ARTS-1

Endoplasmic reticulum aminopeptidase 1
Crystal structure of the open state of human endoplasmic reticulum aminopeptidase 1 ERAP1.[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2YD0​, 3MDJ​, 3QNF​, 3RJO​
Identifiers
Symbols	ERAP1 ; A-LAP; ALAP; APPILS; ARTS-1; ARTS1; ERAAP; ERAAP1; PILS-AP; PILSAP
External IDs	OMIM: 606832 MGI: 1933403 HomoloGene: 56754 ChEMBL: 5939 GeneCards: ERAP1 Gene
Gene ontology Molecular function • aminopeptidase activity • interleukin-6 receptor binding • interleukin-1, Type II receptor binding • tumor necrosis factor receptor binding • protein binding • metalloexopeptidase activity • zinc ion binding • peptide binding • metalloaminopeptidase activity Cellular component • extracellular region • extracellular space • endoplasmic reticulum • endoplasmic reticulum lumen • endoplasmic reticulum membrane • cytosol • membrane • integral component of membrane • extracellular exosome Biological process • angiogenesis • adaptive immune response • antigen processing and presentation of peptide antigen via MHC class I • membrane protein ectodomain proteolysis • regulation of blood pressure • response to bacterium • antigen processing and presentation of endogenous peptide antigen via MHC class I • peptide catabolic process • regulation of innate immune response • fat cell differentiation • positive regulation of angiogenesis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	51752	80898
Ensembl	ENSG00000164307	ENSMUSG00000021583
UniProt	Q9NZ08	Q9EQH2
RefSeq (mRNA)	NM_001040458	NM_030711
RefSeq (protein)	NP_001035548	NP_109636
Location (UCSC)	Chr 5: 96.76 – 96.81 Mb	Chr 13: 74.64 – 74.69 Mb
PubMed search

Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator, also known as endoplasmic reticulum aminopeptidase 1 (ARTS-1), is a protein which in humans is encoded by the ARTS-1 gene.^[2]

Endoplasmic reticulum amino peptidase 1 is active in the endoplasmic reticulum, which is involved in protein processing and transport. This protein is an aminopeptidase, which is an enzyme that cleaves other proteins into smaller fragments called peptides.

Nomenclature

ARTS1 is also known as:

• ER aminopeptidase 1 (ERAP1) the name accepted by the Hugo Gene Nomenclature Committee^[3]
• ER aminopeptidase associated with antigen processing (ERAAP)
• Adipocyte-derived leucine aminopeptidase (ALAP)
• Puromycin-insensitive leucine aminopeptidase (PILS-AP)

Function

ERAP1 has two major functions in the immune system:

• First, ERAP1 cleaves several proteins called cytokine receptors on the surface of cells. Cleaving these receptors reduces their ability to transmit chemical signals into the cell, which affects the process of inflammation.
• Second, ERAP1 trims peptides within the endoplasmic reticulum so that they can be loaded onto major histocompatibility complex (MHC) class I. These peptides are attached to MHC class I in the endoplasmic reticulum and exported to the cell surface, where they are displayed to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by triggering the infected cell to self-destruct.^[4]

ARTS-1 is a member of the M1 family of zinc metallopeptidases which acts as an aminopeptidase that degrades oligopeptides by cleavage starting at the amino terminus. One of the functions of aminopeptidases is to degrade potentially toxic peptides in the cytosol.^[2]

ARTS-1 is a transmembrane protein that is localized to the endoplasmic reticulum. It has been implicated in the following functions:

• Shedding of various cytokine receptors and decoy receptors
• Trimming of antigenic peptides before binding to MHC class I, affecting antigen presentation to cytotoxic T lymphocytes

Clinical significance

Aminopeptidases play a role in the metabolism of several peptides that may be involved in blood pressure and the pathogenesis of essential hypertension.^[2] Mutations in the ARTS-1 have been linked to an increased risk of ankylosing spondylitis but only in HLA-B27 positive patients .^[5]

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.^[2]

References

1. "RCSB Protein Data Bank - Structure Summary for 3QNF - Crystal structure of the open state of human endoplasmic reticulum aminopeptidase 1 ERAP1".
2. EntrezGene 51752
3. "HGNC publisher=HGNC". Retrieved 27 March 2014.
4. "ERAP1 - endoplasmic reticulum aminopeptidase 1 - Genetics Home Reference".
5. Brionez TF, Reveille JD (2008). "The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis". Current Opinion in Rheumatology 20 (4): 384–91. doi:10.1097/BOR.0b013e32830460fe. PMID 18525349.

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (2002). "Construction of Expression-ready cDNA Clones for KIAA Genes: Manual Curation of 330 KIAA cDNA Clones". DNA Research 9 (3): 99–106. doi:10.1093/dnares/9.3.99. PMID 12168954.
• Tsujimoto M, Hattori A (2005). "The oxytocinase subfamily of M1 aminopeptidases". Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 1751: 9–18. doi:10.1016/j.bbapap.2004.09.011. PMID 16054015.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5′-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998). "Prediction of the Coding Sequences of Unidentified Human Genes. IX. The Complete Sequences of 100 New cDNA Clones from Brain Which Can Code for Large Proteins in vitro". DNA Research 5 (1): 31–9. doi:10.1093/dnares/5.1.31. PMID 9628581.
• Hattori A, Matsumoto H, Mizutani S, Tsujimoto M (1999). "Molecular cloning of adipocyte-derived leucine aminopeptidase highly related to placental leucine aminopeptidase/oxytocinase". Journal of Biochemistry 125 (5): 931–8. doi:10.1093/oxfordjournals.jbchem.a022371. PMID 10220586.
• Hattori A, Kitatani K, Matsumoto H, Miyazawa S, Rogi T, Tsuruoka N, Mizutani S, Natori Y, Tsujimoto M (2000). "Characterization of recombinant human adipocyte-derived leucine aminopeptidase expressed in Chinese hamster ovary cells". Journal of Biochemistry 128 (5): 755–62. doi:10.1093/oxfordjournals.jbchem.a022812. PMID 11056387.
• Hattori A, Matsumoto K, Mizutani S, Tsujimoto M (2001). "Genomic organization of the human adipocyte-derived leucine aminopeptidase gene and its relationship to the placental leucine aminopeptidase/oxytocinase gene". Journal of Biochemistry 130 (2): 235–41. doi:10.1093/oxfordjournals.jbchem.a002977. PMID 11481040.
• Yamamoto N, Nakayama J, Yamakawa-Kobayashi K, Hamaguchi H, Miyazaki R, Arinami T (2002). "Identification of 33 polymorphisms in the adipocyte-derived leucine aminopeptidase (ALAP) gene and possible association with hypertension". Human Mutation 19 (3): 251–7. doi:10.1002/humu.10047. PMID 11857741.
• Cui X, Hawari F, Alsaaty S, Lawrence M, Combs CA, Geng W, Rouhani FN, Miskinis D, Levine SJ (2002). "Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding". Journal of Clinical Investigation 110 (4): 515–26. doi:10.1172/JCI13847. PMC 150410. PMID 12189246.
• Serwold T, Gonzalez F, Kim J, Jacob R, Shastri N (2002). "ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum". Nature 419 (6906): 480–3. doi:10.1038/nature01074. PMID 12368856.
• Saric T, Chang SC, Hattori A, York IA, Markant S, Rock KL, Tsujimoto M, Goldberg AL (2002). "An IFN-γ–induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I–presented peptides". Nature Immunology 3 (12): 1169–76. doi:10.1038/ni859. PMID 12436109.
• York IA, Chang SC, Saric T, Keys JA, Favreau JM, Goldberg AL, Rock KL (2002). "The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues". Nature Immunology 3 (12): 1177–84. doi:10.1038/ni860. PMID 12436110.
• Cui X, Rouhani FN, Hawari F, Levine SJ (2003). "An Aminopeptidase, ARTS-1, Is Required for Interleukin-6 Receptor Shedding". Journal of Biological Chemistry 278 (31): 28677–85. doi:10.1074/jbc.M300456200. PMID 12748171.
• Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A (2003). "The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment". Genome Research 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
• Cui X, Rouhani FN, Hawari F, Levine SJ (2003). "Shedding of the Type II IL-1 Decoy Receptor Requires a Multifunctional Aminopeptidase, Aminopeptidase Regulator of TNF Receptor Type 1 Shedding". The Journal of Immunology 171 (12): 6814–9. doi:10.4049/jimmunol.171.12.6814. PMID 14662887.
• Shibata D, Ando H, Iwase A, Nagasaka T, Hattori A, Tsujimoto M, Mizutani S (2004). "Distribution of Adipocyte-derived Leucine Aminopeptidase (A-LAP)/ER-aminopeptidase (ERAP)-1 in Human Uterine Endometrium". Journal of Histochemistry and Cytochemistry 52 (9): 1169–75. doi:10.1369/jhc.3A6216.2004. PMID 15314084.