Solution structure of ectodomains of the insulin receptor family: The ectodomain of the Type 1 insulin-like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change

Whitten, Andrew E., Smith, Brian J., Menting, John G., Margetts, Mai B., McKern, Neil M., Lovrecz, George O., Adams, Timothy E., Richards, Kim, Bentley, John D., Trewhella, Jill, Ward, Colin W. and Lawrence, Michael C. (2009) Solution structure of ectodomains of the insulin receptor family: The ectodomain of the Type 1 insulin-like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change. Journal of Molecular Biology, 394 5: 878-892. doi:10.1016/j.jmb.2009.10.011


Author Whitten, Andrew E.
Smith, Brian J.
Menting, John G.
Margetts, Mai B.
McKern, Neil M.
Lovrecz, George O.
Adams, Timothy E.
Richards, Kim
Bentley, John D.
Trewhella, Jill
Ward, Colin W.
Lawrence, Michael C.
Title Solution structure of ectodomains of the insulin receptor family: The ectodomain of the Type 1 insulin-like growth factor receptor displays asymmetry of ligand binding accompanied by limited conformational change
Journal name Journal of Molecular Biology   Check publisher's open access policy
ISSN 0022-2836
1089-8638
Publication date 2009-12-18
Sub-type Article (original research)
DOI 10.1016/j.jmb.2009.10.011
Volume 394
Issue 5
Start page 878
End page 892
Total pages 15
Place of publication Camden, London, U.K.
Publisher Academic Press
Language eng
Formatted abstract
The insulin receptor (IR) and the homologous Type 1 insulin-like growth factor receptor (IGF-1R) are cell-surface tyrosine kinase receptors that effect signaling within the respective pathways of glucose metabolism and normal human growth. While ligand binding to these receptors is assumed to result in a structural transition within the receptor ectodomain that then effects signal transduction across the cell membrane, little is known about the molecular detail of these events. Presented here are small-angle X-ray scattering data obtained from the IR and IGF-1R ectodomains in solution. We show that, in solution, the ectodomains of IR and IGF-1R have a domain disposition that is very similar to that seen in the crystal structure of the ectodomain of IR, despite the constituent domains being in relatively sparse contact and potentially mobile. We also show that the IGF-1R ectodomain is capable of binding up to three molecules of IGF-1 in solution, with surprisingly little apparent change in relative domain disposition compared to the apo form. While the observed 3:1 ligand-binding stoichiometry appears to contradict earlier explanations of the absence of a bell-shaped dose–response curve for IGF-1R in ligand displacement assays, it is readily understood in the context of the harmonic oscillator model of the negative cooperativity of ligand binding to IGF-1R. Taken together, our findings suggest that the structural movements within these receptors upon ligand binding are small and are possibly limited to local rotation of domains.
Keyword Type 1 insulin-like growth factor receptor
Insulin receptor
Insulin-like growth factor 1
Small-angle X-ray scattering
Negative cooperativity
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Tue, 20 Sep 2011, 22:35:35 EST by Dr Andrew Whitten on behalf of Institute for Molecular Bioscience