The majority (approximately 98%) of circulating IGFs are bound to one of a six-membered family of IGF-binding proteins, IGFBPs. Of these, IGFBP-3 is the most abundant and therefore binds most of the circulating IGFs. Table 1 lists some of the characteristics of these proteins, each encoded by a separate gene. Figure 1 shows the general structural features of this family of proteins. The IGFBPs have three domains of approximately the same size, the N- and C-domain and the L (linker)-domain. Highly conserved disulfide bonds in these cysteine-rich proteins occur within the two terminal domains giving these parts of the molecule the structural rigidity necessary to form, together, a high-affinity ligand binding domain for one or both IGFs (see Table 1). The mid-region or L-domains of the IGBPs share less than 15% similarity with each other. Considerable posttranslational modification of the residues within this region, such as glycosylation and phosphorylation occurs. These alterations in the proteins probably affect their stability and susceptibility to proteolysis and therefore their half-life in the circulation, but have little or no effect on ligand binding. There is no known function of this region beyond serving as a hinge between the N- and C-domains and thereby promoting maximum ligand binding.
Table1. IGF Binding Proteins
Fig1. Structure of insulin-like growth factor binding proteins (IGFBPs). The six members of the IGFBP family range from 216 to 289 amino acids long (see Table1). They are divided into three domains of about the same size. IGF binding requires both the N- and C-domain as shown by the shaded areas in each of these two domains. There are 12 conserved cysteine residues (purple lines) in the N-domain and 6 in the C-domain. These form disulfide bonds, some of which are depicted by the horizontal lines above the rectangle representing the peptide. IGFBP6 lacks two of the cysteines in the N-terminal portion of the N-domain, but retains the disulfide bonds in the ligand binding region. The L (linker)-domain (green) is not conserved among the members of the family. It undergoes considerable posttranslational modification as indicated. The C-domain, in addition to contributing to IGF-binding, also has interactions with several other proteins in addition to IGF. It also appears to be the site of IGF-independent activities.
Through the interactions of their C-domains with extracellular proteins such as proteoglycans, IGFBPs can either inhibit, by restraining receptor binding or enhance, by raising the effective pericellular concentration of the IGF ligand, the actions of the IGFs (see Table 1). In addition, IGFBPs appear to have IGF-independent actions, attributed to certain protein binding sites, such as those for caveolin and collagen (cell surface association) and fibrinogen and plasminogen (wound healing). A nuclear localization signal and interactions with nuclear receptors such as VDR (vitamin D receptor), RARα (retinoic acid receptor α), and PPARγ (peroxisome proliferator-activated receptor γ) suggests the possibility of the involvement of IGFBPs with nuclear functions, including gene transcription.
