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

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

Confined helium on Lagrange meshes

The Lagrange-mesh method has the simplicity of a calculation on a mesh and can have the accuracy of a variational method. It is applied to the study of a confined helium atom. Two types of confinement are considered. Soft confinements by potentials are studied in perimetric coordinates. Hard confinement in impenetrable spherical cavities is studied in a system of rescaled perimetric coordinates varying in [0,1] intervals. Energies and mean values of the distances between electrons and between an electron and the helium nucleus are calculated. A high accuracy of 11 to 15 significant figures is obtained with small computing times. Pressures acting on the confined atom are also computed. For sphere radii smaller than 1, their relative accuracies are better than $10^{-10}$. For larger radii up to 10, they progressively decrease to $10^{-3}$, still improving the best literature results.Comment: Physical Chemistry Chemical Physics, 201

Early neonatal death in mice homozygous for a null allele of the insulin receptor gene

Insulin action is viewed as a set of branching pathways, with some actions serving to regulate energy metabolism and others to regulate cellular growth and development. Thus far, available genetic evidence has supported this view. In humans, complete lack of insulin receptors due to mutations of the insulin receptor gene results in severe growth retardation and mild diabetes. In mice, targeted inactivation of insulin receptor substrate-1, an important substrate of the insulin receptor kinase, leads to inhibition of growth and mild resistance to the metabolic actions of insulin. To address the question of whether both metabolic and growth-promoting actions of insulin are mediated by the insulin receptor, we have generated mice lacking insulin receptors by targeted mutagenesis in embryo-derived stem (ES) cells. Unlike human patients lacking insulin receptors, mice homozygous for a null allele of the insulin receptor gene are born at term with apparently normal intrauterine growth and development. Within hours of birth, however, homozygous null mice develop severe hyperglycaemia and hyperketonaemia, and die as the result of diabetic ketoacidosis in 48-72 hours. These data are consistent with a model in which the insulin receptor functions primarily to mediate the metabolic actions of insulin

Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity

Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles