Abstract
The conventional definition of an insulin-like growth factor binding protein (IGFBP) is a protein whose major function is to act as a carrier for the insulin-like growth factors (IGFs). Based on this simple criterion, six IGFBPs that bind IGFs with high affinity, designated IGFBP-1 to -6 (33) have been identified to date from numerous biological systems. Although distinct structural differences exist among the six IGFBPs, a key conserved feature is the high number of cysteines (16–20 cysteines) found in IGFBPs. The clustering of the invariant cysteines at the amino (N)-terminal and carboxy (C)-terminal thirds (Fig. 1) of the proteins has led to models proposing that the N-terminus and C-terminus are two domains that, together, form the tertiary site necessary for high-affinity IGF binding. This striking structural feature, as well as the capacity of the proteins to bind IGFs with high affinity, have become the signature criteria for determining whether a protein is a member of the IGFBP family. However, this conventional dogma for IGFBPs has been challenged recently; a group of cysteine-rich proteins (8,28,45) has been identified whose N-terminus is homologous to the IGFBP N-terminal domain, but that deviate from the common IGFBP structure in the mid-region and C-terminus (Fig. 1). The relatedness of these proteins to the IGFBPs is substantiated further by the demonstration that they can also bind IGFs, albeit at a lower affinity than observed with IGFBP-1 to -6 (18,30). These findings suggest that the IGFBP family should be expanded to include those proteins that share significant domain conservation as well as demonstrable abilities to bind IGFs. Furthermore, it is proposed that these new IGFBP-related proteins, together with the conventional IGFBPs, constitute an IGFBP superfamily (18). The concept of a superfamily denotes that members are united by some common structural and functional features that are conserved through evolution. We suggest that the proteins of the IGFBP superfamily be subgrouped into those that bind IGF with high affinity (IGFBP-1 to -6), and those that bind IGF with low affinity (new members).
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Hwa, V. et al. (1999). The IGF Binding Protein Superfamily. In: Rosenfeld, R.G., Roberts, C.T. (eds) The IGF System. Contemporary Endocrinology, vol 17. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-712-3_14
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DOI: https://doi.org/10.1007/978-1-59259-712-3_14
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