insulin-degrading enzyme in complex with insulin B chain
Homo sapiens (human)
Insulin-degrading enzyme (IDE), a Zn2+ metalloprotease, degrades insulin and amyloid-β. It also degrades amylin and glucagon so that IDE is one of the rare enzymes degrading a wide range of substrate with high affinity.
Crystal structure of Zn2+ bound, catalytically inactive IDE mutant IDE-E111Q in complex with insulin B chain has been solved at 2.25Å resolution. IDE consists of four structurally homologous domains. Domain 1 and 2 are in the N-terminal part (IDE-N) and Domain 3 and 4 in the C-terminal part (IDE-C). The IDE structure described is the closed form, which captures insulin B chain in a triangular prism-like chamber.
The IDE domain 1 contains the catalytic cleft with Zn2+. At this site, the insulin B chain, which is one of the possible substrates, does a conformational change from the native structure to form β strands on its N terminus and catalytic sites. It then attaches to the IDE by forming β sheets. In this structure, the remaining regions are disordered (Fig. 1).
Contributing factors for substrate recognition by IDE were revealed. Favorable binding of the substrate N terminus and cleavage sites are crucial. In addition, charge distribution in the C terminus is also important. The surface of the IDE-C chamber is positively charged so that substrates without positive charges in their C terminus are suitable. Another factor is size, because the catalytic chamber of IDE can accommodate only relatively small peptides. Insulin fits these conditions. In addition, amyloid-β, amylin, and glucagon are also acceptable as IDE substrates and their complex structures have been solved (xPSSS:2G47, xPSSS:2G48, and xPSSS:2G49 respectively). These substrates also form β strands to contact IDE, which is consistent with insulin B chain.
Although it seems that IDE changes allosterically its open-closed conformation, details including key small molecules remain unknown.
(Fig. 1) Conformational change of the insulin B chain.
Protein Data Bank (PDB)
Shen, Y. Joachimiak, A. Rosner, M.R. Tang, W.-J.; "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism"; Nature; (2006) 443:870-874.
author: Naoya Fujita