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The crystal structure of Cellular Repressor of E1A-stimulated Genes (CREG)
Structural highlights
FunctionCREG1_HUMAN May contribute to the transcriptional control of cell growth and differentiation. Antagonizes transcriptional activation and cellular transformation by the adenovirus E1A protein. The transcriptional control activity of cell growth requires interaction with IGF2R.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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] The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation.,Sacher M, Di Bacco A, Lunin VV, Ye Z, Wagner J, Gill G, Cygler M Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18326-31. Epub 2005 Dec 12. PMID:16344469[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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