PROSITE documentation PDOC00194
Insulin-like growth factor binding protein (IGFBP) N-terminal domain signature and profile


The insulin-like growth factors (IGF-I and IGF-II) bind to specific binding proteins in extracellular fluids with high affinity [1,2,3]. 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. The IGFBP family comprises six proteins (IGFBP-1 to -6) that bind to IGFs with high affinity. The precursor forms of all six IGFBPs have secretory signal peptides. All IGFBPs share a common domain organization and also a high degree of similarity in their primary protein structure. The highest conservation is found in the N- and C-terminal cysteine-rich regions. Twelve conserved cysteines (ten in IGFBP-6) are found in the N-terminal domain, and six are found in the C-terminal domain. Both the N- and C-terminal domains participate in binding to IGFs, although the specific roles each of these domains in IGF binding have not been decisively established. In general, the strongest binding to IGFs is shown by amino-terminal fragments, which, however bind to IGF with 10- to 1000-fold lower affinity than full length IGFBPs. The central weakly conserved part (L domain) contains most of the cleavage sites for specific proteases [4,5].

The N-terminal domain is ~80 residues in length and has an L-like structure (see <PDB:1WQJ>). It can be divided into two subdomains that are connected by a short stretch of amino acids. The two subdomains are perpendicular to each other, creating the "L" shape for the whole N-terminal domain. The core of the first subdomain presents a novel fold stabilized by a short two-stranded β sheet and four disulfide bridges forming a disulfide bond ladder-like structure. The β sheet and disulfide bridges are all in one plane, making the structure appear flat from one side like a "palm" of a hand. The palm is extended with a "thumb" segment in various IGFBPs. The thumb segment consists of the very N-terminal residues and contains a consensus XhhyC motif, where h is a hydrophobic amino acid and y is positively charged. The second subdomain adopts a globular fold whose scaffold is secured by an inside packing of two cysteines bridges stabilized by a three-stranded β sheet [4,5].

The following growth-factor inducible proteins are structurally related to IGFBPs and could function as growth-factor binding proteins [6,7]:

  • Mouse protein cyr61 and its probable chicken homolog, protein CEF-10.
  • Human connective tissue growth factor (CTGF) and its mouse homolog, protein FISP-12.
  • Vertebrate protein NOV.

As a signature pattern we have used a conserved cysteine-rich region located in the N-terminal IGFBP domain. We also developed a profile that covers the entire IGFBP N-terminal domain.

Expert(s) to contact by email:

Landale E.C.

Last update:

January 2023 / Profile revised.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

IGFBP_N_2, PS51323; Insulin-like growth factor-binding protein (IGFBP) N-terminal domain profile  (MATRIX)

IGFBP_N_1, PS00222; Insulin-like growth factor-binding protein (IGFBP) N-terminal domain signature  (PATTERN)


1AuthorsRechler M.M.
TitleInsulin-like growth factor binding proteins.
SourceVitam. Horm. 47:1-114(1993).
PubMed ID7680510

2AuthorsShimasaki S. Ling N.
TitleIdentification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6).
SourceProg. Growth Factor Res. 3:243-266(1991).
PubMed ID1725860

3AuthorsClemmons D.R.
SourceTrends Endocrinol. Metab. 1:412-417(1990).

4AuthorsKalus W. Zweckstetter M. Renner C. Sanchez Y. Georgescu J. Grol M. Demuth D. Schumacher R. Dony C. Lang K. Holak T.A.
TitleStructure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): implications for IGF and IGF-I receptor interactions.
SourceEMBO J. 17:6558-6572(1998).
PubMed ID9822601

5AuthorsSiwanowicz I. Popowicz G.M. Wisniewska M. Huber R. Kuenkele K.-P. Lang K. Engh R.A. Holak T.A.
TitleStructural basis for the regulation of insulin-like growth factors by IGF binding proteins.
SourceStructure 13:155-167(2005).
PubMed ID15642270

6AuthorsBradham D.M. Igarashi A. Potter R.L. Grotendorst G.R.
TitleConnective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.
SourceJ. Cell Biol. 114:1285-1294(1991).
PubMed ID1654338

7AuthorsJoliot V. Martinerie C. Dambrine G. Plassiart G. Brisac M. Crochet J. Perbal B.
TitleProviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas.
SourceMol. Cell. Biol. 12:10-21(1992).
PubMed ID1309586

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