Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Sacher, M. et al.

Sacher, Di Bacco, Lunin, Ye, Wagner, Gill, Cygler,

The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation.

The cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein that inhibits proliferation and enhances differentiation of human embryonal carcinoma cells. CREG binds to the cation-independent mannose 6-phosphate (M6P)/insulin-like growth factor II (IGF2) receptor (IGF2R) (M6P/IGF2R), and this receptor has been shown to be required for CREG-induced growth suppression. To better understand CREG function in cellular growth and differentiation, we solved the 3D crystal structure of this protein to 1.9-A resolution. CREG forms a tight homodimeric complex, and CREG monomers display a beta-barrel fold. The three potential glycosylation sites on CREG map to a confined patch opposite the dimer interface. Thus, dimerization of glycosylated CREG likely presents a bivalent ligand for the M6P/IGF2R. Closely related structural homologs of CREG are FMN-binding split-barrel fold proteins that bind flavin mononucleotide. Our structure shows that the putative flavin mononucleotide-binding pocket in CREG is sterically blocked by a loop and several key bulky residues. A mutant of CREG lacking a part of this loop maintained overall structure and dimerization, as well as M6P/IGF2R binding, but lost the growth suppression activity of WT CREG. Thus, analysis of a structure-based mutant of CREG revealed that binding to M6P/IGF2R, while necessary, is not sufficient for CREG-induced growth suppression. These findings indicate that CREG utilizes a known fold for a previously undescribed function [corrected][1]

References

The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation. Sacher, M., Di Bacco, A., Lunin, V.V., Ye, Z., Wagner, J., Gill, G., Cygler, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]

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