How IGF-1 activates its receptor

Jennifer M. Kavran, Jacqueline M. McCabe, Patrick O. Byrne, Mary Katherine Connacher, Zhihong Wang, Alexander Ramek, Sarvenaz Sarabipour, Yibing Shan, David E. Shaw, Kalina Hristova, Philip A. Cole, Daniel J. Leahy

Research output: Contribution to journalArticle

Abstract

The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation.

Original languageEnglish (US)
Article numbere03772
JournaleLife
Volume3
DOIs
StatePublished - Sep 25 2014

Keywords

  • FRET
  • IGF1 receptor
  • biochemistry
  • biophysics
  • human
  • kinetics
  • mechanism
  • structural biology

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Kavran, J. M., McCabe, J. M., Byrne, P. O., Connacher, M. K., Wang, Z., Ramek, A., Sarabipour, S., Shan, Y., Shaw, D. E., Hristova, K., Cole, P. A., & Leahy, D. J. (2014). How IGF-1 activates its receptor. eLife, 3, [e03772]. https://doi.org/10.7554/eLife.03772