Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands

  1. Jie Li
  2. Guijun Shang
  3. Yu-Ju Chen
  4. Chad A Brautigam
  5. Jen Liou
  6. Xuewu Zhang  Is a corresponding author
  7. Xiao-chen Bai  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States

Abstract

RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ligands but also co-receptors for activation, the mechanisms of which remain unclear due to lack of high-resolution structures of the ligand/co-receptor/receptor complexes. Here, we report cryo-EM structures of the extracellular region ternary complexes of GDF15/GFRAL/RET, GDNF/GFRα1/RET, NRTN/GFRα2/RET and ARTN/GFRα3/RET. These structures reveal that all the four ligand/co-receptor pairs, while using different atomic interactions, induce a specific dimerization mode of RET that is poised to bring the two kinase domains into close proximity for cross-phosphorylation. The NRTN/GFRα2/RET dimeric complex further pack into a tetrameric assembly, which is shown by our cell-based assays to regulate the endocytosis of RET. Our analyses therefore reveal both the common mechanism and diversification in the activation of RET by different ligands.

Data availability

Cryo-EM maps and the corresponding models of RET/co-receptors/ligands complexes have been deposited in EMDB and PDB under the accession codes EMD-20572/EMD-20573/EMD-20575/EMD-20576/EMD-20577/EMD-20578/EMD-20579/EMD-20580 and 6Q2J/6Q2N/6Q2O/6Q2R/6Q2S, respectively. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 5 and Figure 5-Supplement 1.

Article and author information

Author details

  1. Jie Li

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1059-280X
  2. Guijun Shang

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0187-7934
  3. Yu-Ju Chen

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chad A Brautigam

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6563-1338
  5. Jen Liou

    Department of Physiology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1546-3115
  6. Xuewu Zhang

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    xuewu.zhang@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3634-6711
  7. Xiao-chen Bai

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Xiaochen.Bai@UTSouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4234-5686

Funding

Cancer Prevention and Research Institute of Texas (RR160082)

  • Xiao-chen Bai

Welch Foundation (I-1944-20180324)

  • Xiao-chen Bai

National Institutes of Health (GM088197)

  • Xuewu Zhang

National Institutes of Health (R35GM130289)

  • Xuewu Zhang

Welch Foundation (I-1702)

  • Xuewu Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mark Lemmon, Yale University School of Medicine, United States

Publication history

  1. Received: April 12, 2019
  2. Accepted: September 18, 2019
  3. Accepted Manuscript published: September 19, 2019 (version 1)
  4. Version of Record published: September 25, 2019 (version 2)

Copyright

© 2019, Li 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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  1. Jie Li
  2. Guijun Shang
  3. Yu-Ju Chen
  4. Chad A Brautigam
  5. Jen Liou
  6. Xuewu Zhang
  7. Xiao-chen Bai
(2019)
Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands
eLife 8:e47650.
https://doi.org/10.7554/eLife.47650

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