Endoplasmic reticulum aminopeptidase 1 (ERAP1)
The protein contains 941 amino acids for an estimated molecular weight of 107235 Da.
Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney. (updated: Oct. 10, 2018)
Protein identification was indicated in the following studies:
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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No binding partner found
Biological Process
Adaptive immune response
Angiogenesis
Antigen processing and presentation of endogenous peptide antigen via MHC class I
Antigen processing and presentation of peptide antigen via MHC class I
Cell-cell signaling
Fat cell differentiation
Membrane protein ectodomain proteolysis
Peptide catabolic process
Positive regulation of angiogenesis
Proteolysis
Regulation of blood pressure
Regulation of innate immune response
Response to bacterium
Signal transduction
The reference OMIM entry for this protein is 606832
Endoplasmic reticulum aminopeptidase 1; erap1
Adipocyte-derived leucine aminopeptidase; alap
Aminopeptidase regulator of tnfr1 shedding 1; arts1
Puromycin-insensitive leucyl-specific aminopeptidase; pilsap
Endoplasmic reticulum aminopeptidase
DESCRIPTION
Aminopeptidases play a role in the metabolism of several peptides that may be involved in blood pressure and the pathogenesis of essential hypertension (145500). Adipocyte-derived leucine aminopeptidase (ALAP) is a member of the M1 family of zinc metallopeptidases.CLONING
By searching for cDNAs with the potential to encode large proteins expressed in brain, Nagase et al. (1998) identified a partial cDNA encoding ERAP1, which they called KIAA0525. The 875-amino acid protein was predicted to be 44% identical to ALPP (171800) over 428 amino acids. RT-PCR analysis detected highest expression in placenta, ovary, kidney, and thymus. By searching an EST database for sequences similar to ALPP, Hattori et al. (1999) obtained a full-length cDNA encoding ALAP. The deduced 941-amino acid protein contains an N-terminal signal peptide, 5 potential N-glycosylation sites, a potential membrane-spanning domain, and a zinc-binding motif. Northern blot analysis revealed expression of 3.6- and 5.1-kb transcripts in all tissues tested except brain, where only the 5.1-kb mRNA was expressed. An additional 5.6-kb transcript was expressed in spleen and ovary. Hattori et al. (1999) identified an ALAP splice variant encoding a protein with 948 residues. Western blot analysis showed expression of an approximately 100-kD cytoplasmic protein, close to the predicted size. Functional analysis indicated a preference for leucine substrates. By expressing recombinant ALAP in Chinese hamster ovary cells, Hattori et al. (2000) showed that ALAP is a monomeric protein with a molecular mass of 120 kD that hydrolyzes a variety of bioactive peptides, including angiotensin II (see 106150). ALAP was expressed widely in human tissues, including the cortex of the kidney, where tissue kallikrein (147910) is localized. The authors suggested that ALAP plays a role in the regulation of blood pressure through inactivation of angiotensin II and/or generation of bradykinin (see 113503) in the kidney. Schomburg et al. (2000) cloned rat Alap, which they termed puromycin-insensitive, leucyl-specific aminopeptidase, or Pilsap. Pilsap is a 930-amino acid protein, and its hydrolytic activity appeared to be restricted to leucine and, to a lesser extent, methionine. Serwold et al. (2002) biochemically purified and cloned the 930-amino acid mouse aminopeptidase, which they termed Eraap. Western blot and immunofluorescence microscopy showed that the approximately 106-kD glycosylated protein, which is upregulatable by gamma-interferon (IFNG; 147570), trims N-terminal lysine, leucine, tyrosine, and asparagine residues when they are not followed by proline in the endoplasmic reticulum (ER) to yield the optimal octamer, primarily, and nonamer peptides for antigen presentation by major histocompatibility complex (MHC) molecules. Serwold et al. (2002) concluded that cytoplasmic proteolysis generates only the C terminus of antigenic peptides. After transport by TAP (170260), N-terminally extended peptides bind to MHC in the ER and are then trimmed by Eraap to acquire the optimal length before export from the ER, explaining why peptides presented by MHC class I have precise lengths.GENE STRUCTURE
By genomic sequence analysis, Hattori et al. (2001) determined that the ERAP1 gene contains 20 exons and spans approximately 47 kb. Primer extension analysis revealed 2 transcriptional initiation sites but no TATA or CAAT boxes. Luciferase reporter assays revealed a fu ... More on the omim web site
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).
Oct. 19, 2018: Protein entry updated
Automatic update: OMIM entry 606832 was added.