Structural and functional characteristics of the Val(44)Met insulin-like growth factor I missense mutation: Correlation with effects on growth and development

Denley, A; Wang, CXC; McNeil, KA; Walenkamp, MJE; van Duyvenvoorde, H; Wit, JM; Wallace, JC; Norton, RS; Karperien, M; Forbes, BE

Author(s): Denley, A; Wang, CXC; McNeil, KA; Walenkamp, MJE; van Duyvenvoorde, H; Wit, JM; Wallace, JC; Norton, RS; Karperien, M; Forbes, BE;
Details: Publication Year 2005-03,Volume 19,Issue #3,Page 711-721
Journal Title: MOLECULAR ENDOCRINOLOGY
Publication Type: Journal Article
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 (Va(l4)4Met 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, Val(44)Met 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 Val(44) as an essential residue involved in the IGF-IGF-1R interaction.
Publisher: ENDOCRINE SOC
Keywords: DIABETES-ASSOCIATED MUTATIONS; HIGH-AFFINITY BINDING; RECEPTOR-BINDING; IGF-I; BACKBONE DYNAMICS; MUTANT INSULIN; FACTOR (IGF)-I; ALPHA-HELIX; TYPE-1 IGF; A-CHAIN
Publisher's Version: https://doi.org/10.1210/me.2004-0409
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2005-03-01 12:00:00