TY - JOUR
T1 - Structural basis of the activation of type 1 insulin-like growth factor receptor
AU - Li, Jie
AU - Choi, Eunhee
AU - Yu, Hongtao
AU - Bai, Xiao chen
N1 - Funding Information:
We thank Xuewu Zhang for his comments on our paper. Single particle cryo-EM data were collected at the University of Texas Southwestern Medical Center (UTSW) Cryo-Electron Microscopy Facility that is funded by a Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Support Award (RP170644). We thank D. Nicastro and D. Stoddard for facility access and data acquisition. X.B. is the Virginia Murchison Linthicum Scholar in Medical Research at UTSW. Research in his lab is supported in part by CPRIT (RR160082) and the Welch foundation (I-1944–20180324). H.Y is an Investigator with the Howard Hughes Medical Institute, and supported by grants from CPRIT (RP120717-P2 and RP160667-P2) and the Welch Foundation (I-1441).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-12564-0
DO - 10.1038/s41467-019-12564-0
M3 - Article
C2 - 31594955
AN - SCOPUS:85073062920
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4567
ER -