Harmonic oscillator model of the insulin and IGF1 receptors’ allosteric binding and activation

• Published in: Molecular systems biology 2009, Vol.5 (1), p.243-n/a
• Main Authors: Kiselyov, Vladislav V, Versteyhe, Soetkin, Gauguin, Lisbeth, De Meyts, Pierre
• Format: Article
• Language: English
• Subjects: Activation; activation mechanism; Allosteric properties; Allosteric Regulation; Binding; binding kinetics; Binding sites; Combinatorial analysis; Complexity; Crosslinking; Cytokine receptors; Diabetes; EMBO37; EMBO40; Growth factors; harmonic oscillator model; Harmonic oscillators; Humans; Insulin; insulin receptor; Insulin-like growth factor I; Kinases; Kinetics; Ligands; mathematical modelling; Mathematical models; Metabolism; Models, Biological; Models, Molecular; Mutagenesis; Parameter estimation; Protein Binding; Receptor, IGF Type 1 - metabolism; Receptor, Insulin - metabolism; Receptors; Robustness (mathematics); Signal transduction; Tyrosine
• ISSN: 1744-4292; 1744-4292
• DOI: 10.1038/msb.2008.78

The insulin and insulin‐like growth factor 1 receptors activate overlapping signalling pathways that are critical for growth, metabolism, survival and longevity. Their mechanism of ligand binding and activation displays complex allosteric properties, which no mathematical model has been able to account for. Modelling these receptors’ binding and activation in terms of interactions between the molecular components is problematical due to many unknown biochemical and structural details. Moreover, substantial combinatorial complexity originating from multivalent ligand binding further complicates the problem. On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator. Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters. The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G‐protein‐coupled receptors where ligand crosslinking occurs. Synopsis Insulin and insulin‐like growth factor 1 (IGF1) have similar structures and exert their action by activating two closely related receptor tyrosine kinases—insulin receptor (IR) and IGF1 type I receptor (IGF1R), which have virtually identical signalling pathways (De Meyts and Whittaker, 2002 ). Despite this similarity, the two hormones produce markedly different responses: mostly metabolic for insulin and mitogenic for IGF1 (Kim and Accili, 2002 ). So far, there is poor understanding of how these hormones produce such markedly different biological effects using basically the same machinery (Kim and Accili, 2002 ). In recent years, it has become clear that a systems biology approach is required to understand the combinatorial nature of signalling specificity (Kholodenko, 2007 ). However, the two receptors’ mechanism of ligand binding and activation displays complex allosteric properties (i.e. negative cooperativity and ligand dependence of the receptor dissociation rate), which no mathematical model has been able to account for. Therefore, development of a reliable mathematical model describing the two receptors’ binding kinetics and activation is a critical firs