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

Jie Li, Eunhee Choi (), Hongtao Yu () and Xiao-chen Bai ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12564-0

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