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https://hdl.handle.net/2440/27484
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dc.contributor.author | Denley, A. | - |
dc.contributor.author | Wang, C. | - |
dc.contributor.author | McNeil, K. | - |
dc.contributor.author | Walenkamp, M. | - |
dc.contributor.author | van Duyvenvoorde, H. | - |
dc.contributor.author | Wit, J. | - |
dc.contributor.author | Wallace, J. | - |
dc.contributor.author | Norton, R. | - |
dc.contributor.author | Karperien, M. | - |
dc.contributor.author | Forbes, B. | - |
dc.date.issued | 2005 | - |
dc.identifier.citation | Molecular Endocrinology, 2005; 19(3):711-721 | - |
dc.identifier.issn | 0888-8809 | - |
dc.identifier.issn | 1944-9917 | - |
dc.identifier.uri | http://hdl.handle.net/2440/27484 | - |
dc.description | Copyright © 2005 by The Endocrine Society | - |
dc.description.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. | - |
dc.description.statementofresponsibility | 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 | - |
dc.language.iso | en | - |
dc.publisher | Endocrine Soc | - |
dc.source.uri | http://dx.doi.org/10.1210/me.2004-0409 | - |
dc.subject | Fibroblasts | - |
dc.subject | Humans | - |
dc.subject | Insulin | - |
dc.subject | Mitogen-Activated Protein Kinase 1 | - |
dc.subject | Mitogen-Activated Protein Kinase 3 | - |
dc.subject | Receptor, IGF Type 1 | - |
dc.subject | Valine | - |
dc.subject | Methionine | - |
dc.subject | Insulin-Like Growth Factor I | - |
dc.subject | Proto-Oncogene Proteins | - |
dc.subject | Protein Isoforms | - |
dc.subject | Recombinant Proteins | - |
dc.subject | DNA | - |
dc.subject | Thymidine | - |
dc.subject | Ligands | - |
dc.subject | Blotting, Western | - |
dc.subject | Biological Assay | - |
dc.subject | Magnetic Resonance Spectroscopy | - |
dc.subject | Surface Plasmon Resonance | - |
dc.subject | DNA Mutational Analysis | - |
dc.subject | Immunoprecipitation | - |
dc.subject | Inhibitory Concentration 50 | - |
dc.subject | Signal Transduction | - |
dc.subject | Cell Proliferation | - |
dc.subject | Binding Sites | - |
dc.subject | Binding, Competitive | - |
dc.subject | Protein Binding | - |
dc.subject | Phosphorylation | - |
dc.subject | Dose-Response Relationship, Drug | - |
dc.subject | Phenotype | - |
dc.subject | Mutation | - |
dc.subject | Mutation, Missense | - |
dc.subject | Plasmids | - |
dc.subject | Models, Molecular | - |
dc.subject | Time Factors | - |
dc.subject | Proto-Oncogene Proteins c-akt | - |
dc.subject | Protein Serine-Threonine Kinases | - |
dc.title | Structural and functional characteristics of the Val44Met insulin-like growth factor I missense mutation: Correlation with effects on growth and development | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1210/me.2004-0409 | - |
pubs.publication-status | Published | - |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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