Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism

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Abstract
Insulin-degrading enzyme (IDE) is involved in the clearance of insulin and amyloid β. This is necessary to maintain proper blood sugar levels and to prevent accumulation of amyloid β in the brain. The crystal structure of IDE in complex with four substrates has now been determined, revealing the molecular basis for substrate recognition. This should aid the design of IDE-based drugs for Alzheimer's disease and type II diabetes. The crystal structure of insulin-degrading enzyme (IDE) in complex with four substrates is presented, revealing the molecular basis for substrate recognition by IDE. Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-β (refs 1–3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-β, whereas enhanced IDE activity effectively reduces brain amyloid-β (refs 4–7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-β peptide (1–40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form β-sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-β and blood sugar concentrations1,8,9.