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Submitted on October 13, 2004
Accepted on November 22, 2004
School of Molecular and Biomedical Science, The University of Adelaide, Australia; Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; The Walter and Eliza Hall Institute of Medical Research, Vic 3050, Australia
* To whom correspondence should be addressed. E-mail: briony.forbes{at}adelaide.edu.au.
We have previously described the phenotype resulting from a missense mutation in the insulin-like growth factor I (IGF-I) gene, which leads to expression of IGF-I with a methionine instead of valine at position 44 (Val44Met IGF-I) (1). This mutation caused severe growth and mental retardation as well as deafness evident at birth and growth retardation in childhood, but is relatively well tolerated in adulthood. We have conducted a biochemical and structural analysis of Val44Met IGF-I to provide a molecular basis for the phenotype observed. Val44Met IGF-I exhibits a 90-fold decrease in type-1 IGF receptor (IGF-1R) binding compared with wild-type human IGF-I and only poorly stimulates autophosphorylation of the IGF-1R. The ability of Val44Met IGF-I to signal via the Erk1/2 and Akt/PKB pathways and to stimulate DNA-synthesis is correspondingly poorer. Binding or activation of both insulin receptor isoforms is not detectable even at micromolar concentrations. However, Val44Met IGF-I binds IGFBP-2, IGFBP-3 and IGFBP-6 with equal affinity to IGF-I suggesting maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by NMR confirms retention of near native structure with only local side chain disruptions, despite the significant loss of function. To our knowledge, our results provide the first structural study of a naturally occurring mutant human IGF-I associated with growth and developmental abnormalities and identifies Val44 as an essential residue involved in the IGF-IGF-1R interaction.
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