Insulin-Degrading Enzyme: Structure-Function Relationship and its Possible Roles in Health and Disease

Abstract

Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn(2+) -dependent endopeptidase with an "inverted" HxxEH motif. In vivo, IDE contributes to regulate the steady state levels of peripheral insulin and cerebral amyloid beta peptide (Abeta) of Alzheimer's disease. In vitro, substrates of IDE include a broad spectrum of peptides with relevant physiological functions such as atrial natriuretic factor, insulin-like growth factor-II, transforming growth factor-alpha, beta-endorphin, amylin or glucagon. The recently solved crystal structures of an inactive IDE mutant bound to four different substrates indicate, in accordance with previous compelling biochemical data, that peptide backbone conformation and size are major determinants of IDE recognition and substrate selectivity. IDE-N and IDE-C halves contribute to substrate binding and may rotate away from each other leading to open and closed conformers that permit or preclude the entry of substrates. Noteworthy, stabilization of substrate beta strands in their IDE-bound form may explain the preference of IDE for peptides with a high tendency to self-assembly as amyloid fibrils. These structural requirements may underlie the capability of some amyloid peptides of forming extremely stable complexes with IDE and raise the possibility of a dead-end chaperone-like function of IDE independent of catalysis. Furthermore, the recent recognition of IDE as a varicella zoster virus receptor and its putative involvement in muscle cell differentiation, steroid receptor signaling or proteasome modulation suggest that IDE is a multi-functional protein with broad and relevant roles in several basic cellular processes. Accordingly, IDE functions, regulation or trafficking may partake in the molecular pathogenesis of major human diseases and become potential targets for therapeutic intervention.

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

“…Intracellular insulin degradation occurs via the action of IDE [28,41], a 110 kDa zinc-dependent metalloproteinase present in most insulin-responsive cells, mainly hepatocytes. Given the importance of insulin clearance to type 2 diabetes and the role of IDE in its control, it is not surprising that alterations in IDE levels and activity are closely related to type 2 diabetes onset and development [34,41].…”

“…Given the importance of insulin clearance to type 2 diabetes and the role of IDE in its control, it is not surprising that alterations in IDE levels and activity are closely related to type 2 diabetes onset and development [34,41]. On the basis of this, we evaluated how CNTF could control hepatic degradation of insulin by measuring Ide expression and alternative splicing in mouse liver and hepatocyte HEPG2 cells.…”

Insulin-degrading Enzyme (IDE)

“…In the last decade, there have been studies that have also linked IDE to the etiology of some diseases, such as Alzheimer Disease (AD) and Type 2 Diabetes Mellitus (DM2) (4, 10 -12), associating the protein to a wide range of cellular processes, such as Varicella Zoster Virus infection, steroid receptor signaling, and insulin-dependent proteasome modulation (13)(14)(15)(16)(17). It has also been proposed to play a role in rat muscle cell differentiation and rat development, envisaging for IDE multiple functions related to cellular growth and tissue homeostasis (18,19).…”

Metal ions affect insulin-degrading enzyme activity

“…It is also interesting to outline that if we compare these parameters with those obtained for the amyloid peptides Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and Aβ [16][17][18][19][20][21][22][23][24][25][26][27][28] several similarities and some differences emerge [54]. In particular, the overall proteolytic activity toward the main cleavage sites (i.e., Phe 24 [16][17][18][19][20][21][22][23][24][25][26][27][28] ) is somewhat higher in the case of the B20-30 peptide due to a slightly more efficient cleavage rate-limiting step (see Table 2), whereas the substrate affinity of B20-30 appears intermediate between that of Aβ [1][2][3]…”

“…For this reason, as hyperinsulinemia is associated with a high risk of Alzheimer's disease (AD) [6,7], IDE could play a critical role in the mechanism associating hyperinsulinemia and type 2 diabetes (DM2) with AD. Despite the evident role of IDE in various diseases, relatively little is known about its physiological functions and for this reason the control of its activity has been recently targeted as a viable approach in the study of diseases such as AD and insulindependent diabetes [8][9][10].…”