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https://hdl.handle.net/2440/27484
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Type: | Journal article |
Title: | Structural and functional characteristics of the Val44Met insulin-like growth factor I missense mutation: Correlation with effects on growth and development |
Author: | Denley, A. Wang, C. McNeil, K. Walenkamp, M. van Duyvenvoorde, H. Wit, J. Wallace, J. Norton, R. Karperien, M. Forbes, B. |
Citation: | Molecular Endocrinology, 2005; 19(3):711-721 |
Publisher: | Endocrine Soc |
Issue Date: | 2005 |
ISSN: | 0888-8809 1944-9917 |
Statement of Responsibility: | Adam Denley, Chunxiao C. Wang, Kerrie A. McNeil, Marie J. E. Walenkamp, Hermine van Duyvenvoorde, Jan M. Wit, John C. Wallace, Raymond S. Norton, Marcel Karperien, and Briony E. Forbes |
Abstract: | We have previously described the phenotype resulting from a missense mutation in the IGF-I gene, which leads to expression of IGF-I with a methionine instead of a valine at position 44 (Val44Met IGF-I). 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 extracellular signal-regulated kinase 1/2 and Akt/protein kinase B 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 IGF-binding protein-2 (IGFBP-2), IGFBP-3, and IGFBP-6 with equal affinity to IGF-I, suggesting the maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by nuclear magnetic resonance 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. |
Keywords: | Fibroblasts Humans Insulin Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Receptor, IGF Type 1 Valine Methionine Insulin-Like Growth Factor I Proto-Oncogene Proteins Protein Isoforms Recombinant Proteins DNA Thymidine Ligands Blotting, Western Biological Assay Magnetic Resonance Spectroscopy Surface Plasmon Resonance DNA Mutational Analysis Immunoprecipitation Inhibitory Concentration 50 Signal Transduction Cell Proliferation Binding Sites Binding, Competitive Protein Binding Phosphorylation Dose-Response Relationship, Drug Phenotype Mutation Mutation, Missense Plasmids Models, Molecular Time Factors Proto-Oncogene Proteins c-akt Protein Serine-Threonine Kinases |
Description: | Copyright © 2005 by The Endocrine Society |
DOI: | 10.1210/me.2004-0409 |
Published version: | http://dx.doi.org/10.1210/me.2004-0409 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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