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Structural and biochemical analyses of human insulin‐degrading enzyme reveal a new substrate recognition mechanism
Author(s) -
Tang WeiJen,
Shen Yuequan,
Joachimiak Andrzej,
Rosner Marsha,
Li Pengyun
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a648-a
Subject(s) - insulin degrading enzyme , substrate (aquarium) , chemistry , amylin , enzyme , biochemistry , amyloid (mycology) , peptide , biophysics , insulin , biology , islet , inorganic chemistry , ecology , endocrinology
Insulin‐degrading enzyme (IDE), a 113 kDa zinc‐metalloprotease, is involved in the clearance of insulin and amyloid‐beta. 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. We performed biochemical analyses to show that the N‐terminal half of IDE (57 kDa IDE‐N) serves as the catalytic domain while the C‐terminal half of IDE (56 kDa IDE‐C) functions to facilitate the binding of substrates and oligomerization (BBRC 343 :, 2006). We also determined structures of human IDE in complex with four substrates (insulin B chain, amyloid‐beta peptide (1–40), amylin and glucagon) (Nature 443 :, 2006). Our structures show that IDE‐N and IDE‐C domains 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.