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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

Abstract

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.

Keywords

Insulin Receptor Insulin Binding Insulin Molecule Negative Cooperativity Alanine Scanning 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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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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