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Insights Into the Mechanism of Signal-Induced IKK Activation
- Shumate, Kyle Toyojiro
- Advisor(s): Ghosh, Gourisankar
Abstract
NF-κB transcription factors are essential for inflammation, proliferation, survival, growth and differentiation. The exact mechanism for NF-κB activation by IKK phosphorylation is not well understood. However, it is well known that the partners IKK1/α, IKK2/β, NEMO and Linear Ubn chains are essential for IKK activity. Moreover, phosphorylation of serines 177/181 is a key event in IKK activation, which can be performed by upstream kinases or trans-autophosphorylation by IKK2/β. We confirmed previous results which showed that IKK2/β-NEMO will form a higher molecular weight complex in size exclusion chromatography and we show that Ub4 can bind sub-stoichiometrically to this complex. In addition to an established IKK2/β-ΝΕΜΟ interacting domain we discovered a secondary site of interaction between IKK2/β and the 339 to C-terminal region of NEMO that is Ub4 dependent. We propose that IKK complex oligomerizes and this higher order structure requires both IKK2/β and NEMO to oligomerize. Moreover, since Ub4 is essential for trans-autophosphorylation, (IKK activation), the binding of Ub4 to oligomerized NEMO-IKK2/β may induce a conformational change which allows for IKK trans-autophosphorylation. IKK2/β-NEMO interaction through a secondary site, mediated by Ub4, may have a pivotal role in trans-autophosphorylation.
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