Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex
- University of Texas Southwestern Medical Center, United States
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
Abstract
Insulin signaling controls metabolic homeostasis. Here, we report the cryo-EM structure of full-length insulin receptor (IR) and insulin complex in the active state. This structure unexpectedly reveals that maximally 4 insulins can bind the 'T'-shaped IR dimer at 4 distinct sites related by 2-fold symmetry. Insulins 1 and 1' bind to sites 1 and 1', formed by L1 of one IR protomer and α-CT and FnIII-1 of the other. Insulins 2 and 2' bind to sites 2 and 2' on FnIII-1 of each protomer. Mutagenesis and cellular assays show that both sites 1 and 2 are required for optimal insulin binding and IR activation. We further identify a homotypic FnIII-2-FnIII-2 interaction in mediating the dimerization of membrane proximal domains in the active IR dimer. Our results indicate that binding of multiple insulins at two distinct types of sites disrupts the autoinhibited apo-IR dimer and stabilizes the active dimer.
Data availability
Cryo-EM maps and the corresponding bulit models of insulin receptor/insulin complex have been deposited in EMDB and PDB under the accession codes EMD-20522/EMD-20523 and 6PXV/6PXW, respectively.All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure2, Figure 3, Figure 4, Figure1-Supplement 1, Figure3-Supplement 2 and Figure3-Supplement 3
Article and author information
Author details
Funding
Cancer Preventation and Research Institute of Texas (RR160082)
- Xiao-chen Bai
Welch Foundation (I-1944)
- Xiao-chen Bai
Cancer Preventation and Research Institute of Texas (RP120717-P2)
- Hongtao Yu
Cancer Preventation and Research Institute of Texas (RP160667-P2)
- Hongtao Yu
Howard Hughes Medical Institute
- Hongtao Yu
Welch Foundation (I-1441)
- Hongtao Yu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Axel T Brunger, Stanford University, United States
Version history
- Received: May 21, 2019
- Accepted: August 21, 2019
- Accepted Manuscript published: August 22, 2019 (version 1)
- Version of Record published: September 3, 2019 (version 2)
- Version of Record updated: September 9, 2019 (version 3)
Copyright
© 2019, Uchikawa 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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Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex
eLife 8:e48630.
https://doi.org/10.7554/eLife.48630
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