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

• Published in: Nature communications 2019-10, Vol.10 (1), p.4567-11, Article 4567
• Main Authors: Li, Jie, Choi, Eunhee, Yu, Hongtao, Bai, Xiao-chen
• Format: Article
• Language: English
• Subjects: 101/28; 631/45/612/1237; 631/535/1258/1259; 631/80/86/2368; Activation; Binding sites; Cryoelectron Microscopy; Dimerization; Dimers; Domains; Growth factors; Humanities and Social Sciences; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - isolation & purification; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - ultrastructure; Insulin-like growth factor II; Insulin-like growth factors; Kinases; Molecular Docking Simulation; Molecular structure; multidisciplinary; Protein Domains; Protein Multimerization; Protein-tyrosine kinase receptors; Receptor mechanisms; Receptor, IGF Type 1 - isolation & purification; Receptor, IGF Type 1 - metabolism; Receptor, IGF Type 1 - ultrastructure; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Recombinant Proteins - ultrastructure; Science; Science (multidisciplinary); Structure-Activity Relationship; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12564-0

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. The activation mechanism of type 1 insulin-like growth factor receptor (IGF1R) is not fully understood. Here, the authors determine the cryo-EM structure of full-length, IGF1-bound IGF1R in the active conformation, providing insights into how IGF1 triggers receptor activation.