Mechanisms by which IκB proteins control NF-κB activity

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