Insulin and IGF-I Receptor Structure and Binding Mechanism

  • Pierre De Meyts
  • Waseem Sajid
  • Jane Palsgaard
  • Anne-Mette Theede
  • Lisbeth Gauguin
  • Hassan Aladdin
  • Jonathan Whittaker


The insulin and IGF-I receptors are members of the superfamily of receptor tyrosine kinases (RTKs). Unlike most RTKs that are single-chain monomeric transmembrane polypeptides, the insulin and IGF-I receptors are covalent dimers composed of two extracellular α subunits and two transmembrane β subunits containing the tyrosine kinase domains. The α subunits contain the ligand binding sites, of which at least three subdomains have been defined by photoaffinity crosslinking, alanine-scanning mutagenesis or minimized receptor constructs. All RTKs are dimeric or oligomeric in the ligand-activated form. The residues of insulin involved in receptor binding have been mapped by alanine-scanning mutagenesis. They form at least two major epitopes that partially overlap with the dimer- and hexamer-forming surfaces of the insulin molecule, and we propose that insulin is using those surfaces to asymmetrically cross-link the two receptor α subunits. This mechanism provides a structural basis for high affinity binding and negative cooperativity, and probably also operates in the IGF-receptor interaction. It also provides a structural basis for the approximation and transphosphorylation of the kinase domains and triggering of the signalling cascade.


Insulin Receptor Insulin Binding Insulin Molecule Negative Cooperativity Alanine Scanning 
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Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Pierre De Meyts
    • 1
  • Waseem Sajid
  • Jane Palsgaard
  • Anne-Mette Theede
  • Lisbeth Gauguin
  • Hassan Aladdin
  • Jonathan Whittaker
  1. 1.Receptor Systems Biology LaboratoryHagedorn Research InstituteGentofteDenmark

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