Insulin-degrading enzyme, also known as IDE, is an enzyme. Known alternatively as insulysin or insulin protease, IDE is a large zinc-binding protease of the M16 metalloprotease family known to cleave multiple short polypeptides that vary considerably in sequence. Other members of this family include the mitochondrial processing peptidase and presequence protease. Structure Gene The gene IDE encodes protein Insulin-degrading enzyme. The human gene IDE has 28 exons and is located at chromosome band 10q23-q25. Protein Due to alternative splicing, The human protein Insulin-degrading Enzyme has two isoforms. Isoform1 is ~118 kDa in size and composed of 1019 amino acids while the isoform 2 is ~54.2 kDa size and composed of 464 amino acids (missing 1-555 amino acids). The calculated theoretical pI of this protein isoform is 6.26. Structural studies of IDE by Shen et al. have provided insight into the functional mechanisms of the protease. Reminiscent of the previously determined structure of the bacterial protease pitrilysin, the IDE crystal structure reveals defined N and C terminal units that form a proteolytic chamber containing the zinc-binding active site. In addition, it appears that IDE can exist in two conformations: an open conformation, in which substrates can access the active site, and a closed state, in which the active site is contained within the chamber formed by the two concave domains. Targeted mutations that favor the open conformation result in a 40-fold increase in catalytic activity. Based upon this observation, it has been proposed that a possible therapeutic approach to Alzheimer’s might involve shifting the conformational preference of IDE to the open state, and thus increasing Aβ degradation, preventing aggregation, and, ideally, preventing the neuronal loss that leads to disease symptoms. Function IDE was first identified by its ability to degrade the B chain of the hormone insulin. This activity was observed over sixty years ago, though the enzyme specifically responsible for B chain cleavage was identified more recently. This discovery revealed considerable amino acid sequence similarity between IDE and the previously characterized bacterial protease pitrilysin, suggesting a common proteolytic mechanism. IDE, which migrates at 110 kDa during gel electrophoresis under denaturing conditions, has since been shown to have additional substrates, including the signaling peptides glucagon, TGF alpha, and β-endorphin. Clinical Significance Alzheimer's disease Considerable interest in IDE has been stimulated due to the discovery that IDE can degrade amyloid beta (Aβ), a peptide implicated in the pathogenesis of Alzheimer's disease. The