1rmj
From Proteopedia
|
C-terminal domain of insulin-like growth factor (IGF) binding protein-6: structure and interaction with IGF-II
Overview
IGFs are important mediators of growth. IGF binding proteins (IGFBPs) 1-6, regulate IGF actions and have IGF-independent actions. The C-terminal, domains of IGFBPs contribute to high-affinity IGF binding and modulation, of IGF actions and confer some IGF-independent properties, but, understanding how they achieve this has been constrained by the lack of a, three-dimensional structure. We therefore determined the solution, structure of the C-domain of IGFBP-6 using nuclear magnetic resonance, (NMR). The domain consists of a thyroglobulin type 1 fold comprising an, alpha-helix followed by a loop, a three-stranded antiparallel beta-sheet, incorporating a second loop, and finally a disulfide-bonded flexible third, loop. The IGF-II binding site on the C-domain was identified by examining, NMR spectral changes upon complex formation. It consists of a largely, hydrophobic surface patch involving the alpha-helix, the first, beta-strand, and the first and second loops. The site was confirmed by, mutagenesis of several residues, which resulted in decreased IGF binding, affinity. The IGF-II binding site lies adjacent to surfaces likely to be, involved in glycosaminoglycan binding of IGFBPs, which might explain their, decreased IGF affinity when bound to glycosaminoglycans, and nuclear, localization. Our structure provides a framework for understanding the, roles of IGFBP C-domains in modulating IGF actions and conferring, IGF-independent actions, as well as ultimately for the development of, therapeutic IGF inhibitors for diseases including cancer.
About this Structure
1RMJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
C-terminal domain of insulin-like growth factor (IGF) binding protein-6: structure and interaction with IGF-II., Headey SJ, Keizer DW, Yao S, Brasier G, Kantharidis P, Bach LA, Norton RS, Mol Endocrinol. 2004 Nov;18(11):2740-50. Epub 2004 Aug 12. PMID:15308688
Page seeded by OCA on Mon Nov 12 19:05:31 2007
