IDE

This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.

Full Name

Insulin Degrading Enzyme

Alternative Names

Insulin Degrading Enzyme

Function

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-associated isoform acts as an entry receptor for varicella-zoster virus (VZV).

Biological Process

Amyloid-beta clearance Source: ARUK-UCL
Amyloid-beta clearance by cellular catabolic process Source: ARUK-UCL
Amyloid-beta metabolic process Source: UniProtKB
Antigen processing and presentation of endogenous peptide antigen via MHC class I Source: UniProtKB
Bradykinin catabolic process Source: UniProtKB
Cellular protein catabolic process Source: UniProtKB
Determination of adult lifespan Source: UniProtKB
Hormone catabolic process Source: UniProtKB
Insulin catabolic process Source: UniProtKB
Insulin metabolic process Source: UniProtKB
Insulin receptor signaling pathway Source: UniProtKB
Peptide catabolic process Source: UniProtKB
Positive regulation of protein binding Source: UniProtKB
Positive regulation of protein catabolic process Source: ARUK-UCL
Protein catabolic process Source: ARUK-UCL
Proteolysis Source: UniProtKB
Proteolysis involved in cellular protein catabolic process Source: UniProtKB
Regulation of aerobic respiration Source: ARUK-UCL
Ubiquitin recycling Source: UniProtKB

Cellular Location

Cytosol; Secreted; Cell membrane. Present at the cell surface of neuron cells. The membrane-associated isoform is approximately 5 kDa larger than the known cytosolic isoform.

PTM

The N-terminus is blocked.