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Abstract

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.