Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor

  1. Jie Li
  2. Jiayi Wu
  3. Catherine Hall
  4. Xiao-chen Bai  Is a corresponding author
  5. Eunhee Choi  Is a corresponding author
  1. The University of Texas Southwestern Medical Center, United States
  2. Columbia University, United States

Abstract

The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.

Data availability

All cryo-EM maps and models reported in this work has been deposited into EMDB/PDB database under the entry ID: PDB-8EYR and EMD-28693 (IGF1R/IGF1, symmetric conformation), PDB-8EYX and EMD-28723 (IR-3CS/insulin, asymmetric conformation 1), PDB-8EYY and EMD-28724 (IR-3CS/insulin, asymmetric conformation 2), and PDB-8EZ0 and EMD-28725 (IR-3CS/insulin, symmetric conformation). Source data are provided with this paper.

The following data sets were generated

Article and author information

Author details

  1. Jie Li

    Department of Biophysics, The 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. Jiayi Wu

    Department of Pathology and Cell Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9692-2864
  3. Catherine Hall

    Department of Pathology and Cell Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiao-chen Bai

    Department of Biophysics, The 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
  5. Eunhee Choi

    Department of Pathology and Cell Biology, Columbia University, New York, United States
    For correspondence
    ec3477@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3286-6477

Funding

National Institute of General Medical Sciences (R35GM142937)

  • Eunhee Choi

National Institute of General Medical Sciences (R01GM136976)

  • Xiao-chen Bai

National Institute of Diabetes and Digestive and Kidney Diseases (1P30DK132710)

  • Eunhee Choi

Welch Foundation (I-1944)

  • Xiao-chen Bai

Cancer Prevention and Research Institute of Texas (RP160082)

  • Xiao-chen Bai

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

Reviewing Editor

  1. Emily J Gallagher, Icahn School of Medicine at Mount Sinai

Publication history

  1. Received: June 22, 2022
  2. Accepted: November 16, 2022
  3. Accepted Manuscript published: November 22, 2022 (version 1)

Copyright

© 2022, 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. Jiayi Wu
  3. Catherine Hall
  4. Xiao-chen Bai
  5. Eunhee Choi
(2022)
Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor
eLife 11:e81286.
https://doi.org/10.7554/eLife.81286
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