Insulin-degrading enzyme (IDE)
The protein contains 1019 amino acids for an estimated molecular weight of 117968 Da.
Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling (PubMed:2293021, PubMed:10684867, PubMed:26968463, PubMed:17051221, PubMed:17613531, PubMed:18986166, PubMed:19321446, PubMed:23922390, PubMed:24847884, PubMed:26394692, PubMed:29596046, PubMed:21098034). Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin (PubMed:23922390, PubMed:26394692, PubMed:29596046). Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP (By similarity). Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia (PubMed:9830016, PubMed:26394692) (Probable). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP (PubMed:21098034). Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients (PubMed:21098034). Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I.', '(Microbial infection) The membrane-associat (updated: Feb. 10, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- 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.
- 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.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
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, is annotated as membranous in UniProt.
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| Variant | Description |
|---|---|
| dbSNP:rs2229708 |
Biological Process
Amyloid-beta clearance
Amyloid-beta clearance by cellular catabolic process
Amyloid-beta metabolic process
Antigen processing and presentation of endogenous peptide antigen via MHC class I
Bradykinin catabolic process
Cellular protein catabolic process
Determination of adult lifespan
Hormone catabolic process
Insulin catabolic process
Insulin metabolic process
Insulin receptor signaling pathway
Negative regulation of proteolysis
Peptide catabolic process
Positive regulation of protein binding
Positive regulation of protein catabolic process
Positive regulation of protein oligomerization
Protein catabolic process
Protein heterooligomerization
Protein homooligomerization
Protein homotetramerization
Protein localization
Protein targeting to peroxisome
Proteolysis
Proteolysis involved in cellular protein catabolic process
Regulation of aerobic respiration
Ubiquitin recycling
Viral process
Cellular Component
Basolateral plasma membrane
Cell surface
Cytoplasm
Cytosol
Cytosolic proteasome complex
External side of plasma membrane
Extracellular exosome
Extracellular space
Mitochondrion
Nucleoplasm
Nucleus
Obsolete cell
Peroxisomal matrix
Peroxisome
Plasma membrane
Molecular Function
Amyloid-beta binding
ATP binding
ATPase
Beta-endorphin binding
Endopeptidase activity
Glycoprotein binding
Identical protein binding
Insulin binding
Metalloendopeptidase activity
Peptide binding
Protein homodimerization activity
Protein-containing complex binding
Signaling receptor binding
Ubiquitin binding
Ubiquitin-dependent protein binding
Virus receptor activity
Zinc ion binding
The reference OMIM entry for this protein is 146680
Insulin-degrading enzyme; ide
Insulysin
Insulinase
DESCRIPTION
Insulin-degrading enzyme (EC 3.4.24.56), also known as insulysin, is a 110-kD neutral metallopeptidase that can degrade a number of peptides, including insulin (176730) and beta-amyloid (104760) (Qiu et al., 1998).CLONING
Affholter et al. (1988) isolated and sequenced a cDNA coding for IDE. The deduced amino acid sequence of the enzyme contained the sequences of 13 peptides derived from the isolated protein. The cDNA transcribed in vitro yielded a synthetic RNA that in cell-free translations produced a protein that coelectrophoresed with the native proteinase and could be immunoprecipitated with monoclonal antibodies to IDE. Since the deduced sequence of this proteinase did not contain the consensus sequences for any of the known classes of proteinases (i.e., metallo, cysteine, aspartic, or serine), it may be a member of a family of proteases that are involved in intercellular peptide signaling. It did show homology to an Escherichia coli proteinase (called protease III), which also cleaves insulin and is present in the periplasmic space; thus, they may be members of the same family of proteases.GENE FUNCTION
Qiu et al. (1998) determined that the extracellular thiol metalloprotease capable of degrading amyloid-beta protein identified by Qiu et al. (1997) is the same as IDE. By Western blot analysis, they found a full-length 110-kD IDE band in the CSF of normal individuals and of patients with Alzheimer disease (AD; 104300) or non-Alzheimer dementia. They found no difference in IDE levels of the normal and patient populations. By biochemical analysis of IDE purified from the medium of a mouse microglial cell line, they determined that IDE could degrade both endogenous and synthetic amyloid-beta protein and that it could catalyze the oligomerization of this protein. Through a series of inhibitor studies, in vitro translation, and biochemical assays of rat IDE expressed by transfected human kidney cells, Edbauer et al. (2002) determined that IDE may be the protease responsible for the clearance of the cytoplasmic fragment of the amyloid-beta precursor protein (APP) following liberation of the amyloid-beta protein. IDE has a preferential affinity for insulin such that the presence of insulin will inhibit IDE-mediated degradation of other substances, including beta-amyloid. Cook et al. (2003) found that hippocampal IDE levels were reduced by approximately 50% in AD patients with the APOE4 (107741) allele compared to AD patients without the APOE4 allele and to controls with or without the APOE4 allele. The findings suggested that reduced IDE expression may be a risk factor for AD, and that IDE may interact with APOE status to affect beta-amyloid metabolism. Varicella-zoster virus (VZV) causes chickenpox and shingles. While varicella is likely spread as cell-free virus to susceptible hosts, the virus is transmitted by cell-to-cell spread in the body and in vitro. Li et al. (2006) found that the extracellular domain of IDE interacted with VZV glycoprotein E (gE), a protein essential for viral infection. Downregulation of IDE by small interfering RNA or blocking IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-asso ... More on the omim web site
Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 146680 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed