors (KIR by classical pMHC-I; CD94-NKG2A by nonclassical pMHC-I), leading to NK cell killing; the protective effect of pMHC-I could be restored by addition of high-affinity peptides, indicating ERAP1 positively modifies the affinity of natural MHC ligands. siRNA knockdown and pharmacological inhibition of ERAP1; NK cell cytotoxicity assays; flow cytometry of MHC-I surface expression; peptide rescue experiments; killing of autologous/allogeneic lymphoblastoid cell lines Cancer research Medium 25592150
2019 ERAP1-mediated trimming of MHC I-bound precursor peptides requires peptides of at least 14 amino acids in length; N-terminal residue extensions protrude out of the HLA-B*0801 A pocket while the core peptide adopts the standard bound conformation; HLA-B*0801 residue 62 is critical for opening the A pocket to accommodate extended peptides. X-ray crystallography of HLA-B*0801 complexes with nested N-terminally extended peptides (1.40–1.65 Å); thermal stability assays; in vitro ERAP1 trimming assay The Journal of biological chemistry High 31601650
2021 Solution SAXS and X-ray crystallography demonstrate that ERAP1 undergoes domain closure in solution upon binding of long peptide substrates and allosteric activators; structural reconfigurations of the ERAP1 active site are physically linked to domain closure; chemical crosslinking localizes alternate C-terminal binding sites; the K528R polymorphism disease association is mechanistically explained by its role in domain closure dynamics. Small-angle X-ray scattering (SAXS) in solution; X-ray crystallography; chemical crosslinking with mass spectrometry; enzymatic assays with allosteric modulators Nature communications High 34489420
2017 HCMV miR-UL112-5p targets the ERAP1 3′ UTR to inhibit ERAP1 expression and processing of the HCMV pp65495-503 peptide, thereby reducing CTL lysis of infected cells; a naturally occurring rs17481334 G variant in the ERAP1 3′ UTR prevents miR-UL112-5p binding and preserves ERAP1 expression, making GG homozygous fibroblasts more efficient at viral antigen trimming and more susceptible to CTL killing. miRNA target-site validation (3′ UTR reporter assay); ERAP1 RNA and protein quantification in genotyped fibroblasts; in vitro trimming assay; CTL cytotoxicity assay; HCMV seropositivity analysis Cell reports Medium 28746870
2021 In psoriasis, ERAP1 generates the causative HLA-C*06:02-restricted melanocyte autoantigen by trimming N-terminally elongated peptide precursors; an ERAP1 risk haplotype produces the autoantigen much more efficiently and increases HLA-C expression and stimulation of a psoriatic autoreactive TCR significantly more than a protective haplotype; HLA-C surface expression decreases more upon ERAP1 knockout than overall HLA class I. ERAP1 genetically modified cell lines; TCR activation assay with psoriatic autoreactive TCR; flow cytometry of HLA-C surface expression; ERAP1 knockout; in vitro peptide trimming with recombinant ERAP1 variants Journal of immunology Medium 34580106
2022 ERAP1 functions as an inflammation-induced hepatokine: hepatic ERAP1 overexpression attenuates systemic and skeletal muscle insulin sensitivity while knockdown has the opposite effect; mechanistically, secreted ERAP1 interacts with β2 adrenergic receptor (ADRB2) and reduces its expression by decreasing USP33-mediated deubiquitination, thereby disrupting ADRB2-stimulated insulin signaling in skeletal muscle. Hepatic ERAP1 overexpression and knockdown in mice (HFD model); serum ERAP1 measurement; co-immunoprecipitation of ERAP1 with ADRB2; ubiquitination assay; ADRB2 protein quantification; insulin signaling pathway analysis in skeletal muscle Diabetes Medium 35192681
2018 ERAP1 deletion in ERAP1−/− mice leads to development of hallmark skeletal features of ankylosing spondylitis (spinal ankylosis, osteoporosis, spinal inflammation), spontaneous intestinal dysbiosis, and increased susceptibility to DSS-induced colitis; these mice have reduced Tr1-like regulatory T cells and tolerogenic dendritic cells while maintaining normal Foxp3+ Treg numbers. ERAP1 knockout mice; µCT imaging; histology; microbiota transfer (cross-fostering); flow cytometry of immune cell populations Scientific reports Medium 30127455

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nature immunology 383 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
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 158 16754858
2011 Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1. Nature immunology 157 21892175
2018 How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins. Frontiers in immunology 136 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) 128 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
2008 Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues. Journal of cellular physiology 83 18393273
2016 ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. Scientific reports 82 27514473
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) 71 24928998
2013 ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases. Molecular immunology 69 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
2011 CD39+ regulatory T cells suppress generation and differentiation of Th17 cells in human malignant pleural effusion via a LAP-dependent mechanism. Respiratory research 52 21663645
2000 Molecular characterization of a puromycin-insensitive leucyl-specific aminopeptidase, PILS-AP. European journal of biochemistry 52 10824104
2019 Regulation of ERAP1 and ERAP2 genes and their disfunction in human cancer. Human immunology 51 30825518
2017 The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis. Clinical and experimental immunology 51 28759104
2019 ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP. Nature communications 50 31341163
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
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
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
2019 Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations. Human immunology 47 30797823
2018 Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis. Human molecular genetics 47 30215709
2012 ERAP1 genetic variations associated with HLA-B27 interaction and disease severity of syndesmophytes formation in Taiwanese ankylosing spondylitis. Arthritis research & therapy 45 22632381
2019 Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1). Cancer immunology, immunotherapy : CII 44 31222486
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
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) 42 34580106
2011 ERAP1 polymorphisms and haplotypes are associated with ankylosing spondylitis susceptibility and functional severity in a Spanish population. Rheumatology (Oxford, England) 42 21865284
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 40 21281511
2020 ERAP1: a potential therapeutic target for a myriad of diseases. Expert opinion on therapeutic targets 37 32249641
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
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
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 31 31601650
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
2022 Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity. Annals of the rheumatic diseases 30 35922122
2021 Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism. Nature communications 30 34489420
2019 ERAP1 shapes just part of the immunopeptidome. Human immunology 30 30849449
2012 Investigating the genetic association between ERAP1 and spondyloarthritis. Annals of the rheumatic diseases 30 22896742
2014 Epistatic interaction of ERAP1 and HLA-B in Behçet disease: a replication study in the Spanish population. PloS one 29 25019531
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
2017 ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism. Oncoimmunology 28 28811980
2014 Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis. Genes and immunity 28 25354578
2020 The Differential Expression of ERAP1/ERAP2 and Immune Cell Activation in Pre-eclampsia. Frontiers in immunology 27 32210971
2014 ERAP1 in the pathogenesis of ankylosing spondylitis. Immunologic research 27 25434650
2010 ERAP1 is associated with ankylosing spondylitis in Han Chinese. The Journal of rheumatology 27 21078719
2011 The association between seven ERAP1 polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis involving 8,530 cases and 12,449 controls. Rheumatology international 25 21229357
2008 An association between RBMX, a heterogeneous nuclear ribonucleoprotein, and ARTS-1 regulates extracellular TNFR1 release. Biochemical and biophysical research communications 25 18445477
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
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
2021 ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers. Investigative ophthalmology & visual science 20 34727153
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 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 18 33651148
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 18 25087231
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
2018 Association analysis of ERAP1 gene single nucleotide polymorphism in susceptibility to ankylosing spondylitis in Iranian population. Immunology letters 17 30412714
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
2023 Cell-Specific and Variant-Linked Alterations in Expression of ERAP1, ERAP2, and LNPEP Aminopeptidases in Psoriasis. The Journal of investigative dermatology 15 36716917
2017 Association of polymorphisms in ERAP1 and risk of ankylosing spondylitis in a Chinese population. Gene 15 29278768

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