Solution structure of ectodomains of the insulin receptor family: the ectodomain of the type 1 insulin-like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change

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dc.contributor.authorWhitten, AEen_AU
dc.contributor.authorSmith, BJen_AU
dc.contributor.authorMenting, JGen_AU
dc.contributor.authorMargetts, MBen_AU
dc.contributor.authorMcKern, NMen_AU
dc.contributor.authorLovrecz, GOen_AU
dc.contributor.authorAdams, TEen_AU
dc.contributor.authorRichards, Ken_AU
dc.contributor.authorBentley, JDen_AU
dc.contributor.authorTrewhella, Jen_AU
dc.contributor.authorWard, CWen_AU
dc.contributor.authorLawrence, MCen_AU
dc.date.accessioned2010-02-08T03:59:29Zen_AU
dc.date.accessioned2010-04-30T05:07:42Zen_AU
dc.date.available2010-02-08T03:59:29Zen_AU
dc.date.available2010-04-30T05:07:42Zen_AU
dc.date.issued2009-12-18en_AU
dc.date.statistics2009-12-18en_AU
dc.description.abstractThe insulin receptor (IR) and the homologous Type 1 insulin-like growth factor receptor (IGF-1R) are cell-surface tyrosine kinase receptors that effect signaling within the respective pathways of glucose metabolism and normal human growth. While ligand binding to these receptors is assumed to result in a structural transition within the receptor ectodomain that then effects signal transduction across the cell membrane, little is known about the molecular detail of these events. Presented here are small-angle X-ray scattering data obtained from the IR and IGF-1R ectodomains in solution. We show that, in solution, the ectodomains of IR and IGF-1R have a domain disposition that is very similar to that seen in the crystal structure of the ectodomain of IR, despite the constituent domains being in relatively sparse contact and potentially mobile. We also show that the IGF-1R ectodomain is capable of binding up to three molecules of IGF-1 in solution, with surprisingly little apparent change in relative domain disposition compared to the apo, form. While the observed 3:1 ligand-binding stoichiometry appears to contradict earlier explanations of the absence of a bell-shaped dose-response curve for IGF-1R in ligand displacement assays, it is readily understood in the context of the harmonic oscillator model of the negative cooperativity of ligand binding to IGF-1R. Taken together, our findings suggest that the structural movements within these receptors upon ligand binding are small and are possibly limited to local rotation of domains. © 2009, Elsevier Ltd.en_AU
dc.identifier.citationWhitten, A. E., Smith, B. J., Menting, J. G., Margetts, M. B., McKern, N. M., & Lovrecz, G. O., Adams, T. E., Richards, K., Bentley, J. D., Trewhella, J., Ward, C. W., & Lawrence, M. C.(2009). Solution structure of ectodomains of the insulin receptor family: the ectodomain of the type 1 insulin-like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change. Journal of Molecular Biology, 394(5), 878-892. doi:10.1016/j.jmb.2009.10.011en_AU
dc.identifier.govdoc1495en_AU
dc.identifier.issn0022-2836en_AU
dc.identifier.issue5en_AU
dc.identifier.journaltitleJournal of Molecular Biologyen_AU
dc.identifier.pagination878-892en_AU
dc.identifier.urihttp://dx.doi.org/10.1016/j.jmb.2009.10.011en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/2854en_AU
dc.identifier.volume394en_AU
dc.language.isoenen_AU
dc.publisherElsevieren_AU
dc.subjectInsulinen_AU
dc.subjectGrowth factorsen_AU
dc.subjectSmall angle scatteringen_AU
dc.subjectReceptorsen_AU
dc.subjectLigandsen_AU
dc.subjectConformational changesen_AU
dc.titleSolution structure of ectodomains of the insulin receptor family: the ectodomain of the type 1 insulin-like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational changeen_AU
dc.typeJournal Articleen_AU
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