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

Emiko Uchikawa, Eunhee Choi, Guijun Shang, Hongtao Yu, Xiaochen Bai

Research output: Contribution to journalArticle

Abstract

Insulin 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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Aug 22 2019

Keywords

  • cryo-EM
  • human
  • insulin receptor
  • molecular biophysics
  • site 2
  • structural biology

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Activation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex. / Uchikawa, Emiko; Choi, Eunhee; Shang, Guijun; Yu, Hongtao; Bai, Xiaochen.

In: eLife, Vol. 8, 22.08.2019.

Research output: Contribution to journalArticle

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AU - Bai, Xiaochen

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N2 - Insulin 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.

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