Mechanisms by which IkappaB proteins control NF-kappaB activity.

The biological activity of the transcription factor NF-kappaB is differentially controlled by three IkappaB proteins, Ikappa Balpha, Ikappa Bbeta, and Ikappa Bepsilon. We have examined the molecular basis for the differential inhibitory strengths of IkappaB proteins by constructing hybrid IkappaBs and found that the first ankyrin repeat of Ikappa Balpha is responsible for its strong inhibitory effect. Swapping a putative beta-turn within the first ankyrin repeat between the strong Ikappa Balpha and the weak IkappaBbeta inhibitors switches their in vivo inhibitory activity on NF-kappaB. The qualitatively distinct contacts made by this beta-turn in Ikappa Balpha and Ikappa Bbeta with NF-kappaB determine the efficiency by which IkappaBs sequester NF-kappaB to the cytoplasm, thus explaining their distinct effects on gene activity.