期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 45, 页码 15946-15951出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1408552111
关键词
I kappa B; NF-kappa B; transcription; structure; kappaBsome
资金
- NIH [AI064326, GM071862]
- Tumor Biology Training Grant [T32 CA009523]
Degradation of I kappaB (kappa B) inhibitors is critical to activation of dimeric transcription factors of the NF-kappa B family. There are two types of I kappa B inhibitors: the prototypical I kappa Bs (I kappa B alpha, I kappa B beta, and I kappa B epsilon), which form low-molecular-weight (MW) I kappa B: NF-kappa B complexes that are highly stable, and the precursor I kappa Bs (p105/I kappa B gamma and p100/I kappa B delta), which form high-MW assemblies, thereby suppressing the activity of nearly half the cellular NF-kappa B [Savinova OV, Hoffmann A, Ghosh G (2009) Mol Cell 34(5):591-602]. The identity of these larger assemblies and their distinct roles in NF-kappa B inhibition are unknown. Using the X-ray crystal structure of the C-terminal domain of p100/I kappa B delta and functional analysis of structure-guided mutants, we show that p100/I kappa B delta forms high-MW(I kappa B delta)(4):(NF-kappa B)(4) complexes, referred to as kappaBsomes. These I kappa B delta-centric kappaBsomes are distinct from the 2: 2 complexes formed by I kappa B gamma. The stability of the I kappa B delta tetramer is enhanced upon association with NF-kappa B, and hence the high-MW assembly is essential for NF-kappa B inhibition. Furthermore, weakening of the I kappa B delta tetramer impairs both its association with NF-kappa B subunits and stimulus-dependent processing into p52. The unique ability of p100/I kappa B delta to stably interact with all NF-kappa B subunits by forming kappaBsomes demonstrates its importance in sequestering NF-kappa B subunits and releasing them as dictated by specific stimuli for developmental programs.
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