ERAP1

Official Full Name

endoplasmic reticulum aminopeptidase 1

Organism

Homo sapiens

Gene ID

51752

Background

The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

Synonyms

ALAP; A-LAP; ARTS1; ERAAP; APPILS; ARTS-1; ERAAP1; PILSAP; PILS-AP

Cat.No.	Product Name	Price
CSC-DC005024	Panoply™ Human ERAP1 Knockdown Stable Cell Line	Inquiry
CSC-SC005024	Panoply™ Human ERAP1 Over-expressing Stable Cell Line	Inquiry

Cat.No.	Product Name	Price
AD05555Z	Human ERAP1 adenoviral particles	Inquiry
LV11874L	human ERAP1 (NM_016442) lentivirus particles	Inquiry
LV11875L	human ERAP1 (NM_001040458) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH286781	shRNA set against Mouse ERAP1 (NM_030711.4)	Inquiry
SHH286777	shRNA set against Human ERAP1 (NM_016442.3)	Inquiry
SHH286786	shRNA set against Rat ERAP1 (NM_030836.1)	Inquiry

Cat.No.	Product Name	Price
CDCR263674	Mouse Erap1 ORF Clone(NM_030711.4)	Inquiry
CDFG000301	Human ERAP1 cDNA Clone(NM_016442.3)	Inquiry
CDFG000302	Human ERAP1 cDNA Clone(NM_016442.3)	Inquiry
CDFH006037	Human ERAP1 cDNA Clone(NM_001040458.1)	Inquiry
CDFR012368	Rat Erap1 cDNA Clone(NM_030836.1)	Inquiry
MiUTR1H-00613	ERAP1 miRNA 3'UTR clone	Inquiry
MiUTR1H-00614	ERAP1 miRNA 3'UTR clone	Inquiry
MiUTR1M-01719	ERAP1 miRNA 3'UTR clone	Inquiry
MiUTR1R-00403	ERAP1 miRNA 3'UTR clone	Inquiry
CDCB156202	Rat ERAP1 ORF clone (BC098664.1)	Inquiry
CDCB186522	Rabbit ERAP1 ORF clone (XM_008261967.1)	Inquiry
CDCR061000	Human ERAP1 ORF clone (NM_016442.3)	Inquiry
CDCR061002	Human ERAP1 ORF clone (NM_001040458.1)	Inquiry
CDCR379415	Rat Erap1 ORF Clone(NM_030836.1)	Inquiry

Detailed Information

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme in the aminopeptidase M1 family. It is involved in blood pressure regulation, angiogenesis, extracellular domain of cytokine receptors, and plays a role in the processing of antigenic peptides presented to the major histocompatibility complex class I (MHC I). ERAP1 allelic variants are associated with a variety of human diseases, including autoimmune ankylosing spondylitis (AS), diabetes, cervical cancer, and hypertension.

ERAP1 is also closely related to tumors. The expression and tissue distribution of ERAP1 and ERAP2 can be detected in lymphoid and non-lymphoid tumors. The surface expression of MHC I molecules was significantly correlated with ERAP1, but not with ERAP2, suggesting that ERAP1 has a dominant role in the production of MHC I epitopes. In addition, tumor tissue types are different, and the expression patterns of the two enzymes are also different. Down-regulation of ERAP1 and/or ERAP2 expression is mainly present in ovarian, breast and lung cancers, and up-regulation is mainly present in large intestine and thyroid tumors.

ERAP1 Features

ERAP1 has two main functions. The first is to prune antigenic peptides to help present endogenous antigens. The endogenous antigenic peptide is degraded into a smaller peptide by the protease complex in the cytoplasm. These peptides are then transported to the endoplasmic reticulum by transporter associated with antigen processing (TAP). ERAP1 in the endoplasmic reticulum precisely prunes these peptides from the N-terminus into small fragments of 8-9 amino acids. Peptides of this length are best suited for binding to MHC class I molecules, including HLA-B27. After the MHC I molecule binds to the antigen peptide, it reaches the cell membrane through the Golgi apparatus and presents the antigen peptide to CD8+ T cells. In addition, ERAP1 also has the effect of clearing the cell membrane pro-inflammatory cytokine receptor. These receptors are IL-1R II, IL-6Rα, and TNFRI.

ERAP1 Figure 1. Role of ERAP1 in the MHC I antigen processing and presentation pathway. (Reeves, et al. 2014)

ERAP1 has two open and closed conformations. When it opens, the antigenic peptide is accepted by ERAP1 and then turns into a closed state. At this time, ERAP1 is active, and the amino acid can be cleaved from the N-terminus of the antigen peptide. This process can be repeated until the antigenic peptide is cut to the appropriate length. An antigen peptide of a suitable length will bind to the MHC I molecule and be presented to the cell membrane surface.

ERAP1 and AS

AS is highly correlated with genetic background and is most closely related to human leukocyte antigen (HLA)-B27. Although up to 95% of AS patients carry the HLA-B27 gene, only 1% to 5% of HLA-B27 gene carriers develop into AS patients. This suggests that HLA-B27 is not the only factor in the development of AS, but also depends on the participation of other genes. The main function of ERAP1 is to cleave antigen peptides of appropriate length for MHC I molecules to be presented. Dysfunctional ERAP1 is associated with AS pathogenesis. In the process, ERAP1 works closely with HLA-B27. ERAP1 molecular polymorphisms produce abnormal antigen peptide presentation profiles and HLA-B27 molecule expression, and mediate AS pathogenesis through innate and adaptive immune mechanisms.

According to Sanz-Bravo and other studies, ERAP1 is the second highest-ranking gene after HLA-B27 and AS, accounting for about 26% of the total genetic risk of AS. The correlation between the single nucleotide polymorphism (SNP) of ERAP1 gene and AS risk has been confirmed in different ethnic groups. The expression of MHC molecules on the surface of ERAP1-deficient mouse cell membranes is decreased, and this is also the case for cells carrying the AS-susceptible ERAP1 gene.

ERAP1 Gene Polymorphism

The ERAP1 gene polymorphism determines its different endoplasmic reticulum aminopeptidase activity. Compared with wild-type ERAP1, the R528 (rs30187) mutation and the Q725 (rs17482078) mutation significantly reduced the enzymatic activity of ERAP1 (~40%). Reeves et al. have found that the ERAP1 allele is highly polymorphic. Thirteen ERAP1 (ERAP1*001~013) alleles/allotypes have been identified to date, and there is a significant difference in the distribution of AS patients and normal controls. The ERAP1 gene polymorphism affects the immune recognition and restricted immune response of HLA-B27 molecules. Reeves et al. showed that the main mechanism of functional interaction between ERAP1/HLA-B27 is to alter the balance between antigenic epitope production and destruction induced by the ERAP1 polymorphism. These changes are both mutant-specific and polypeptide-specific and are highly dependent on the susceptibility of amino acid residues at the N-terminal P1 site.

References:

Reeves E., Elliottt T., et al. (2014). ERAP1 in the pathogenesis of ankylosing spondylitis. Immunologic Research, 60(2-3):257-69.
Alvareznavarro, C., & López, J. D. C. (2014). Erap1 structure, function and pathogenetic role in ankylosing spondylitis and other mhc-associated diseases. Molecular Immunology, 57(1), 12-21.
anz‐Bravo, A., Campos, J., Mazariegos, M. S., & López, d. C. J. A. (2015). Dominant role of the erap1 polymorphism r528k in shaping the hla–b27 peptidome through differential processing determined by multiple peptide residues. Arthritis & Rheumatology, 67(3), 692-701.
Reeves, E., Colebatchbourn, A., Elliott, T., Edwards, C. J., & James, E. (2014). Functionally distinct erap1 allotype combinations distinguish individuals with ankylosing spondylitis. Proceedings of the National Academy of Sciences of the United States of America, 111(49), 17594-9.
Reeves, E., Edwards, C. J., Elliott, T., & James, E. (2013). Naturally occurring erap1 haplotypes encode functionally distinct alleles with fine substrate specificity. Journal of Immunology, 191(1), 35-43.
Zhang, Z., Dai, D., Yu, K., Yuan, F., Jin, J., & Ding, L., et al. (2016). Association of hla-b27 and erap1 with ankylosing spondylitis susceptibility in beijing han chinese. HLA, 83(5), 324-329.

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