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TitleActivation mechanism of the insulin receptor revealed by cryo-EM structure of the fully liganded receptor-ligand complex.
Journal, issue, pagesElife, Vol. 8, Year 2019
Publish dateAug 22, 2019
AuthorsEmiko Uchikawa / Eunhee Choi / Guijun Shang / Hongtao Yu / Xiao-Chen Bai /
PubMed AbstractInsulin 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 ...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.
External linksElife / PubMed:31436533 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.2 Å
Structure data

20522

6pxv

EMDB-20522, PDB-6pxv:
Cryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the extracellular region.
Method: EM (single particle) / Resolution: 3.2 Å

20523

6pxw

EMDB-20523, PDB-6pxw:
Cryo-EM structure of full-length insulin receptor bound to 4 insulin. 3D refinement was focused on the top part of the receptor complex.
Method: EM (single particle) / Resolution: 3.1 Å

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN/HORMONE / insulin receptor / insulin / SIGNALING PROTEIN-HORMONE complex

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