ERAP1 is commonly known as ER aminopeptidase associated with antigen processing or ER aminopeptidase1 ERAP1 to denote its localization and presumed function as antigen processing molecules and involvement in regulation of the immune response.
ERAP1 is a zinc metallopeptidase with typical motifs characteristic for members of the M1 aminopeptidase family as described above. In a cell, the complex repertoire of endogenous proteins is initially degraded in the cytoplasm by the multi-unit proteasome complex, generating peptide fragments up to 25 aa in length.
ERAP1 is known to cleave substrates more efficiently with a hydrophobic C-terminal residue. Classical MHC Class I biological pathway involving M1 aminopeptidases that are genetically associated with immune-mediated diseases.
Nine splice variants of ERAP1 gene are known so far, with no association to any disease. ERAP1 shows two distinct conformations: an open and a closed one Figure 2. The structure 3 , 39 , 40 reveals extensive domain movements, including an active site closure as well as three different open conformations, 3 thus providing critical insights into the ERAP1 catalytic processes.
A large cavity between domains II and IV is presumably a substrate-binding site that could accommodate different length peptides for catalysis.
The amino-acid residue is located near the entrance of the substrate pocket and may contribute to the substrate-binding affinity with the enzyme. ArgGln rs can affect substrate sequence or specificity because they are exposed on the inner surface of the C-terminal cavity and hence reduces enzyme activity.
In vitro studies of ERAP1 function have suggested that the rs Asn enzyme activity is unaffected 9 when the position is mutated, making it more likely Gln is the key functional variant on this haplotype rather than Asn Unlike its homolog ERAP1 , there have been limited in vivo studies of ERAP2 due to its absence in rodent models, for example, mouse, rat, rabbit and guinea pig.
ERAP2 44 is known as a highly homologous aminopeptidase that is colocalized with ERAP1 but presents distinct specificity for the N-terminal residue of the peptide substrate. The crystal structure of ERAP2 has been resolved to 3. The protein shares overall similar domain homology with ERAP1 and has four domains Figure 3 , spanning residues 1—, —, —, —, respectively; only the closed form of ERAP2 has been crystallized Figure 3 so far. Molecular model image was generated using the Pymol software.
ERAP1 and ERAP2 are jointly responsible for trimming peptides to the optimum length for recognition by the immune system, thus have an important role in the regulation of the immune response.
There is strong association seen across ERAP2 with AS, IBD and psoriasis, and by purely genetic means it is difficult to distinguish the key disease-associated variants. However, the synonymous SNP rs AS- and IBD-protective G allele has been shown to lead to skipping of a standard exon 10 splice site, extending exon 10 but leading to premature termination of transcription, as the extended exon 10 contains new stop codons not found in the wild-type transcripts.
This in turn leads to reduced MHC class I surface expression. NPEPPS , also known as puromycin-sensitive aminopeptidase or cytosol alanyl aminopeptidase, is another zinc metallopeptidase which hydrolyzes N-terminal amino acids from its peptide substrates. NPEPPS is expressed in most tissues as a cytosolic aminopeptidase, but a membrane-associated form has also been identified in the brain. There are handful of mutagenesis studies which predicted that mutating the catalytic glutamate at position converts the NPEPPS enzyme into an inactive binding protein, and constitute evidence that this residue is essential for catalysis whereas the effect of mutating conserved tyrosine results in complete loss of catalytic activity of the NPEPPS.
In the same year, the first crystal structure of ERAP1 3 was determined in both open and closed form which provided the first snapshots along the ERAP1 catalytic pathway. In another study, 55 , 56 , 57 , 58 , 59 the hypothesis that ERAP1 variant-related structural alterations affect the repertoire of antigenic peptides, stability and function bound to the HLA-B27 molecules was tested.
A detailed peptide analyses revealed longer peptides to be more abundant in the presence of AS-protective polymorphisms, consistent with diminished enzymatic activity.
This study demonstrated that ERAP1 variants affect both the quantity of antigenic peptide presented by HLA-B27, and the nature of presented peptides both in terms of length and sequence.
Such alteration is both variant and peptide specific, and it depends on the N-terminal flanking and P1 residues of natural HLA-B27 ligand. In , an independent group 60 analyzed the effects of ERAP1 on the HLA-B27 peptide repertoire and peptide presentation to cytotoxic T lymphocytes and also showed that ERAP1 directly alters the repertoire of peptides and peptide presentation.
These collective findings from various researchers strongly suggest that functional perturbations in ERAP1 polymorphisms have a major impact on HLA Class I expression, and peptide handling and stability.
In contrast, no such differences were observed with HLA-B7 expressing mice, although it is very likely that the B7 immunodominant NP epitope NP is also initially produced as an N-terminally extended peptide, as otherwise NP would be predicted not to be transported into the ER by the TAP protein.
Understanding the physiological processes underlying antigenic peptide generation in relation to MHC class I presentation and regulation of adaptive immune responses may pave the way for developing new enzyme-based targeted therapies for IMDs and also other diseases such as cancer and viral infections.
Rawlings ND, Salvesen G. Handbook of Proteolytic Enzymes. Elsevier, London, UK, Google Scholar. Evolutionary families of peptidases. Biochem J. Crystal structures of the endoplasmic reticulum aminopeptidase-1 ERAP1 reveal the molecular basis for N-terminal peptide trimming. Proc Natl Acad Sci ; : — Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1.
Nat Struct Mol Biol ; 18 : — The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing. Biochemistry ; 51 : — Membrane bound members of the M1 family: more than aminopeptidases. Protein Pept Lett ; 11 : — Aminopeptidase B is structurally related to leukotriene-A4 hydrolase but is not a bifunctional enzyme with epoxide hydrolase activity. Biochem J ; : — Inadequate tolerance induction may induce pre-eclampsia. J Reprod Immunol.
Mol Genet Genomic Med ; 1 : 98— Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma. Cancer Immunol Immunother ; 57 : — Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma.
Genes Chromosomes Cancer ; 48 : — Genes Immun ; 10 : — Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet ; 45 : — Reveille JD. The genetic basis of ankylosing spondylitis. Curr Opin Rheumatol ; 18 : — Brown MA. Genetics of ankylosing spondylitis. Curr Opin Rheumatol ; 22 : — Nat Genet ; 42 : — Article Google Scholar. Curr Opin Rheumatol ; 26 : 56— A functional variant in ERAP1 predisposes to multiple sclerosis.
Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut ; 62 : — Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.
Association scan of 14, nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet ; 39 : — Nat Genet ; 43 : — J Rheumatol ; 38 : — J Rheumatol ; 37 : — Clin Exp Rheumatol ; 27 : — Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.
ERAP1 polymorphisms and haplotypes are associated with ankylosing spondylitis susceptibility and functional severity in a Spanish population. Rheumatology Oxford ; 50 : — Ann Rheum Dis ; 70 : — Arthritis Rheum ; 60 : — Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. CHR an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.
Cancer Res ; 68 : — Positioning of aminopeptidase inhibitors in next generation cancer therapy. Amino Acids ; 46 : — Nat Immunol ; 3 : — Evolutionary signatures of common human cis-regulatory haplotypes. Investigating the genetic association between ERAP1 and ankylosing spondylitis. Hum Mol Genet ; 18 : — Stratikos E, Stern LJ.
Antigenic peptide trimming by ER aminopeptidases—insights from structural studies. Mol Immunol ; 55 : — Glutamine is crucial in the enzymatic activity and substrate specificity of human endoplasmic-reticulum aminopeptidase Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature ; : — Haroon N, Inman RD.
Endoplasmic reticulum aminopeptidases: Biology and pathogenic potential. Nat Rev Rheumatol ; 6 : — Crystallization and preliminary X-ray diffraction analysis of human endoplasmic reticulum aminopeptidase 2. Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides.
The sequence of this isoform differs from the canonical sequence as follows: : Missing. Manual assertion based on opinion in i. You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser. The new UniProt website is here!
Your basket is currently empty. Methionine aminopeptidase 2. Note that the 'protein existence' evidence does not give information on the accuracy or correctness of the sequence s displayed.
Select a section on the left to see content. Release of N-terminal amino acids, preferentially methionine, from peptides and arylamides. Search chemical reactions in Rhea for this molecule. See the description of this molecule in ChEBI. Short name:.
Alternative name s :. World J. DMDM i Proteome Res. O-glycosylation is required for EIF2S1 binding. By similarity 6 Publications Manual assertion based on experiment in i Ref. P With Exp. Methionine aminopeptidase eukaryotic type 2 subfamily.
The information is filed in different subsections. Additionally, this section gives relevant information on each alternative protein isoform. Align Add to basket Added to basket This entry has 3 described isoforms and 6 potential isoforms that are computationally mapped.
Length: Mass Da : 52, It is useful for tracking sequence updates. The algorithm is described in the ISO standard. Mass Da : 50, Full view. Enhydra lutris kenyoni. These are stable identifiers and should be used to cite UniProtKB entries. Upon integration into UniProtKB, each entry is assigned a unique accession number, which is called 'Primary citable accession number'. Do not show this banner again. Priority is given to the annotation of physiological ligands.
The nature of the metal is indicated in the 'Description' field. Aminopeptidase , Hydrolase , Protease. BioCyc i. Pathway Commons web resource for biological pathway data More PathwayCommons i. Reactome - a knowledgebase of biological pathways and processes More Reactome i. Search reactions for this EC number in Rhea. Homo sapiens Human. This is known as the 'taxonomic identifier' or 'taxid'.
It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first. Human Gene Nomenclature Database More HGNC i. MIM i. VEuPathDB i. DisGeNET i. Open Targets More OpenTargets i. PharmGKB i. Pharos i. ChEMBL i. Drug and drug target database More DrugBank i. DrugCentral More DrugCentral i. BioMuta curated single-nucleotide variation and disease association database More BioMuta i. DMDM i. N-acetylalanine Combined sources Manual assertion inferred from combination of experimental and computational evidence i Ref.
Phosphoserine Combined sources Manual assertion inferred from combination of experimental and computational evidence i Ref. Phosphoserine; alternate Combined sources Manual assertion inferred from combination of experimental and computational evidence i Ref. O-linked GlcNAc serine; alternate By similarity.
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P [ P ]. GlyGen i. MetOSite database of methionine sulfoxide sites More MetOSite i. PhosphoSitePlus i. SwissPalm database of S-palmitoylation events More SwissPalm i. Bgee i. ExpressionAtlas i. Genevisible search portal to normalized and curated expression data from Genevestigator More
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