Insulin degrading enzyme
Insulin Degrading Enzyme (IDE) is a large zinc-binding protease of the M16A metalloprotease subfamily known to cleave multiple short polypeptides that vary considerably in sequence.  Known alternatively as insulysin or insulin protease, IDE was first identified by its ability to degrade the B chain of the hormone insulin.  This activity was observed over fifty years ago , though the enzyme specifically responsible for B chain cleavage was identified more recently .  This discovery revealed considerable amino acid sequence homology 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 -endorphin.

# IDE and Alzheimer's Disease
Considerable interest in IDE has been stimulated due to the discovery that IDE can degrade amyloid beta (A), a peptide implicated in the pathogenesis of Alzheimers disease.  The underlying cause or causes of the disease are unclear, though the primary neuropathology observed is the formation of amyloid plaques and neurofibrillary tangles.  One hypothesized mechanism of disease, called the amyloid hypothesis, suggests that the causative agent is the hydrophobic peptide A, which forms quaternary structures that, by an unclear mechanism, cause neuronal death.  A is a byproduct generated as the result of proteolytic processing of the amyloid precursor protein (APP) by proteases referred to as the  and  secretases. The physiological role of this processing is unclear, though it may play a role in nervous system development.
Numerous in vitro and in vivo studies have shown correlations between IDE, A degradation, and Alzheimers disease.  Mice engineered to lack both alleles of the IDE gene exhibit a 50% decrease in A degradation, resulting in cerebral accumulation of A.  Studies of genetically inherited forms of Alzheimers show reduction in both IDE expression and catalytic activity among affected individuals.  Despite the evident role of IDE in disease, relatively little is known about its physiological functions.  These may be diverse, as IDE has been localized to several locations, including the cytosol, peroxisomes, endosomes, proteasome complexes, and the surface of cerebrovascular endothelial cells.

# IDE Structure and Function
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 prevent the closed conformation result in a 40-fold increase in catalytic activity.  Based upon this observation, it has been proposed that a possible therapeutic approach to Alzheimers might involve shifting the conformational preference of IDE to the open state, and thus increasing A degradation, preventing aggregation, and, ideally, preventing the neuronal loss that leads to disease symptoms.