Crystal structure of the ankyrin repeat domain of Bcl-3: a unique member of the IκB protein family

IκB proteins associate with the transcription factor NF-κB via their ankyrin repeat domain. Bcl-3 is an unusual IκB protein because it is primarily nucleoplasmic and can lead to enhanced NF-κB-dependent transcription, unlike the prototypical IκB protein IκBα, which inhibits NF-κB activity by retaining it in the cytoplasm. Here we report the 1.9 Å crystal structure of the ankyrin repeat domain of human Bcl-3 and compare it with that of IκBα bound to NF-κB. The two structures are highly similar over the central ankyrin repeats but differ in the N-terminal repeat and at the C-terminus, where Bcl-3 contains a seventh repeat in place of the acidic PEST region of IκBα. Differences between the two structures suggest why Bcl-3 differs from IκBα in selectivity towards various NF-κB species, why Bcl-3 but not IκBα can associate with its NF-κB partner bound to DNA, and why two molecules of Bcl-3 but only one of IκBα can bind to its NF-κB partner. Comparison of the two structures thus provides an insight into the functional diversity of IκB proteins.