Domain

Insulin-like growth factor-binding protein, IGFBP (IPR000867)

Short name: IGFBP-like

Overlapping homologous superfamilies

Domain relationships

None.

Description

Insulin-like Growth Factor Binding Proteins (IGFBP) are a group of vertebrate secreted proteins, which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGFs. The IGFBP family has six distinct subgroups, IGFBP-1 through 6, based on conservation of gene (intron-exon) organisation, structural similarity, and binding affinity for IGFs. Across species, IGFBP-5 exhibits the most sequence conservation, while IGFBP-6 exhibits the least sequence conservation. The IGFBPs contain inhibitor domain homologues, which are related to MEROPS protease inhibitor family I31 (equistatin, clan IX).

All IGFBPs share a common domain architecture (IPR000867:IPR000716). While the N-terminal (IPR000867, IGF binding protein domain), and the C-terminal (IPR000716, thyroglobulin type-1 repeat) domains are conserved across vertebrate species, the mid-region is highly variable with respect to protease cleavage sites and phosphorylation and glycosylation sites. IGFBPs contain 16-18 conserved cysteines located in the N-terminal and the C-terminal regions, which form 8-9 disulphide bonds [PMID: 11874691].

As demonstrated for human IGFBP-5, the N terminus is the primary binding site for IGF. This region, comprised of Val49, Tyr50, Pro62 and Lys68-Leu75, forms a hydrophobic patch on the surface of the protein [PMID: 9822601]. The C terminus is also required for high affinity IGF binding, as well as for binding to the extracellular matrix [PMID: 9725901] and for nuclear translocation [PMID: 7519375, PMID: 9660801] of IGFBP-3 and -5.

IGFBPs are unusually pleiotropic molecules. Like other binding proteins, IGFBP can prolong the half-life of IGFs via high affinity binding of the ligands. In addition to functioning as simple carrier proteins, serum IGFBPs also serve to regulate the endocrine and paracrine/autocrine actions of IGF by modulating the IGF available to bind to signalling IGF-I receptors [PMID: 12379487, PMID: 12379489]. Furthermore, IGFBPs can function as growth modulators independent of IGFs. For example, IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs [PMID: 11874691]. The binding of IGFBP to its putative receptor on the cell membrane may stimulate the signalling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBP-1 and -2, but not other IGFBPs, contain a C-terminal Arg-Gly-Asp integrin-binding motif. Thus, IGFBP-1 can also stimulate cell migration of CHO and human trophoblast cells through an action mediated by alpha 5 beta 1 integrin [PMID: 7504269]. Finally, IGFBPs transported into the nucleus (via the nuclear localisation signal) may also exert IGF-independent effects by transcriptional activation of genes.

This entry represents insulin-like growth factors (IGF-I and IGF-II), which bind to specific binding proteins in extracellular fluids with high affinity [PMID: 7680510, PMID: 1725860, PMID: 2480830]. These IGF-binding proteins (IGFBP) prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cells culture. They seem to alter the interaction of IGFs with their cell surface receptors. There are at least six different IGFBPs and they are structurally related. The following growth-factor inducible proteins are structurally related to IGFBPs and could function as growth-factor binding proteins [PMID: 1654338, PMID: 1309586], mouse protein cyr61 and its probable chicken homolog, protein CEF-10; human connective tissue growth factor (CTGF) and its mouse homolog, protein FISP-12; and vertebrate protein NOV.

GO terms

Biological Process

No terms assigned in this category.

Molecular Function

GO:0005520 insulin-like growth factor binding

Cellular Component

GO:0005576 extracellular region

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
PROSITE profiles
SMART
Pfam