User:Korbin H.J. West/Sandbox 1

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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 (GILMORE).

The activation of NF- κB occurs in a few different pathways; however, the most prominent are the canonical and the non-canonical pathways. In the canonical pathway, NF- κB is normally in an inactive dimer form in the cytosol, bound to an inhibitor kappa-B protein (IκB). The binding of IκB interferes with nuclear localization signal of NF- κB. Once a ligand binds to a cellular receptor, the signal is relayed through adaptors such as TRAFs to an IκB kinase (IKK) complex (GILMORE). The canonical IKK complex is built up by alpha and beta catalytic subunits and two regulatory scaffold NF-κB essential modulator (NEMO) proteins (GILMORE). This IKK complex is activated by clusters of adaptors, and upon activation it will phosphorylate the IκB. Once phosphorylated, IκB is subsequently ubiquitinated and degraded by the proteasome (Oeckinghaus and Ghosh, 2009). With its inhibitor degraded, NF- κB’s nuclear localization signal is freed, allowing it to move to the nucleus and bind to κB sites of DNA to prompt transcription. These κB sites are usually 9-10 base pairs that follow the general form 5'-GGGRNWYYCC-3' (R: A or G; N: any nucleotide; W: A or T; Y: C or T) (GILMORE).

Alternatively, NF- κB can be activated through the non-canonical pathway, however it affects mainly p100/RelB complexes. The non-canonical pathway is initiated upon binding of very specific ligands (B-cell activating factor, CD40, etc.) (GILMORE). This cellular signal is then passed onto the NF-κB-inducing kinase (NIK), which in turn phosphorylates and activates an alpha IKK catalytic dimer. This activated catalytic dimer phosphorylates serine residues in the C-terminal domain of p100 (Oeckinghaus Ghosh). This phosphorylation prompts partial proteolysis, creating a p52/RelB complex which will go on to enter the nucleus and bind to DNA.

Active NF- κB promotes IκB expression, creating a negative feedback loop(Oeckinghaus and Ghosh, 2009). Since NF- κB is essential to so many processes, its regulation includes post-translational modifications to differentiate between the processes. Moreover, NF- κB response can depend on its modifications, as the degradation of IκB does not guarantee maximal activity (Oeckinghaus Ghosh). **************************** 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(Oeckinghaus Ghosh 2009).

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(Muller et al., 1995). 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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