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

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 ?-shaped asymmetric IGF1R dimer. The IGF1-binding site is formed by the L1 and CR domains of one IGF1R protomer and the ?-CT and FnIII-1 domains of the other. The liganded ?-CT forms a rigid beam-like structure with the unliganded ?-CT, which hinders the conformational change of the unliganded ?-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.

SUBMITTER: Li J

PROVIDER: S-EPMC6783537 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Li Jie J Choi Eunhee E Yu Hongtao H Bai Xiao-Chen XC

Nature communications 20191008 1

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 ligande ...[more]

PMID: 31594955

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