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Activation of the insulin receptor by insulin-like growth factor 2

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Listed:
  • Weidong An

    (University of Texas Southwestern Medical Center)

  • Catherine Hall

    (Columbia University)

  • Jie Li

    (University of Texas Southwestern Medical Center)

  • Albert Hung

    (Columbia University)

  • Jiayi Wu

    (Columbia University)

  • Junhee Park

    (Columbia University)

  • Liwei Wang

    (University of Texas Southwestern Medical Center)

  • Xiao-chen Bai

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

  • Eunhee Choi

    (Columbia University)

Abstract

Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin’s function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.

Suggested Citation

  • Weidong An & Catherine Hall & Jie Li & Albert Hung & Jiayi Wu & Junhee Park & Liwei Wang & Xiao-chen Bai & Eunhee Choi, 2024. "Activation of the insulin receptor by insulin-like growth factor 2," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46990-6
    DOI: 10.1038/s41467-024-46990-6
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    References listed on IDEAS

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    1. Eunhee Choi & Sotaro Kikuchi & Haishan Gao & Karolina Brodzik & Ibrahim Nassour & Adam Yopp & Amit G. Singal & Hao Zhu & Hongtao Yu, 2019. "Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    2. Neil M. McKern & Michael C. Lawrence & Victor A. Streltsov & Mei-Zhen Lou & Timothy E. Adams & George O. Lovrecz & Thomas C. Elleman & Kim M. Richards & John D. Bentley & Patricia A. Pilling & Peter A, 2006. "Structure of the insulin receptor ectodomain reveals a folded-over conformation," Nature, Nature, vol. 443(7108), pages 218-221, September.
    3. John G. Menting & Jonathan Whittaker & Mai B. Margetts & Linda J. Whittaker & Geoffrey K.-W. Kong & Brian J. Smith & Christopher J. Watson & Lenka Žáková & Emília Kletvíková & Jiří Jiráček & Shu Jin C, 2013. "How insulin engages its primary binding site on the insulin receptor," Nature, Nature, vol. 493(7431), pages 241-245, January.
    4. 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.
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