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dc.contributor.authorAllan, Gordon J.
dc.contributor.authorTonner, Elizabeth
dc.contributor.authorSzymanowska, Malgorzata
dc.contributor.authorShand, John H.
dc.contributor.authorKelly, Sharon M.
dc.contributor.authorPhillips, Kirsten
dc.contributor.authorClegg, Roger A.
dc.contributor.authorGow, Iain F.
dc.contributor.authorBeattie, James
dc.contributor.authorFlint, David J.
dc.date.accessioned2018-06-29T21:34:12Z
dc.date.available2018-06-29T21:34:12Z
dc.date.issued2006-01-31
dc.identifierER4383
dc.identifier.citationAllan, 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,
dc.identifier.issn0013-7227
dc.identifier.urihttp://press.endocrine.org/doi/full/10.1210/en.2005-0582
dc.identifier.urihttps://eresearch.qmu.ac.uk/handle/20.500.12289/4383
dc.description.abstractWe 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.
dc.format.extent338-349
dc.publisherEndocrine Society
dc.relation.ispartofEndocrinology
dc.titleCumulative 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.
dc.typearticle
dcterms.accessRightsrestricted
dc.description.facultysch_die
dc.description.volume147
dc.identifier.doihttp://10.1210/en.2005-0582
dc.description.ispublishedpub
dc.description.eprintid4383
rioxxterms.typearticle
refterms.dateAccepted2005-09-29
qmu.authorGow, Iain F.
dc.description.statuspub
dc.description.number1


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