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https://hdl.handle.net/2440/44570
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Type: | Journal article |
Title: | Cooperativity of the N- and C-terminal domains of insulin-like growth factor (IGF) binding protein 2 in IGF binding |
Author: | Kuang, Z. Yao, S. McNeil, K. Thompson, J. Bach, L. Forbes, B. Wallace, J. Norton, R. |
Citation: | Biochemistry, 2007; 46(48):13720-13732 |
Publisher: | Amer Chemical Soc |
Issue Date: | 2007 |
ISSN: | 0006-2960 1520-4995 |
Statement of Responsibility: | Zhihe Kuang, Shenggen Yao, Kerrie A. McNeil, Julian A. Thompson, Leon A. Bach, Briony E. Forbes, John C. Wallace, and Raymond S. Norton |
Abstract: | A family of six insulin-like growth factor (IGF) binding proteins (IGFBP-1-6) binds IGF-I and IGF-II with high affinity and thus regulates their bioavailability and biological functions. IGFBPs consist of N- and C-terminal domains, which are highly conserved and cysteine-rich, joined by a variable linker domain. The role of the C-domain in IGF binding is not completely understood in that C-domain fragments have very low or even undetectable IGF binding affinity, but loss of the C-domain dramatically disrupts IGF binding by IGFBPs. We recently reported the solution structure and backbone dynamics of the C-domain of IGFBP-2 (C-BP-2) and identified a pH-dependent heparin binding site [Kuang, Z., Yao, S., Keizer, D. W., Wang, C. C., Bach, L. A., Forbes, B. E., Wallace, J. C., and Norton, R. S. (2006) Structure, dynamics and heparin binding of the C-terminal domain of insulin-like growth factor-binding protein-2 (IGFBP-2), J. Mol. Biol. 364, 690-704]. Here, we have analyzed the molecular interactions among the N-domain of IGFBP-2 (N-BP-2), C-BP-2, and IGFs using cross-linking and nuclear magnetic resonance (NMR) spectroscopy. The binding of C-BP-2 to the IGF-I·N-BP-2 binary complex was significantly stronger than the binding of C-BP-2 to IGF-I alone, switching from intermediate exchange to slow exchange on the NMR time scale. A conformational change or stabilization of the IGF-I Phe49-Leu54 region and the Phe49 aromatic ring upon binding to the N-domains, as well as an interdomain interaction between N-BP-2 and C-BP-2 (which is also detectable in the absence of ligand), may contribute to this cooperativity in IGF binding. Glycosaminoglycan binding by IGFBPs can affect their IGF binding although the effects appear to differ among different IGFBPs; here, we found that heparin bound to the IGF-I·N-BP-2·C-BP-2 ternary complex, but did not cause it to dissociate. |
Keywords: | Humans Insulin-Like Growth Factor I Insulin-Like Growth Factor Binding Protein 2 DNA Primers Nuclear Magnetic Resonance, Biomolecular Base Sequence Protein Binding Models, Molecular |
Description: | Copyright © 2007 American Chemical Society |
DOI: | 10.1021/bi701251d |
Published version: | http://pubs.acs.org/cgi-bin/article.cgi/bichaw/2007/46/i48/pdf/bi701251d.pdf |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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