The N-terminal subdomain of insulin-like growth factor (IGF) binding protein 6. Structure and interaction with IGFs

Chandrashekaran, IR; Yao, SG; Wang, CC; Bansal, PS; Alewood, PF; Forbes, BE; Wallace, JC; Bach, LA; Norton, RS

Author(s): Chandrashekaran, IR; Yao, SG; Wang, CC; Bansal, PS; Alewood, PF; Forbes, BE; Wallace, JC; Bach, LA; Norton, RS;
Details: Publication Year 2007-03-20,Volume 46,Issue #11,Page 3065-3074
Journal Title: BIOCHEMISTRY
Publication Type: Journal Article
Abstract: Insulin-like growth factor binding proteins (IGFBPs) modulate the activity and distribution of insulin-like growth factors (IGFs). IGFBP-6 differs from other IGFBPs in being a relatively specific inhibitor of IGF-II actions. Another distinctive feature of IGFBP-6 is its unique N-terminal disulfide linkages; the N-domains of IGFBPs 1-5 contain six disulfides and share a conserved GCGCC motif, but IGFBP-6 lacks the two adjacent cysteines in this motif, so its first three N-terminal disulfide linkages differ from those of the other IGFBPs. The contributions of the N- and C-domains of IGFBP-6 to its IGF binding properties and their structure-function relationships have been characterized in part, but the structure and function of the distinctive N-terminal subdomain of IGFBP-6 are unknown. Here we report the solution structure of a polypeptide corresponding to residues 1-45 of the N-terminal subdomain of IGFBP-6 (NN-BP-6). The extended structure of the N-terminal subdomain of IGFBP-6 is very different from that of the short two-stranded beta-sheet of the N-terminal subdomain of IGFBP-4 and, by implication, the other IGFBPs. NN-BP-6 contains a potential cation-binding motif; lanthanide ion binding was observed, but no significant interaction was found with physiologically relevant metal ions like calcium or magnesium. However, this subdomain of IGFBP-6 has a higher affinity for IGF-II than IGF-I, suggesting that it may contribute to the marked IGF-II binding preference of IGFBP-6. The extended structure and flexibility of this subdomain of IGFBP-6 could play a role in enhancing the rate of ligand association and thereby be significant in IGF recognition.
Publisher: AMER CHEMICAL SOC
Keywords: FACTOR-BINDING PROTEIN-5; DISEASE ANTIGEN OSPA; CHEMICAL-SHIFTS; FACTOR-I; NMR; DOMAIN; IDENTIFICATION; INHIBITION; PEPTIDES; RECEPTOR
Publisher's Version: https://doi.org/10.1021/bi0619876
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2007-03-20 12:00:00