Structural organization of NF-κB, IκB, and IKK proteins. (A) NF-κB subunits. NF-κB comprises a group of 5 related transcription factors that share a highly conserved amino-terminal Rel homology domain (RHD), which is responsible for dimerization, nuclear translocation, DNA binding, and interaction with inhibitory IκB proteins. RelA, RelB, and c-Rel additionally possess a carboxy-terminal transactivation domain (TAD) that initiates transcription from NF-κB–binding sites in target genes. The ankyrin repeat (A) containing NF-κB1 and NF-κB2 precursor proteins p105 and p100 can be proteolytically processed to p50 and p52. (B) IκB proteins. The IκB proteins are characterized by the presence of 6 or 7 ankyrin repeats (A) to mediate protein-protein interactions. The ankyrin repeat motif can bind to the nuclear localization sequence of NF-κB proteins and is important for the retention of NF-κB in an inactive state in the cytoplasm. The mammalian IκB family members are IκB-α, IκB-β, IκB-γ, IκB-ϵ, and BCL-3. In addition, NF-κB1 and NF-κB2 precursor proteins p100 and p105 can also function as IκBs. (C) IKK proteins. The IKK complex contains the catalytic kinase subunits IKKα and IKKβ, as well as a regulatory subunit IKKγ (NEMO). IKKα and IKKβ possess a helix-loop-helix region (HLH) and a leucine zipper (LZ), which are responsible for both homodimerization and heterodimerization of IKKα and IKKβ. The catalytic subunits interact through their NEMO-binding domain (NBD) with IKKγ, which contains a coiled coil (CC) domain and a leucine zipper (LZ). Illustration by Kenneth Probst.