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

I kappaB proteins associate with the transcription factor NF-kappaB via the ir ankyrin repeat domain. Bcl-3 is an unusual I kappaB protein because it i s primarily nucleoplasmic and can lead to enhanced NF-kappaB-dependent tran scription, unlike the prototypical I kappaB protein I kappaB alpha, which i nhibits NF-kappaB activity by retaining it in the cytoplasm. Here we report the 1.9 Angstrom crystal structure of the ankyrin repeat domain of human B cl-3 and compare it with that of I kappaB alpha bound to NF-kappaB. 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 seve nth repeat in place of the acidic PEST region of I kappaB alpha Differences between the two structures suggest why Bcl-3 differs from I kappaB alpha i n selectivity towards various NF-kappaB species, why Bcl-3 but not I kappaB alpha can associate with its NF-kappaB partner bound to DNA, and why two m olecules of Bcl-3 but only one of I kappaB alpha can bind to its NF-kappaB partner. Comparison of the two structures thus provides an insight into the functional diversity of I kappaB proteins.