7UPZ

Structural basis for cell type specific DNA binding of C/EBPbeta: the case of cell cycle inhibitor p15INK4b promoter

Summary for 7UPZ

• Entry DOI: 10.2210/pdb7upz/pdb
• Descriptor: CCAAT/enhancer-binding protein beta, DNA (5'-D(*AP*TP*TP*CP*TP*TP*AP*AP*GP*AP*AP*AP*GP*AP*CP*G)-3'), DNA (5'-D(*TP*CP*GP*TP*CP*TP*TP*TP*CP*TP*TP*AP*AP*GP*AP*A)-3'), ... (4 entities in total)
• Functional Keywords: c/ebpbeta-dna interactions, dna sequence motif, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 28987.57

Authors

Lountos, G.T.,Cherry, S.,Tropea, J.E.,Wlodawer, A.,Miller, M. (deposition date: 2022-04-18, release date: 2022-11-23, Last modification date: 2023-10-18)

Primary citation

Lountos, G.T.,Cherry, S.,Tropea, J.E.,Wlodawer, A.,Miller, M.
Structural basis for cell type specific DNA binding of C/EBP beta : The case of cell cycle inhibitor p15INK4b promoter.
J.Struct.Biol., 214:107918-107918, 2022

PubMed Abstract: C/EBPβ is a key regulator of numerous cellular processes, but it can also contribute to tumorigenesis and viral diseases. It binds to specific DNA sequences (C/EBP sites) and interacts with other transcription factors to control expression of multiple eukaryotic genes in a tissue and cell-type dependent manner. A body of evidence has established that cell-type-specific regulatory information is contained in the local DNA sequence of the binding motif. In human epithelial cells, C/EBPβ is an essential cofactor for TGFβ signaling in the case of Smad2/3/4 and FoxO-dependent induction of the cell cycle inhibitor, p15INK4b. In the TGFβ-responsive region 2 of the p15INK4b promoter, the Smad binding site is flanked by a C/EBP site, CTTAA•GAAAG, which differs from the canonical, palindromic ATTGC•GCAAT motif. The X-ray crystal structure of C/EBPβ bound to the p15INK4b promoter fragment shows how GCGC-to-AAGA substitution generates changes in the intermolecular interactions in the protein-DNA interface that enhances C/EBPβ binding specificity, limits possible epigenetic regulation of the promoter, and generates a DNA element with a unique pattern of methyl groups in the major groove. Significantly, CT/GA dinucleotides located at the 5'ends of the double stranded element maintain local narrowing of the DNA minor groove width that is necessary for DNA recognition. Our results suggest that C/EBPβ would accept all forms of modified cytosine in the context of the CpT site. This contrasts with the effect on the consensus motif, where C/EBPβ binding is modestly increased by cytosine methylation, but substantially decreased by hydroxymethylation.

PubMed: 36343842
DOI: 10.1016/j.jsb.2022.107918

Experimental method

X-RAY DIFFRACTION (2.487 Å)