Sandbox Reserved 427
From Proteopedia
| This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439. |
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Contents |
Introduction
The insulin receptor is a tyrosine kinase, that is a type of ligand-activated receptor kinase. Insulin receptors are expressed at the cell surface as disulfide-linked homodimers composed of alpha/beta . The folded over conformation of the ectodomain places ligands in the correct relative positions for activity. (green scene) The receptor mediates activity by the addition of phosphate to tyrosines on specific proteins in cell
Insulin receptors are found in many diverse organisms organisms, from cnidarians and insects to humans. In humans, correctly functioning insulin receptors are essential for maintaining glucose levels in the blood. The insulin receptor also has role in growth and development (through insulin growth factor II); studies have shown that signalling through IGF2 plays a role in the mediation embryonic growth (Kitamura et al).
In everyday function, insulin receptor substrate 1 (IRS-1) binding leads to increase in the high-affinity glucose transporter (Glut4) molecules on the outer membrane of the cell in muscle and adipose tissue. Glut4 mediates the transport of glucose into the cell, so an increase in Glut4 leads to increased glucose uptake.
Maintaining appropriate blood glucose levels is essential for appropriate life-sustaining metabolic function, and insulin receptor malfunction is associated with several severe diseases. Insulin insensitivity, or decreased insulin receptor signalling, leads to diabetes mellitus type 2. Type 2 diabetes is also known as non-insulin-dependent or adult onset diabetes, and is believed to be caused by a combination of obesity and genetic predisposition. In type 2 diabetes, cells are unable to uptake glucose due to decreased insulin receptor signaling, which leads to hyperglycemia (increased circulating glucose). Type 2 diabetes can be managed with dietary and lifestyle modifications to aid in proper metabolism.
Mutations in both copies of the insulin receptor gene causes Donohue syndrome, which is also known as leprechaunism. Donohue syndrome is an autosomal recessive disorder that results in a totally non-functional insulin receptor. The disorder results in distorted facial features, severe growth retardation, and often death within a year.
Overall Structure
-Ectodomain is a of 2 identical monomers (dimer green scene)
-Monomers composed of 6 domains (monomer green scene)
-Leucine-rich repeat domain (L1), secondary structures (green scene)
-Cystine-rich region (CR), secondary structures (green scene)
-Leucine-rich repeat domain (L2), secondary structures (green scene)
-Fibronectin Type III domain 1 (FnIII-1), secondary structures (green scene)
-Fibronectin Type III domain 2 (FnIII-2), secondary structures, insert domain (green scene)
-Fibronectin Type III domain 3 (FnIII-3), secondary structures (green scene)
Binding Interactions
2dtg transmembrane receptor activated in the presence of insulin, a member of the tyrosine kinase class of receptor proteins
Tyrosine Kinases in General Class of receptor proteins that add a phosphate group to a tyrosine on their specific substrate.
Interactions with insulin (IRS-1) and subsequent binding/phosphorylation. This leads to an increase in the glucose transporter (Glut-4) which has a high affinity for glucose molecules. This occurs mainly in muscle and adipose tissues where glucose uptake is most needed. This increase in Glut-4 causes an increase in glucose uptake from blood. Simply stated, 2dtg is activated by insulin which signals for an increase in Glut-4. Glut-4 finds its way to the cell surface where it can perform its function (transport glucose into the cell).
Green scene of the active site of 2dtg (tyrosine kinase) . This green scene is quite complex! Simplify to make your point clearly... Prof T.
Additional Features
Insulin Receptor has the ability to become desensitized to the binding of insulin, and because of a lower affinity, insulin resistance develops.
Insulin Resistance: Happens when the cells essentially don't open the door when insulin comes knocking. When this happens, the body puts out more insulin to stabilize blood glucose (and so the cells can use the glucose). This allows for a vicious cycle where the cells become more and more desensitized as the concentration of insulin increases. This occurs when the insulin receptor cannot activate the Glu-4 once insulin binds, which lowers the storage of sugar. This resistance can be ameliorated by better dietary practice and increased intake of necessary vitamins and minerals.
The insulin-binding cavity within the receptor homodimer may provide a target for the design of helical mimetic nonpeptide agonists, perhaps achievable in part by molecules the size of antibiotics and could be “druggable.”
Use of drugs with similar design to insulin as well as antibodies can provide a stronger affinity for the insulin receptor binding site, increasing sensitivity.
Credits
Introduction - Rebecca Bishop
Overall Structure - Kathryn Liedell
Drug Binding Site - Ryan Deeney
Additional Features - Jeffrey Boerth
I suggest that one of you show us what insulin looks like and which are thought to be the binding surfaces on insulin and on the receptor. Prof T -->I think I can work that into the intro. Bec
