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

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.

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.

Metrics

  • 11,084
    views
  • 1,682
    downloads
  • 160
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2014)
How IGF-1 activates its receptor
eLife 3:e03772.
https://doi.org/10.7554/eLife.03772

Share this article

https://doi.org/10.7554/eLife.03772

Further reading

    1. Structural Biology and Molecular Biophysics
    Surbhi Dhingra, Prachi M Chopade ... Janesh Kumar
    Research Article

    Kainate receptors are key modulators of synaptic transmission and plasticity in the central nervous system. Different kainate receptor isoforms with distinct spatiotemporal expressions have been identified in the brain. The GluK1-1 splice variant receptors, which are abundant in the adult brain, have an extra fifteen amino acids inserted in the amino-terminal domain (ATD) of the receptor resulting from alternative splicing of exon 9. However, the functional implications of this post-transcriptional modification are not yet clear. We employed a multi-pronged approach using cryogenic electron microscopy, electrophysiology, and other biophysical and biochemical tools to understand the structural and functional impact of this splice insert in the extracellular domain of GluK1 receptors. Our study reveals that the splice insert alters the key gating properties of GluK1 receptors and their modulation by the cognate auxiliary Neuropilin and tolloid-like (Neto) proteins 1 and 2. Mutational analysis identified the role of crucial splice residues that influence receptor properties and their modulation. Furthermore, the cryoEM structure of the variant shows that the presence of exon 9 in GluK1 does not affect the receptor architecture or domain arrangement in the desensitized state. Our study thus provides the first detailed structural and functional characterization of GluK1-1a receptors, highlighting the role of the splice insert in modulating receptor properties and their modulation.

    1. Structural Biology and Molecular Biophysics
    Aya Matsui, Cathy Spangler ... Eric Gouaux
    Research Article

    Chemical synapses are the major sites of communication between neurons in the nervous system and mediate either excitatory or inhibitory signaling. At excitatory synapses, glutamate is the primary neurotransmitter and upon release from presynaptic vesicles, is detected by postsynaptic glutamate receptors, which include ionotropic AMPA and NMDA receptors. Here, we have developed methods to identify glutamatergic synapses in brain tissue slices, label AMPA receptors with small gold nanoparticles (AuNPs), and prepare lamella for cryo-electron tomography studies. The targeted imaging of glutamatergic synapses in the lamella is facilitated by fluorescent pre- and postsynaptic signatures, and the subsequent tomograms allow for the identification of key features of chemical synapses, including synaptic vesicles, the synaptic cleft, and AuNP-labeled AMPA receptors. These methods pave the way for imaging brain regions at high resolution, using unstained, unfixed samples preserved under near-native conditions.