Structural Basis for the Regulation of Insulin-like Growth Factors by IGF Binding Proteins
ABSTRACT 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.
Full-textDOI: · Available from: Magdalena Wisniewska, May 19, 2014
- SourceAvailable from: Madhulika B Gupta
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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). "
ABSTRACT: Fetal growth restriction (FGR) increases the risk of perinatal complications and predisposes the infant to developing metabolic, cardiovascular, and neurological diseases in childhood and adulthood. The pathophysiology underlying FGR remains poorly understood and there is no specific treatment available. Biomarkers for early detection are also lacking. The insulin-like growth factor (IGF) system is an important regulator of fetal growth. IGF-I is the primary regulator of fetal growth, and fetal circulating levels of IGF-I are decreased in FGR. IGF-I activity is influenced by a family of IGF binding proteins (IGFBPs), which bind to IGF-I and decrease its bioavailability. During fetal development the predominant IGF-I binding protein in fetal circulation is IGFBP-1, which is primarily secreted by the fetal liver. IGFBP-1 binds IGF-I and thereby inhibits its bioactivity. Fetal circulating levels of IGF-I are decreased and concentrations of IGFBP-1 are increased in FGR. Phosphorylation of human IGFBP-1 at specific sites markedly increases its binding affinity for IGF-I, further limiting IGF-I bioactivity. Recent experimental evidence suggests that IGFBP-1 phosphorylation is markedly increased in the circulation of FGR fetuses suggesting an important role of IGFBP-1 phosphorylation in the regulation of fetal growth. Understanding of the significance of site-specific IGFBP-1 phosphorylation and how it is regulated to contribute to fetal growth will be an important step in designing strategies for preventing, managing, and/or treating FGR. Furthermore, IGFBP-1 hyperphosphorylation at unique sites may serve as a valuable biomarker for FGR.Journal of Cell Communication and Signaling 02/2015; 9(2). DOI:10.1007/s12079-015-0266-x
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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). "
ABSTRACT: Insulin-like growth factor binding proteins (IGFBP-1 to -6) bind insulin-like growth factors-I and -II (IGF-I and IGF-II) with high affinity. These binding proteins maintain IGFs in the circulation and direct them to target tissues, where they promote cell growth, proliferation, differentiation, and survival via the type 1 IGF receptor. IGFBPs also interact with many other molecules, which not only influence their modulation of IGF action but also mediate IGF-independent activities that regulate processes such as cell migration and apoptosis by modulating gene transcription. IGFBPs-1 to -6 are structurally similar proteins consisting of three distinct domains, N-terminal, linker, and C-terminal. There have been major advances in our understanding of IGFBP structure in the last decade and a half. While there is still no structure of an intact IGFBP, several structures of individual N- and C-domains have been solved. The structure of a complex of N-BP-4:IGF-I:C-BP-4 has also been solved, providing a detailed picture of the structural features of the IGF binding site and the mechanism of binding. Structural studies have also identified features important for interaction with extracellular matrix components and integrins. This review summarizes structural studies reported so far and highlights features important for binding not only IGF but also other partners. We also highlight future directions in which structural studies will add to our knowledge of the role played by the IGFBP family in normal growth and development, as well as in disease.Frontiers in Endocrinology 03/2012; 3:38. DOI:10.3389/fendo.2012.00038
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- "The three dimensional structure of IGF-1 has been determined by both NMR spectroscopy (Cooke et al., 1991; Sato et al., 1993) and X-ray crystallography method (Brzozowski et al., 2002; Siwanowicz et al., 2005; Vajdos et al., 2001; Zeslawski et al., 2001). The B-and A-domains are similar to those observed in the crystal structure of insulin (Baker et al., 1988; Bentley et al., 1976). "
ABSTRACT: The identification in the 1950s of insulin, an essential carbohydrate regulatory hormone, as consisting of not one but two peptide chains linked by three disulfide bonds in a distinctive pattern was a milestone in peptide chemistry. When it was later found that relaxin also possessed a similar overall structure, the term 'insulin superfamily' was coined. Use of methods of conventional protein chemistry followed by recombinant DNA and more recently bioinformatics has led to the recognition that insulin is the precursor to a large protein superfamily that extends beyond the human. Insulin-like peptides are found not only in vertebrates such as mammals, birds, reptiles, amphibians but also in the invertebrates such as chordates, molluscs and insects. All superfamily members share the distinctive insulin structural motif. In the human, there exists ten members of the superfamily, each of which are expressed on the ribosome as a single-chain pre-prohormone that undergoes proteolytic processing to produce eight double-chain mature proteins and two single-chain forms. The six cysteine residues that form the three insulin disulfide cross-links - one intramolecular within the A-chain and two intermolecular between that A- and B-chains - are absolutely conserved across all members of the superfamily. They are responsible for imparting a similar overall tertiary structure. The human insulin superfamily members have each evolved to assume remarkably distinctive biological functions ranging from glucose homeostasis to neuroendocrine actions. That such diversity is contained within a modestly sized superfamily is testament to efficiency of the insulin structural motif as an evolutionary template.Vitamins & Hormones 02/2009; 80:1-31. DOI:10.1016/S0083-6729(08)00601-8 · 1.78 Impact Factor