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    Cumulative mutagenesis of the basic residues in the 201-218 region of insulin-like growth factor (IGF)-binding protein-5 results in progressive loss of both IGF-I binding and inhibition of IGF-I biological action.

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    eResearch%204383.pdf (535.0Kb)
    Date
    2006-01-31
    Author
    Allan, Gordon J.
    Tonner, Elizabeth
    Szymanowska, Malgorzata
    Shand, John H.
    Kelly, Sharon M.
    Phillips, Kirsten
    Clegg, Roger A.
    Gow, Iain F.
    Beattie, James
    Flint, David J.
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    Citation
    Allan, G., Tonner, E., Szymanowska, M., Shand, J., Kelly, S., Phillips, K., Clegg, R., Gow, I., Beattie, J. & Flint, D. (2006) Cumulative mutagenesis of the basic residues in the 201-218 region of insulin-like growth factor (IGF)-binding protein-5 results in progressive loss of both IGF-I binding and inhibition of IGF-I biological action., Endocrinology, vol. 147, , pp. 338-349,
    Abstract
    We have reported previously that mutation of two conserved nonbasic amino acids (G203 and Q209) within the highly basic 201-218 region in the C-terminal domain of IGF-binding protein-5 (IGFBP-5) decreases binding to IGFs. This study reveals that cumulative mutagenesis of the 10 basic residues in this region, to create the C-Term series of mutants, ultimately results in a 15-fold decrease in the affinity for IGF-I and a major loss in heparin binding. We examined the ability of mutants to inhibit IGF-mediated survival of MCF-7 cells and were able to demonstrate that this depended not only upon the affinity for IGF-I, but also the kinetics of this interaction, because IGFBP-5 mutants with similar affinity constants (K(D)) values, but with different association (Ka) and dissociation (Kd) rate values, had markedly different inhibitory properties. In contrast, the affinity for IGF-I provided no predictive value in terms of the ability of these mutants to enhance IGF action when bound to the substratum. Instead, these C-Term mutants appeared to enhance the actions of IGF-I by a combination of increased dissociation of IGF-IGFBP complexes from the substratum, together with dissociation of IGF-I from IGFBP-5 bound to the substratum. These effects of the IGFBPs were dependent upon binding to IGF-I, because a non-IGF binding mutant (N-Term) was unable to inhibit or enhance the actions of IGF-I. These results emphasize the importance of the kinetics of association/dissociation in determining the enhancing or inhibiting effects of IGFBP-5 and demonstrate the ability to generate an IGFBP-5 mutant with exclusively IGF-enhancing activity.
    Official URL
    http://press.endocrine.org/doi/full/10.1210/en.2005-0582
    URI
    https://eresearch.qmu.ac.uk/handle/20.500.12289/4383
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    • Dietetics, Nutrition and Biological Sciences

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