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.
Highlights
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
Previous FRET analyses suggest a model in which IGF1 releases the autoinhibition and induces large structural rearrangements of IGF1R to bring the two intracellular kinase domains into proximity for receptor activation[8]. This release-of-autoinhibition model for IGF1R activation is supported by a crystal structure of the IGF1R ectodomain in complex with IGF1, showing that IGF1 binding to IGF1R breaks the autoinhibitory interactions between the L1 and FnIII-2′ domains in the apo state[7]
The IGF1binding site is formed by the L1 and CR domains (CRD) of one IGF1R protomer, and the α-CT′ and FnIII-1′ domains of the other
Summary
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. 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. Previous FRET analyses suggest a model in which IGF1 releases the autoinhibition and induces large structural rearrangements of IGF1R to bring the two intracellular kinase domains into proximity for receptor activation[8] This release-of-autoinhibition model for IGF1R activation is supported by a crystal structure of the IGF1R ectodomain in complex with IGF1, showing that IGF1 binding to IGF1R breaks the autoinhibitory interactions between the L1 and FnIII-2′ domains in the apo state[7]. This interaction plays an important role in receptor activation through stabilizing the active IGF1R dimer
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