Structure of the insulin receptor ectodomain reveals a folded-over conformation
| Autor: | M. J. Frenkel, V. Chandana Epa, Timothy E. Adams, Elizabeth Da Silva, Peter A. Hoyne, John D. Bentley, Kellie Cartledge, Christine P. Robinson, Meizhen Lou, Colin W. Ward, Violet Stoichevska, T. C. Elleman, Neil M. McKern, George O. Lovrecz, Jennifer L. Lewis, Tam Pham, Ross Fernley, Sonia E. Sankovich, Michael C. Lawrence, Lindsay G. Sparrow, Victor A. Streltsov, Kim M. Richards, Patricia A. Pilling |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Protein Folding Multidisciplinary biology Signal Induction Fibronectin type III domain Crystallography X-Ray Receptor tyrosine kinase Receptor Insulin Protein Structure Tertiary Insulin receptor Immunoglobulin Fab Fragments Microscopy Electron Growth factor receptor Ectodomain Biochemistry biology.protein Biophysics 5-HT5A receptor Binding site Protein Structure Quaternary Dimerization |
| Zdroj: | Nature. 443(7108) |
| ISSN: | 1476-4687 |
| Popis: | The first report of the crystal structure of the whole insulin receptor ectodomain dimer reveals how its multiple domains are organized. The structure also identifies the elusive second binding site on the receptor, and suggests how the high-affinity insulin–receptor complex, which leads to signal induction, is generated. The structure as now published differs dramatically from previous versions based on reconstructions from cryoelectron microscopy data. The crystal structure of the entire ectodomain dimer of the insulin receptor A isoform details the domain arrangement and defines the two sites for insulin binding. The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis1, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development2. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation3. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide5. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models6. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed7. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|