Structural Basis for the Regulation of Insulin-like Growth Factors by IGF Binding Proteins

Max Planck Institut für Biochemie, D-82152 Martinsried, Germany.
Structure (Impact Factor: 5.62). 02/2005; 13(1):155-67. DOI: 10.1016/j.str.2004.11.009
Source: PubMed


Insulin-like growth factor binding proteins (IGFBPs) control the extracellular distribution, function, and activity of IGFs. Here, we report an X-ray structure of the binary complex of IGF-I and the N-terminal domain of IGFBP-4 (NBP-4, residues 3-82) and a model of the ternary complex of IGF-I, NBP-4, and the C-terminal domain (CBP-4, residues 151-232) derived from diffraction data with weak definition of the C-terminal domain. These structures show how the IGFBPs regulate IGF signaling. Key features of the structures include (1) a disulphide bond ladder that binds to IGF and partially masks the IGF residues responsible for type 1 IGF receptor (IGF-IR) binding, (2) the high-affinity IGF-I interaction site formed by residues 39-82 in a globular fold, and (3) CBP-4 interactions. Although CBP-4 does not bind individually to either IGF-I or NBP-4, in the ternary complex, CBP-4 contacts both and also blocks the IGF-IR binding region of IGF-I.

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Available from: Magdalena Wisniewska, May 19, 2014
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    • "The sites of IGFBP-1 phosphorylation All IGFBPs contain structured N-and C-terminal domains and an unstructured central flexible linker domain. The structures of the N-and C-terminal domains of the IGFBPs have been extensively studied by nuclear magnetic resonance (Sitar et al. 2006; Siwanowicz et al. 2005) mass spectrometry (Neumann and Bach. 1999) and mutation analysis (Imai et al. 2000; Buckway et al. 2001; Yan et al. 2004). "
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    • "Importantly, the role of the IGFBP linker domain in IGF binding remains unclear. A significant proportion of the linker domain can be removed with little effect on overall binding affinity (Qin et al., 1998a) and individual N-and C-domains can bind IGFs with only a ∼10-fold lower affinity compared to intact IGFBPs (Payet et al., 2003; Siwanowicz et al., 2005). Experience from fragment-based drug design shows that linkage of two separate binding entities results in a molecule with a binding affinity that approximates the product of the two individual affinities (Hajduk and Greer, 2007). "
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    • "In the tissues, the release of IGFs from the IGFBPs can be modulated by three mechanisms; which function to decrease the affinity of the IGFBPs to the IGFs and act as a sustaining local source of IGFs to the IGF receptors. The first mechanism is association of the IGFBPs to the extracellular matrix (ECM) or specific cell membranes, second is the cleavage of the IGFBPs by specific proteases, and third is dephosphorylation [49]. "
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