Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor
- The University of Texas Southwestern Medical Center, United States
- 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.
Article and author information
Author details
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
- Emily J Gallagher, Icahn School of Medicine at Mount Sinai
Version history
- Received: June 22, 2022
- Preprint posted: July 6, 2022 (view preprint)
- Accepted: November 16, 2022
- Accepted Manuscript published: November 22, 2022 (version 1)
- Version of Record published: December 8, 2022 (version 2)
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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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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