Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2001 Jul 16;20(14):3638-44.
doi: 10.1093/emboj/20.14.3638.

The interaction of insulin-like growth factor-I with the N-terminal domain of IGFBP-5

W Zesławski  1 , H G Beisel, M Kamionka, W Kalus, R A Engh, R Huber, K Lang, T A Holak
Affiliations

The interaction of insulin-like growth factor-I with the N-terminal domain of IGFBP-5

W Zesławski et al. EMBO J. .

Abstract

Insulin-like growth factors (IGFs) are key regulators of cell proliferation, differentiation and transformation, and are thus pivotal in cancer, especially breast, prostate and colon neoplasms. They are also important in many neurological and bone disorders. Their potent mitogenic and anti-apoptotic actions depend primarily on their availability to bind to the cell surface IGF-I receptor. In circulation and interstitial fluids, IGFs are largely unavailable as they are tightly associated with IGF-binding proteins (IGFBPs) and are released after IGFBP proteolysis. Here we report the 2.1 A crystal structure of the complex of IGF-I bound to the N-terminal IGF-binding domain of IGFBP-5 (mini-IGFBP-5), a prototype interaction for all N-terminal domains of the IGFBP family. The principal interactions in the complex comprise interlaced hydrophobic side chains that protrude from both IGF-I and the IGFBP-5 fragment and a surrounding network of polar interactions. A solvent-exposed hydrophobic patch is located on the IGF-I pole opposite to the mini-IGFBP-5 binding region and marks the IGF-I receptor binding site.

PubMed Disclaimer

Figures

None
Fig. 1. Sequence and structure alignment (A) of IGFs and single-chain insulin (SCI). Residues that make contacts with mini-IGFBP-5 within 4 Å are highlighted in magenta; residues responsible for binding to IGF-1R are in red and residues in green showed no electron density. (B) Mini-IGFBP-5 with the corresponding N-terminal domains of IGFBP-3, IGFBP-rP1 and IGFBP-rP2; consensus amino acid residues are shown above the sequences; conserved residues are indicated by blue letters. Residues that interact with IGF-I (within 4 Å) are highlighted in magenta. The mini-IGFBP-5 construct had additional Gly and Ser residues from the cloning vector at the N-terminus; residues in green showed no electron density.
None
Fig. 2. The overall structure of the IGF-I (green)–mini-IGFBP-5 (black) complex. (A) A heavy atom plot. Residues shown in magenta constitute the primary binding sites for interaction with mini-IGFBP-5. Residues in red are determinants for binding to IGF-1R. The first N- and last C-terminal residues are shown in brown and blue, respectively. (B) Interface of the IGF-I–mini-IGFBP-5 complex interactions. Mini-IGFBP-5 is shown as a surface plot (residues in red, negatively charged; blue, positive; white, neutral), IGF is shown in blue. Side chains of the primary binding residues of IGF for mini-IGFBP-5 are shown. (C) Ribbon plot of IGF (green)–mini-IGFBP-5 (grey) with interface residues that form hydrogen bonds highlighted (blue). The interface hydrophobic residues are shown in yellow.
None
Fig. 3. Stereo figure of the 2Fo – Fc electron density map contoured at 1.0σ over the mean at the mini-IGFBP-5–IGF-I interface. The IGF-I peptide segment is at the left, including the interfacial Phe16, seen here packed against two segments of mini-IGFBP-5, between Val49 (below) and Cys60 (above).
See this image and copyright information in PMC

References

    1. Abrahams J.P. and Leslie,A.G.W. (1996) Methods used in the structure determination of bovine mitochondrial F1 ATPase. Acta Crystallogr. D, 52, 30–42. - PubMed
    1. Adams M.J., Blundell,T.L., Dodson,E.J., Vijazan,M., Baker,E.N., Hodgkin,D.C., Rimm,B. and Sheat,S. (1969) Structure of rhombohedral 2 zinc insulin crystals. Nature, 224, 491–495.
    1. Bach L.A., Hsieh,S., Sakano,K., Fujiwara,H., Perdue,J.F. and Rechler,M.M. (1993) Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1–6. J. Biol. Chem., 268, 9246–9254. - PubMed
    1. Baxter R.C., Bayne,M.L. and Cascieri,M.A. (1992) Structural determinants for binary and ternary complex formation between insulin-like growth factor-I (IGF-I) and IGF binding protein-3. J. Biol. Chem., 267, 60–65. - PubMed
    1. Bayne M.L., Applebaum,J., Chicchi,G.G., Miller,R.E. and Cascieri,M.A. (1990) The roles of tyrosine 24, 31, and 60 in the high affinity binding of insulin-like growth factor-I and the type 1 insulin-like growth factor receptor. J. Biol. Chem., 265, 15648–15652. - PubMed

Publication types

MeSH terms

Substances

Associated data