Structure and function of human insulin-like growth factor 1

Raj Gill*, Pierre De Meyts, Jim Pitts, Chandra Verma, Axel Wollmer, Stephen Wood

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)peer-review


Insulin-like growth factor-1 (IGF-1) is a 70 amino acid single-chain serum protein which has many growth-promoting activities. IGF-1 is structurally homologous to insulin and the IGF-1 gene is thought to have arisen from a duplication of the insulin gene approximately 600 million years ago. The related insulin-like growth factor 2 (IGF-2) is thought to have diverged from IGF1 approximately 300 million years ago. The IGFs are able to bind to more than one receptor; IGF-1 binds with highest affinity to the IGF-1 receptor, a tyrosine kinase which is structurally homologous to the insulin receptor which IGF-1 binds with lower affinity. Although IGF-2 also binds to the IGF-1 and insulin receptors, it binds with highest affinity to the IGF-2 receptor which is quite different, being synonymous with the cation independent mannose-6-phosphate receptor. The growth promoting effects of insulin and the metabolic activities of the IGFs are thought to arise from cross-binding to each other’s receptors. Ligand-receptor specificity in the insulin and IGF systems must be determined by the sequence dfferences between the ligands and within the common binding sites of their receptors. Studies on insulin analogues over the last thirty years indicate that a conformational change takes place in the molecule upon binding to the insulin receptor.

This review describes recent work, utilizing a range of techniques and expertise, undertaken to determine whether an analogous conformational change also takes place upon IGF-1 binding to the IGF-1 receptor. We describe the expression and purification of the two disulphide isomers of human IGF-1 secreted from yeast. Isocratic reversed-phase chromatography was employed to ensure complete separation of the isomers. We also describe a 'mini IGF-1' in which the C-region has been removed by site-directed mutagenesis and in which Pro28 and Gly42 are connected by a peptide bond. This molecule is an IGF-1 analogue of single-chain insulin. The properties of mini IGF-I are compared and contrasted with those of wild-type IGF-1 and another C-region mutant in which a 4-Gly bridge spans the 8Å distance between Lys27 and Ala38; 4-Gly IGF-1. We present equilibrium binding data at the human IGF-1 receptor overexpressed at the surface of stably transfected baby hamster kidney (BHK) cells. The IGF-I molecules were also assayed for their ability to stimulate thymidine uptake in NIH 3T3 cells. Binding to IGFBP-3 was determined by Surface Plasmon Resonance using a BIAcoreTM instrument. The IGF-1 molecules were structurally characterized by circular dichroism (CD) spectroscopy and by 2D-NMR where stfficient material was available. In the absence of sufficient material for structural characterisation, molecular dynamics simulations were performed to explore the conformational space accessible to the IGF-I analogues and to probe their flexibility. We relate the biological properties of the IGF-I molecules to their determined or modeled structures in terms of our current understanding of the structure-function relationships of insulin and IGF-1.
Original languageEnglish
Title of host publicationRecent Research Developments in Protein Engineering
Place of PublicationTrivandrum, Kerala, India
PublisherResearch Signpost
Number of pages30
ISBN (Print)8177361473
Publication statusPublished - 2002


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