title: p100/IκBδ sequesters and inhibits NF-κB through kappaBsome formation.
abstract: Degradation of I kappaB (κB) inhibitors is critical to activation of dimeric transcription factors of the NF-κB family. There are two types of IκB inhibitors: the prototypical IκBs (IκBα, IκBβ, and IκBε), which form low-molecular-weight (MW) IκB:NF-κB complexes that are highly stable, and the precursor IκBs (p105/IκBγ and p100/IκBδ), which form high-MW assemblies, thereby suppressing the activity of nearly half the cellular NF-κB [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-κB inhibition are unknown. Using the X-ray crystal structure of the C-terminal domain of p100/IκBδ and functional analysis of structure-guided mutants, we show that p100/IκBδ forms high-MW (IκBδ)4:(NF-κB)4 complexes, referred to as kappaBsomes. These IκBδ-centric "kappaBsomes" are distinct from the 2:2 complexes formed by IκBγ. The stability of the IκBδ tetramer is enhanced upon association with NF-κB, and hence the high-MW assembly is essential for NF-κB inhibition. Furthermore, weakening of the IκBδ tetramer impairs both its association with NF-κB subunits and stimulus-dependent processing into p52. The unique ability of p100/IκBδ to stably interact with all NF-κB subunits by forming kappaBsomes demonstrates its importance in sequestering NF-κB subunits and releasing them as dictated by specific stimuli for developmental programs.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Amanda
authors.initials: A
authors.lastname: Fusco
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: De-Bin
authors.initials: DB
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Kushol
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Daniel
authors.initials: D
authors.lastname: Young Kim
authors.affiliation: Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Van Duyne
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; gghosh@ucsd.edu.
authors.forename: Gourisankar
authors.initials: G
authors.lastname: Ghosh
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D020672:I-kappa B Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D052003:NF-kappa B p52 Subunit; D010446:Peptide Fragments; D011506:Proteins; D014157:Transcription Factors; C083487:I kappa B beta protein; C454819:Nfkbid protein, mouse; C501943:IkappaBgamma protein, human; C498206:NFKB2 protein, human; C498207:Nfkb2 protein, mouse
keywords: IκB; NF-κB; kappaBsome; structure; transcription