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Structural basis for cell type specific DNA binding of C/EBPbeta: the case of cell cycle inhibitor p15INK4b promoter
Structural highlights
FunctionCEBPB_HUMAN Important transcriptional activator in the regulation of genes involved in immune and inflammatory responses. Specifically binds to an IL-1 response element in the IL-6 gene. NF-IL6 also binds to regulatory regions of several acute-phase and cytokines genes. It probably plays a role in the regulation of acute-phase reaction, inflammation and hemopoiesis. The consensus recognition site is 5'-T[TG]NNGNAA[TG]-3'. Functions in brown adipose tissue (BAT) differentiation (By similarity). Regulates the transcriptional induction of peroxisome proliferator-activated receptor gamma (PPARG).[1] Publication Abstract from PubMedC/EBPbeta 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/EBPbeta is an essential cofactor for TGFbeta signaling in the case of Smad2/3/4 and FoxO-dependent induction of the cell cycle inhibitor, p15INK4b. In the TGFbeta-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/EBPbeta 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/EBPbeta 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/EBPbeta 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/EBPbeta binding is modestly increased by cytosine methylation, but substantially decreased by hydroxymethylation. Structural basis for cell type specific DNA binding of C/EBPbeta: The case of cell cycle inhibitor p15INK4b promoter.,Lountos GT, Cherry S, Tropea JE, Wlodawer A, Miller M J Struct Biol. 2022 Nov 4;214(4):107918. doi: 10.1016/j.jsb.2022.107918. PMID:36343842[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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