Structure and Properties of the C-terminal Domain of Insulin-like Growth Factor-binding Protein-1 Isolated from Human Amniotic Fluid

Abstract

Abstract-In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins

“…1). The secondary structure elements comprise two antiparallel helices ␣1 Our structure of the C-terminal domain of IGFBP1 (CBP1) (residues 141-234), in complex with the N-terminal domain of IGFBP 4 (NBP4) (residues 1-92) and IGF1, is less well ordered than that of an isolated CBP1 (residues 147-221) recently published by Sala et al (17). In addition, regions Gln-166(C)-Ile-173(C) and Asp-197(C)-Gly-198(C) in our CBP1 are fully disordered (see Supporting Materials and Methods, which is published as supporting information on the PNAS web site).…”

“…In addition, regions Gln-166(C)-Ile-173(C) and Asp-197(C)-Gly-198(C) in our CBP1 are fully disordered (see Supporting Materials and Methods, which is published as supporting information on the PNAS web site). We will therefore use the structure of Sala et al (17) in comparing CBP1 with CBP4. The defined parts of our CBP1 are nearly identical to those of free CBP1, with the backbone rmsd of 0.96 Å.…”

“…More recently, low-resolution structures of the C-terminal domain of IGFBP6 (12) and its binding surface on IGF2 (3,12) have been determined with NMR spectroscopy. There is, however, no x-ray structure of a ternary complex of the C-terminal domain of any IGFBPs bound to both the N-terminal domain and IGF, although the C-terminal fragment of IGFBP4 was crystallized recently (9), and also the x-ray structure of the isolated C-terminal fragment of IGFBP1 has been solved (17). We recently reported the x-ray structure of the ternary complex of the N-and C-terminal domains of IGFBP4 bound to IGF1 (10) and described ordered structures for the N-terminal domain of IGFBP4 and IGF1.…”

Defining the Disulfide Bonds of Insulin-like Growth Factor-binding Protein-5 by Tandem Mass Spectrometry with Electron Transfer Dissociation and Collision-induced Dissociation

“…In addition, IGFBPs 1-5 share a cysteine-rich motif, GCGCCXXC (where X is any amino acid), within the N-terminal domain (6,8,12). Limited insights into the three-dimensional organization of IGFBPs have come from results of high-resolution x-ray crystallographic analyses of the isolated N-terminal domain of IGFBP-4 and the C-terminal segments of IGFBP-1 and IGFBP-4 (13,14). One consistent observation from these data is that IGFBPs lack inter-domain disulfide bonds (12)(13)(14)(15).…”

“…Limited insights into the three-dimensional organization of IGFBPs have come from results of high-resolution x-ray crystallographic analyses of the isolated N-terminal domain of IGFBP-4 and the C-terminal segments of IGFBP-1 and IGFBP-4 (13,14). One consistent observation from these data is that IGFBPs lack inter-domain disulfide bonds (12)(13)(14)(15). However, as the structure of a fulllength IGFBP has not been solved, possibly because of the dis-ordered nature of the linker segment, this conclusion remains provisional.…”