Insulin is a hormone that is secreted by the pancreas in response to an increased level of glucose in the blood, usually after a meal. Insulin stimulates the muscles and adipose tissue to take up and store the excess glucose. Insulin is a dipeptide that contains a A and B chain. The A chain has an N-terminal helix linked to an anti-parallel C-terminal helix. The B chain has a central helical segment. The two chains are connected by 2 di-sulphide bonds that join the N- and C-terminal helices of the A chain to the central helix of the B chain [1] . When the concentration of glucose in the blood drops, insulin is no longer needed and an insulin-degrading enzyme is produced in order to reduce the amount of insulin in the body.
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Structure
The insulin-degrading enzyme (IDE) is a highly conserved protease that uses zinc (Zn2+) as a cofactor in breaking down insulin and amyloid beta-proteins [4]. The structure of IDE is a monomer with two N-terminal domains, which forms the catalytic site and two C-terminal domains that facilitates the substrate binding. The N-terminal domains are connected to the C-terminal domains via a 28-residue loop that forms a chamber that is shaped like a triangular prism.
Domain 1 houses the active site with two histidine's (his 108 and his 112), one glutamate (Glu 189) and the Zn2+ ion cofactor. Several residues of domains 1 & 4 create a polar area of the triangular cavity, while residues of domains 2 & 3 create a nonpolar region of the cavity.
In the open conformation, the insulin protein enters the enzyme opening causing a conformational change that allows the enzyme to fully recognize the protein and catalyzes protein degradation.
Function
Once the insulin molecule enters the active site and is recognized, the enzyme begins to unfold the insulin and makes initial cleavages in the middle of both the A and B chains. The enzyme then makes six more cleavages. One cleavage site right next to the first one on the A chain and 5 more on the B chain. Three near the middle and two near the C-terminus. There are no cleavage sites that are near the N-terminus of either chain.
Disease
Relevance
Structural highlights
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