期刊
JOURNAL OF CELL BIOLOGY
卷 217, 期 5, 页码 1643-1649出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201711047
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资金
- Deutsche Forschungsgemeinschaft [TRR83 TP18, FOR 2682, GS97]
- German Federal Ministry of Education and Research grant
- Christiane Nusslein-Volhard Foundation grant
- Canadian Institutes of Health Research
- Helmsley Postdoctoral Fellowship from Rockefeller University
Insulin receptor (IR) signaling plays a critical role in the regulation of metabolism and growth in multicellular organisms. IRs are unique among receptor tyrosine kinases in that they exist exclusively as covalent (a beta)(2) homodimers at the cell surface. Transmembrane signaling by the IR can therefore not be based on ligand-induced dimerization as such but must involve structural changes within the existing receptor dimer. In this study, using glycosylated full-length human IR reconstituted into lipid nanodiscs, we show by single-particle electron microscopy that insulin binding to the dimeric receptor converts its ectodomain from an inverted U-shaped conformation to a T-shaped conformation. This structural rearrangement of the ectodomain propagates to the transmembrane domains, which are well separated in the inactive conformation but come close together upon insulin binding, facilitating autophosphorylation of the cytoplasmic kinase domains.
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