Sandbox GGC7

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 convert it to energy or to 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-sulfide 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.

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 ^[2]. IDE can be found predominantly in the cytosol, however it is also located in the cell membrane, secreted into the extracellular regions and is present at the cell surfaces of neuron cells in the brain. Insulin-degrading enzyme is also known as insulysin or insulinase and is active at neutral pH. It can be located in red blood cells, skeletal muscle, liver and brain.

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[3] or to the article describing Jmol ^[4] to the rescue.

Structure

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 changes conformation from the open state to the closed state and 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 ^[5]. 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

• Mutation of Glu-111 causes the enzyme to become inactive • Mutation of Pro-286 reduces the activity of the enzyme • Three mutations, when combined with mutations from another site causes an increase of enzyme activity for the breakdown of insulin and amyloids 1. Ser-132 & Glu-817 2. Asn-184 & Gln-828 3. Asp-426 & Lys-899 Hyperproinsulinemia – Asp 34 mutation and/or His-89 Insulin-dependent diabetes – Cys-55 Permanent neonatal diabetes - ASP-24; ARG-32; SER-32; GLY-43; VAL-47; CYS-48; CYS-89; CYS- 90; TYR-96 AND CYS-108. Alzheimer’s - Ile-714

Relevance

Structural highlights

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