Yt. Kwak et al., Analysis of domains in the IKK alpha and IKK beta proteins that regulate their kinase activity, J BIOL CHEM, 275(19), 2000, pp. 14752-14759
The I kappa B kinases IKK alpha and IKK beta are critical in activating the
NF-kappa B pathway. Although these proteins have a similar structure that
includes kinase, leucine zipper, and helix-loop-helix domains, they exhibit
marked differences in their kinase activity and functional properties. For
example, IKK beta has a 10-20-fold higher level of kinase activity for I k
appa B alpha than does IKK alpha. Furthermore, disruption of the murine IKK
beta gene, but not the IKK alpha gene, results in severe defects in activa
ting the NF-kappa B pathway. Mice lacking IKK beta succumb to severe hepati
c apoptosis because of failure to activate the NF-kappa B pathway, whereas
mice deficient in IKK alpha exhibit skin and skeletal abnormalities and an
embryonic lethal phenotype. To better characterize differences in the funct
ional properties of these kinases, hybrid IKK proteins were constructed by
domain swapping, and their kinase activity was assayed. These studies demon
strated that differences in the IKK alpha and IKK beta helix-loop-helix dom
ains are primarily responsible for differences in their kinase activity. In
contrast, their kinase and leucine zipper domains exhibited relatively con
served function. These studies further define the properties of IKK alpha a
nd IKK beta, which are involved in their unique regulatory roles.