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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"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). "
[Show abstract][Hide abstract] 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.
Full-text · Article · Feb 2015 · Journal of Cell Communication and Signaling
"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). "
[Show abstract][Hide abstract] 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.
Full-text · Article · Mar 2012 · Frontiers in Endocrinology
"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 . "
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma is mainly associated with viral hepatitis B and C. Activation of cell growth stimulator IGF-II gene is observed in tumor formation especially in viral associated hepatocellular carcinoma. Elevated IGF-II levels are indicator of increased risk for cholangiocellular and hepatocellular carcinomas through over saturation of IGF-II binding capacities with IGF receptors leading to cellular dedifferentiation. In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form. IGFBP-6 is a specific inhibitor of IGF-II actions. Affinity of IGFBPs with IGFs is controlled by post-translational modifications. Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II. O-glycosylation and phosphorylation operate the functional expression of cellular proteins, this switching on and off the protein expression is difficult to monitor in vivo. By using neural network based prediction methods, we propose that alternate O-β-GlcNAc modification and phosphorylation on Ser 204 control the binding of IGFBP-6 with IGF-II. This information may be used for developing new therapies by regulating IGFBP-6 assembly with IGF-II to minimize the risk of viral associated hepatocellular carcinoma. We can conclude that during HCV/HBV infection, O-β-GlcNAc of IGFBP-6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression which can lead to hepatocellular carcinoma. Furthermore, this site can be used for developing new therapies to control the IGF-II actions during viral infection to minimize the risk of hepatocellular carcinoma.