1. Structural Biology and Molecular Biophysics
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How IGF-1 activates its receptor

  1. Jennifer M Kavran
  2. Jacqueline M McCabe
  3. Patrick O Byrne
  4. Mary Katherine Connacher
  5. Zhihong Wang
  6. Alexander Ramek
  7. Sarvenaz Sarabipour
  8. Yibing Shan
  9. David E Shaw
  10. Kalina Hristova
  11. Philip A Cole
  12. Daniel Leahy  Is a corresponding author
  1. Johns Hopkins University School of Medicine, United States
  2. University of the Sciences, United States
  3. D.E. Shaw Research, United States
  4. Johns Hopkins University, United States
  5. Columbia University, United States
  6. Johns Hopkins, United States
Research Article
  • Cited 59
  • Views 7,228
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Cite this article as: eLife 2014;3:e03772 doi: 10.7554/eLife.03772

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.

Article and author information

Author details

  1. Jennifer M Kavran

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  2. Jacqueline M McCabe

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Patrick O Byrne

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Mary Katherine Connacher

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. Zhihong Wang

    University of the Sciences, Philadelphia, United States
    Competing interests
    No competing interests declared.
  6. Alexander Ramek

    D.E. Shaw Research, New York, United States
    Competing interests
    No competing interests declared.
  7. Sarvenaz Sarabipour

    Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  8. Yibing Shan

    D.E. Shaw Research, New York, United States
    Competing interests
    No competing interests declared.
  9. David E Shaw

    D.E. Shaw Research, New York, United States
    Competing interests
    No competing interests declared.
  10. Kalina Hristova

    Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  11. Philip A Cole

    Columbia University, New York, United States
    Competing interests
    Philip A Cole, Reviewing editor, eLife.
  12. Daniel Leahy

    Johns Hopkins, Baltimore, United States
    For correspondence
    dleahy@jhmi.edu
    Competing interests
    No competing interests declared.

Reviewing Editor

  1. John Kuriyan, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: June 23, 2014
  2. Accepted: September 23, 2014
  3. Accepted Manuscript published: September 25, 2014 (version 1)
  4. Version of Record published: October 28, 2014 (version 2)

Copyright

© 2014, Kavran et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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