1XHN

The crystal structure of Cellular Repressor of E1A-stimulated Genes (CREG)

Summary for 1XHN

• Entry DOI: 10.2210/pdb1xhn/pdb
• Descriptor: Cellular Repressor of E1A-stimulated Genes (2 entities in total)
• Functional Keywords: beta-barrel, unknown function
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: O75629
• Total number of polymer chains: 4
• Total formula weight: 83026.85

Authors

Sacher, M.,Lunin, V.V.,Cygler, M. (deposition date: 2004-09-20, release date: 2005-11-15, Last modification date: 2024-10-09)

Primary citation

Sacher, M.,Di Bacco, A.,Lunin, V.V.,Ye, Z.,Wagner, J.,Gill, G.,Cygler, M.
The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation
Proc.Natl.Acad.Sci.Usa, 102:18326-18331, 2005

PubMed Abstract: 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]

PubMed: 16344469
DOI: 10.1073/pnas.0505071102

Experimental method

X-RAY DIFFRACTION (1.95 Å)