1. Ben-May Institute for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA
2. Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA

Correspondence to: Wei-Jen Tang¹ Correspondence and requests for materials should be addressed to W.T. (Email: wtang@uchicago.edu). Coordinates of the X-ray structures of the substrate-bound IDE have been deposited in the RCSB Protein Data Bank under accession code 2G54 (Zn²⁺-IDE–insulin-B-chain), 2G56 (Zn²⁺-free IDE–insulin-B-chain), 2G47 (IDE–A(1–40)), 2G48 (IDE–amylin) and 2G49 (IDE–glucagon).

Abstract

Insulin-degrading enzyme (IDE), a Zn²⁺-metalloprotease, is involved in the clearance of insulin and amyloid- (refs 1–3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-, whereas enhanced IDE activity effectively reduces brain amyloid- (refs 4–7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid- 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 -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- and blood sugar concentrations^{1, 8, 9}.

1. Ben-May Institute for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA
2. Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA

Correspondence to: Wei-Jen Tang¹ Correspondence and requests for materials should be addressed to W.T. (Email: wtang@uchicago.edu). Coordinates of the X-ray structures of the substrate-bound IDE have been deposited in the RCSB Protein Data Bank under accession code 2G54 (Zn²⁺-IDE–insulin-B-chain), 2G56 (Zn²⁺-free IDE–insulin-B-chain), 2G47 (IDE–A(1–40)), 2G48 (IDE–amylin) and 2G49 (IDE–glucagon).

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