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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number4567
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

IGF Type 1 Receptor
insulin
Protein Subunits
Receptor Protein-Tyrosine Kinases
Dimerization
Chemical activation
Binding Sites
Cell Proliferation
activation
Insulin
Molecules
Membranes
Cell proliferation
Cell growth
Growth
Dimers
tyrosine
dimerization
molecules
dimers

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Structural basis of the activation of type 1 insulin-like growth factor receptor. / Li, Jie; Choi, Eunhee; Yu, Hongtao; Bai, Xiao chen.

In: Nature communications, Vol. 10, No. 1, 4567, 01.12.2019.

Research output: Contribution to journalArticle

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