Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-beta (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-beta, whereas enhanced IDE activity effectively reduces brain amyloid-beta (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta 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 beta-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-beta and blood sugar concentrations.
Shen
Yuequan
Y
Ben-May Institute for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
Joachimiak
Andrzej
A
Rosner
Marsha Rich
MR
Tang
Wei-Jen
WJ
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005934:Glucagon / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism*; D007339:Insulysin / Q000737:chemistry* / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
D000682:Amyloid; D016229:Amyloid beta-Peptides; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D005934:Glucagon; D007339:Insulysin