Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor–ligand complex

eLife

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[1] Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States;Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States;Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States;Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States;Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States;

关键词: cryo-EM;    insulin receptor;    site 2;    Human;   

DOI  :  10.7554/eLife.48630

来源: publisher

【 摘 要 】

10.7554/eLife.48630.001Insulin signaling controls metabolic homeostasis. Here, we report the cryo-EM structure of full-length insulin receptor (IR) and insulin complex in the active state. This structure unexpectedly reveals that maximally four insulins can bind the ‘T’-shaped IR dimer at four distinct sites related by 2-fold symmetry. Insulins 1 and 1’ bind to sites 1 and 1’, formed by L1 of one IR protomer and α-CT and FnIII-1 of the other. Insulins 2 and 2’ bind to sites 2 and 2’ on FnIII-1 of each protomer. Mutagenesis and cellular assays show that both sites 1 and 2 are required for optimal insulin binding and IR activation. We further identify a homotypic FnIII-2–FnIII-2 interaction in mediating the dimerization of membrane proximal domains in the active IR dimer. Our results indicate that binding of multiple insulins at two distinct types of sites disrupts the autoinhibited apo-IR dimer and stabilizes the active dimer.

【 授权许可】

CC BY