A structural basis for IκB kinase 2 activation via oligomerization-dependent trans auto-phosphorylation.

Abstract

Author SummaryIκB kinase (IKK) is an enzyme that quickly becomes active in response to diverse stresses on a cell. Once activated, IKK promotes an array of cellular defense processes by phosphorylating IκB, thereby promoting its degradation and liberating its partner, the pro-survival transcription factor NF-κB; NF-κB is then free to relocate to the nucleus where it can modulate gene expression. Our X-ray crystallographic studies on an active version of the human IKK2 isoform reveal that the enzyme adopts a unique open conformation that permits pairs of IKK2 enzymes to form higher order assemblies in which their catalytic domains are in close proximity. Disruption of IKK2's ability to form these assemblies, by introducing changes that interfere with the surfaces that mediate oligomerization, results in IKK2 enzymes that are greatly impaired in their ability to become activated in cells. We propose that after oligomerization the neighboring catalytic domains then phosphorylate each other as part of the activation process. Our findings also suggest that targeted small molecules might disrupt cell survival by blocking IKK2 assembly in cells.