ROLE OF NF-kappaB DIMER DYNAMICS IN NF-kappaB DRIVEN TRANSCRIPTION

Abstract

NF-κB family is the family of transcription factors that regulate the expression of a large number of genes, which are essential for human health. The NF-κB transcription factors regulate cell growth, immune responses, inflammatory viral responses, and apoptotic death by binding to thousands of DNA κB sites distributed in the genome. Activation of the NF-κB pathway is strongly regulated, and any inappropriate step in the activation of the NF-κB signaling pathways can result in autoimmunity, chronic inflammation, and various cancers. The family contains five members RelA (also known as p65), RelB, c-Rel (also known as rel), p50, and p52. Each of the NF- B family members includes a well-conserved DNA binding domain called the Rel homology region (RHR). The RHR consists of approximately three hundred amino acids, which can be further divided into the N-terminal domain (NTD) and the dimerization domain (DD). The NTD helps the NF- B dimer identify and bind to the NF- B target DNA sites called Bsites. The Dimerization Domain, which is of about 100 amino acids in single fragment, plays an essential role in the formation of dimers among the NF- B family members. The RHR also has a third region known as the nuclear localization signal (NLS) at the C-terminal of DD, which permits the NF- B dimers to enter the nucleus. All five members of the NF- B family can form up to fifteen different combinations of homo- and hetero-dimers among them. The abundancy and the stability of these dimers vary for each NF-κB dimer combination. RelA and p50 can form three combinations of NF-κB dimers; RelA homodimer, p50 homodimer, and RelA: p50 heterodimer. Among these three, the RelA: p50 heterodimer is the most abundant and stable NF- B dimer in most mammalian cells, which is followed by p50 homodimer and RelA homodimer, respectively. The NF-κB dimer formation depends on the dimerization domains (DDs). The structurally homologous NF-κB DDs possess an immunoglobulin-like (Ig-like) fold comprised of a pair of sandwiched anti-parallel -sheets. One of the three-stranded -sheets of a monomer faces the corresponding -sheets of its partner monomer subunit constituting the dimer interface. The amino acid residues present at these -sheets of dimer interface make contacts to form homodimer and heterodimer among NF-κB subunits. These interactions at the dimer interface make the DDs a crucial factor for the stability of NF-κB dimers. The factors responsible for the stability of the NF-κB dimers are not fully understood. Thus, understanding the dynamics of the NF-κB DDs can give insights about the mechanism of NF-κB dimer formation and structural stability.