CREB (cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes.
Regulation of CREB is far more than PKA (Protein kinase A) merely. It also respond to calclium ion, Ras/RAF/ERK and various neurotransmitter (not shown in the figure but written latter).
CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain and has been shown to be integral in the formation of spatial memory. Disease realted are Alzheimer's disease and MDD (upregulate CREB expression can rescue phenotype in animal model)
Phosphrylation of CREB is closely realted with neurotransmitter and neurotrophins.
e.g. dopamine, glutamate, serotonin, GABA, growth factors (e.g., insulin-like growth factor 1 IGF-1; vascular endothelial growth factor, VEGF, brain-derived neurotrophic factor, BDNF)
When activated, CREB protein recruits other transcriptional coactivators to bind to CRE promoter 5’ upstream region. Hydrophobic leucine amino acids are located along the inner edge of the alpha helix. These leucine residues tightly bind to leucine residues of another CREB protein forming a dimer. This chain of leucine residues forms the leucine zipper motif. The protein also has a magnesium ion that facilitates binding to DNA.
The cAMP response element (CRE) is the response element for CREB which contains the highly conserved nucleotide sequence, 5'-TGACGTCA-3’. CRE sites are typically found upstream of genes, within the promoter or enhancer regions. There are approximately 750,000 palindromic and half-site CREs in the human genome. However, the majority of these sites remain unbound due to cytosine methylation, which physically obstructs protein binding.
