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From Proteopedia

Revision as of 19:52, 9 March 2012

Introduction

Insulin receptor ABOUT 1. tyrosine kinase (ligand-activated receptor kinase)

  a) expressed at cell surface as homodimers composed of alpha/beta 
     i) disulfide-linked ectodomain dimer - folded over conformation places ligands in correct relative positions (green scene)
  b) mediate activity by addition of phophate to tyrosines on specific proteins in cell

2. found in organisms from cnidarians and insects to humans

  a) in humans essential for maintaining glucose levels
  b) also has role in growth and development (insulin growth factor II)
     i) signal through IGF2 to mediate embryonic growth (Kitamura et al)

FUNCTION 1. insulin receptor substrate 1 (IRS-1) binding leads to increase in high affinity glucose transporter (Glut4) molecules on the other membrane of cell (muscles, adipose)

  a) leads to increased glu uptake (Glut4 mediates transport of glu into cell)

DISEASE 1. decreased insulin resceptor signalling (aka insulin insensitivity)leads to diabetes mellitus type 2

   a) cells unable to take up glu => hyperglycemia (increased circulating glucose)
   b) aka non-insulin-dependent or adult onset diabetes
      i) beleived to be caused by obesity and genetic predisposition
      ii) managed with dietary and lifestyle modifications

2. mutations in both copies of the insulin receptor gene causes Donohue syndrome (leprechaunism)

   a) autosomal recessive; results in totally non-functional insulin receptor
   b) results in distorted facial features, growth redardation 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

References