Finding: IKKβ structure reveals a dimer, with each monomer containing 3 domains.
Prediction: This structure is predicted to be shared by other IKKβ family members.
Impact: This first report on the structure of IKKβ may inform therapeutic targeting of this important NF-κB activator.
Nuclear factor κB (NF-κB) family members are transcription factors that play key roles in regulating immune response, inflammation, and apoptosis. NF-κB is typically held in an inactive state in the cytoplasm by the inhibitor of NF-κB (IκB) protein. Upon activation of various signaling pathways, the inhibitor of IκB kinases (IKK) are activated and mark IκB for degradation, allowing NF-κB to move to the nucleus and regulate gene transcription. Given their key role in activation of NF-κB, the IKKs may be potential therapeutic targets in a number of diseases, including cancer. Now, for the first time, Xu and colleagues solve the crystal structure of IKKβ. In the structure, IKKβ forms a dimer that resembles a pair of shears. Within the dimer, each monomer is arranged into three domains. Interestingly, the domains appear to mutually interact and play a role in the activity and substrate specificity of the kinase. Other members of the IKK family—IKKα, TBK1, and IKK-i—are predicted to share this structural organization, providing insight into the mechanism by which the entire family functions. This structure may also serve as an aid to efforts to drug IKKs.
Note: Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.