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Structural basis of the activation of type 1 insulin-like growth factor receptor

Author

Listed:
  • Jie Li

    (University of Texas Southwestern Medical Center)

  • Eunhee Choi

    (University of Texas Southwestern Medical Center)

  • Hongtao Yu

    (University of Texas Southwestern Medical Center)

  • Xiao-chen Bai

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Type 1 insulin-like growth factor receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation, and can be activated by IGF1, IGF2, and insulin. Here, we report the cryo-EM structure of full-length IGF1R–IGF1 complex in the active state. This structure reveals that only one IGF1 molecule binds the Γ-shaped asymmetric IGF1R dimer. The IGF1-binding site is formed by the L1 and CR domains of one IGF1R protomer and the α-CT and FnIII-1 domains of the other. The liganded α-CT forms a rigid beam-like structure with the unliganded α-CT, which hinders the conformational change of the unliganded α-CT required for binding of a second IGF1 molecule. We further identify an L1–FnIII-2 interaction that mediates the dimerization of membrane-proximal domains of IGF1R. This interaction is required for optimal receptor activation. Our study identifies a source of the negative cooperativity in IGF1 binding to IGF1R and reveals the structural basis of IGF1R activation.

Suggested Citation

  • Jie Li & Eunhee Choi & Hongtao Yu & Xiao-chen Bai, 2019. "Structural basis of the activation of type 1 insulin-like growth factor receptor," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12564-0
    DOI: 10.1038/s41467-019-12564-0
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    Cited by:

    1. Junhee Park & Jie Li & John P. Mayer & Kerri A. Ball & Jiayi Wu & Catherine Hall & Domenico Accili & Michael H. B. Stowell & Xiao-chen Bai & Eunhee Choi, 2022. "Activation of the insulin receptor by an insulin mimetic peptide," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Junhong Kim & Na-Oh Yunn & Mangeun Park & Jihan Kim & Seongeun Park & Yoojoong Kim & Jeongeun Noh & Sung Ho Ryu & Yunje Cho, 2022. "Functional selectivity of insulin receptor revealed by aptamer-trapped receptor structures," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Francois Moreau & Nicholas S. Kirk & Fa Zhang & Vasily Gelfanov & Edward O. List & Martina Chrudinová & Hari Venugopal & Michael C. Lawrence & Veronica Jimenez & Fatima Bosch & John J. Kopchick & Rich, 2022. "Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Cristina M. Viola & Orsolya Frittmann & Huw T. Jenkins & Talha Shafi & Pierre Meyts & Andrzej M. Brzozowski, 2023. "Structural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Hyojin Kim & Yaoyao Fu & Ho Jeong Hong & Seong-Gyu Lee & Dong Sun Lee & Ho Min Kim, 2022. "Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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