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School of Molecular and Biomedical Science, University of Adelaide, 5005, Australia
¹ Biomolecular Research Institute, Parkville 3052, Australia
² Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia

(Requests for offprints should be addressed to R S Norton, Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade, Parkville 3050, Australia; Email: Ray.Norton{at}wehi.edu.au)

(F E Carrick is currently at Imclone, New York, USA)

The interaction of IGF binding protein-2 (IGFBP-2) with IGF-I and -II has been investigated in solution using nuclear magnetic resonance (NMR) spectroscopy. Chemical shift perturbations in ¹⁵N- and ²H/¹⁵N-labelled IGF-I or -II upon binding to unlabelled thioredoxin-tagged bovine IGFBP-2 (Trx^1–279IGFBP-2) have been monitored to identify residues involved directly in the binding interaction as well as any affected by conformational changes associated with the interaction. A key step in obtaining high-quality spectra of the complexes was the use of transverse relaxation optimised spectroscopy (TROSY) methods with partially deuterated ligands. Indeed, because the effects of conformational averaging and aggregation are eliminated in IGF-I and -II bound to IGFBP-2, the spectra of the complexes are actually superior to those of the free ligands. Comparison of our results with the crystal structure of the complex between IGF-I and an N-terminal fragment of IGFBP-5 allowed identification of those residues perturbed by the C-domain of IGFBP-2. Other perturbations, such as those of Gly¹⁹ and Asp²⁰ of IGF-I (and the corresponding residues in IGF-II) – which are located in a reverse turn linking N-domain and C-domain interactive surfaces – are due to local conformational changes in the IGF-I and -II. Our results confirm that the C-domain of IGFBP-2 plays a key role in binding regions of IGF-I and -II that are also involved in binding to the type-1 IGF receptor and thereby blocking ligand binding to this receptor.

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