User:David L. Nelson/Sandbox 9
From Proteopedia
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=='''Insulin'''== | =='''Insulin'''== | ||
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| - | [[ Image: | + | [[ Image:Insulin 2D.jpg|300px|left| | thumb| human insulin 1MSO]] |
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===Background=== | ===Background=== | ||
Revision as of 15:25, 9 April 2011
Contents |
Insulin
Background
The major function of Insulin is to counter the concerted action of a number of hyperglycemia-generating hormones and to maintain low blood glucose levels. Because there are numerous hyperglycemic hormones, untreated disorders associated with insulin generally lead to severe hyperglycemia and shortened life span.
In addition to its role in regulating glucose metabolism, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Insulin also modulates transcription, altering the cell content of numerous mRNAs. It stimulates growth, DNA synthesis, and cell replication, effects that it holds in common with the insulin-like growth factors (IGFs) and relaxin.
Insulin is synthesized as a preprohormone in the β-cells of the islets of Langerhans. Its signal peptide is removed in the cisternae of the endoplasmic reticulum and it is packaged into secretory vesicles in the Golgi, folded to its native structure, and locked in this conformation by the formation of 2 disulfide bonds. Specific protease activity cleaves the center third of the molecule, which dissociates as C peptide, leaving the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide.
Insulin secretion from β-cells is principally regulated by plasma glucose levels. Increased uptake of glucose by pancreatic β-cells leads to a concomitant increase in metabolism. The increase in metabolism leads to an elevation in the ATP/ADP ratio. This in turn leads to the inhibition of an ATP-sensitive potassium channel (KATP channel). The net result is a depolarization of the cell leading to Ca2+ influx and insulin secretion.
The KATP channel is a complex of 8 polypeptides comprising four copies of the protein encoded by the ABCC8 (ATP-binding cassette, sub-family C, member 8) gene and four copies of the protein encoded by the KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) gene. The ABCC8 encoded protein is also known as the sulfonylurea receptor (SUR). The KCNJ11 encoded protein forms the core of the KATP channel and is called Kir6.2. As might be expected, the role of KATP channels in insulin secretion presents a viable therapeutic target for treating hyperglycemia due to insulin insufficiency as is typical in type 2 diabetes.
Chronic increases in numerous other hormones, such as growth hormone, placental lactogen, estrogens, and progestins, up-regulate insulin secretion, probably by increasing the preproinsulin mRNA and enzymes involved in processing the increased preprohormone.
PDB Entry
1MBO is a 1 chain structure with sequence from Physeter catodon. The January 2000 RCSB PDB Molecule of the Month feature on Myoglobin by David S. Goodsell is 10.2210/rcsb_pdb/mom_2000_1. Full crystallographic information is available from OCA.
About This Structure
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This representation shows the protein as blue strands surround the heme ligand, with accompanying water molecules. This water is strongly attracted to the protein and is part of the structure of any crystalline protein. reveals that the overall tertiary shape is much like a hockey puck. The α-helix is a prominent secondary structural component. The α-helices can be shown to form two layers of backbone, and myoglobin can be classified as an antiparallel α-helix type of globular protein. The Myoglobin page gives more detail on the secondary structure. The prosthetic group of myoglobin is a , and as shown here it is inserted into a pocket which is nonpolar. There are two histidine residues that are highly conserved among globins: . They play a crucial role in allowing heme to bind oxygen. His 93 is the fifth ligand chelated to Fe2+ (the other four are the nitrogens in the pyrole rings), and it binds to one side of the heme. Show protein atoms displayed as spacefill that are within 0.5 nm of the heme. These are the atoms which form the surface of the heme pocket and serve as a reminder that except for the ones on the surface of the molecule most of these atoms are carbon atoms and produce a nonpolar environment for the heme. This nonpolar, water-excluding environment is important for the function of myoglobin. Whenever Fe2+ is in an aqueous environment and it contacts O2, Fe2+ is oxidized to Fe3+. Myoglobin with a heme containing Fe3+ (called metmyoglobin) can not fulfill its physiological function and therefore must be degraded
Role in Disease
Myoglobin is released from damaged muscle tissue (rhabdomyolysis), which has very high concentrations of myoglobin. The released myoglobin is filtered by the kidneys but is toxic to the renal tubular epithelium and so may cause acute renal failure.
Myoglobin is a sensitive marker for muscle injury, making it a potential marker for heart attack in patients with chest pain. However, elevated myoglobin has low specificity for acute myocardial infarction (AMI) and thus CK-MB, cTnT, ECG, and clinical signs should be taken into account to make the diagnosis.
Reference for the Structure
- Phillips SE. Structure and refinement of oxymyoglobin at 1.6 A resolution. J Mol Biol. 1980 Oct 5;142(4):531-54. PMID:7463482
