Crystal structure of a human I?B kinase ? asymmetric dimer.

ABSTRACT: Phosphorylation of inhibitor of nuclear transcription factor ?B (I?B) by I?B kinase (IKK) triggers the degradation of I?B and migration of cytoplasmic ?B to the nucleus where it promotes the transcription of its target genes. Activation of IKK is achieved by phosphorylation of its main subunit, IKK?, at the activation loop sites. Here, we report the 2.8 ? resolution crystal structure of human IKK? (hIKK?), which is partially phosphorylated and bound to the staurosporine analog K252a. The hIKK? protomer adopts a trimodular structure that closely resembles that from Xenopus laevis (xIKK?): an N-terminal kinase domain (KD), a central ubiquitin-like domain (ULD), and a C-terminal scaffold/dimerization domain (SDD). Although hIKK? and xIKK? utilize a similar dimerization mode, their overall geometries are distinct. In contrast to the structure resembling closed shears reported previously for xIKK?, hIKK? exists as an open asymmetric dimer in which the two KDs are further apart, with one in an active and the other in an inactive conformation. Dimer interactions are limited to the C-terminal six-helix bundle that acts as a hinge between the two subunits. The observed domain movements in the structures of IKK? may represent trans-phosphorylation steps that accompany IKK? activation.

SUBMITTER: Liu S 

PROVIDER: S-EPMC3829360 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature