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  Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): Implications for IGF and IGF-I receptor interactions.

Kalus, W., Zweckstetter, M., Renner, C., Sanchez, Y., Georgescu, J., Grol, M., et al. (1998). Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): Implications for IGF and IGF-I receptor interactions. EMBO Journal, 17(22), 6558-6572. doi:10.1093/emboj/17.22.6558.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-A41E-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-A421-9
Genre: Journal Article

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Kalus, W., Author
Zweckstetter, M.1, Author              
Renner, C., Author
Sanchez, Y., Author
Georgescu, J., Author
Grol, M., Author
Demuth, D., Author
Schumacher, R., Author
Dony, C., Author
Lang, K., Author
Holak, T. A., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: Binding proteins for insulin-like growth factors (IGFs) IGF-I and IGF-II, known as IGFBPs, control the distribution, function and activity of IGFs in various cell tissues and body fluids. Insulin-like growth factor-binding protein-5 (IGFBP-5) is known to modulate the stimulatory effects of IGFs and is the major IGF-binding protein in bone tissue. We have expressed two N-terminal fragments of IGFBP-5 in Escherichia coli; the first encodes the N-terminal domain of the protein (residues 1-104) and the second, mini-IGFBP-5, comprises residues Ala40 to Ile92. We show that the entire IGFBP-5 protein contains only one high-affinity binding site for IGFs, located in mini-IGFBP-5. The solution structure of mini-IGFBP-5, determined by nuclear magnetic resonance spectroscopy, discloses a rigid, globular structure that consists of a centrally located three-stranded anti-parallel beta-sheet. Its scaffold is stabilized further by two inside packed disulfide bridges. The binding to IGFs, which is in the nanomolar range, involves conserved Leu and Val residues localized in a hydrophobic patch on the surface of the IGFBP-5 protein. Remarkably, the IGF-I receptor binding assays of IGFBP-5 showed that IGFBP-5 inhibits the binding of IGFs to the IGF-I receptor, resulting in reduction of receptor stimulation and autophosphorylation. Compared with the full-length IGFBP-5, the smaller N-terminal fragments were less efficient inhibitors of the IGF-I receptor binding of IGFs.

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Language(s): eng - English
 Dates: 1998-11-16
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1093/emboj/17.22.6558
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Title: EMBO Journal
Source Genre: Journal
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Pages: - Volume / Issue: 17 (22) Sequence Number: - Start / End Page: 6558 - 6572 Identifier: -