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Function
NF- κB represents a protein family of transcription factors that control many physiological processes in eukaryotes. NF- κB is activated due to many different cellular responses such as immune responses, viral infections, radiation, oxidative stress, and more.
NF- κB is normally in an inactive dimer form in the cytosol, bound to an inhibitor kappa-B protein (IκB) that interferes with nuclear localization signal of NF- κB. Once the cell has received a chemical signal, this signal is passed onto an IκB kinase (IKK) complex which phosphorylates the IκB. Once phosphorylated, IκB is ubiquitinated and degraded by the proteasome. This lack of IκB bound to NF-κB activates the transcription factor. Once activated, dimeric NF- κBs bind to κB sites of DNA, prompting transcription. NF- κB’s nuclear localization signal is freed, allowing it to move to the nucleus and bind to κB sites of DNA.
Active NF- κB promotes IκB expression, creating a negative feedback loop. Since NF- κB is essential to so many processes, its regulation includes post-translational modifications to differentiate between the processes. NF- κB, IκB, and IKK can each be modified for different purposes with phosphorylation, ubiquitination, and acetylation.
Disease
Dysregulation and deficiencies of NF- κB lead to serious consequences such as immunodeficiency, autoimmunity, or cancer.
Relevance
NF- κB transcription factors play an essential role in nearly every cell’s processes. Regulation is key to its various purposes with plenty of PTMs to specify cellular responses. Its recognition motif allows for site-specific binding of DNA to initiate transcription.
Structural highlights
The N-terminal domain contains recognition loops that interact with DNA bases. The defined recognition motif for NF-κB is the Arg57, Arg 59, and Glu 63 that hydrogen bond with DNA bases. The arginine residues donate hydrogen bonding to O6 and N7 of the guanines while the glutamic acid accept hydrogen bonding from the N4 of cytosine.
Phosphate interactions anchor the dimer to the DNA through hydrogen bonding. Polar and charged amino acid such as Lys, Tyr, His, Gln, or Arg residues all play into the hydrogen bonding between the protein and DNA. Phosphate contacts occur in both the C- and N-terminal domains and are generally conserved throughout the family.
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