4ot9 | pdb_00004ot9
crystal structure of the C-terminal domain of p100/NF-kB2
Structural highlights
Disease[NFKB2_HUMAN] Note=A chromosomal aberration involving NFKB2 is found in a case of B-cell non Hodgkin lymphoma (B-NHL). Translocation t(10;14)(q24;q32) with IGHA1. The resulting oncogene is also called Lyt-10C alpha variant. Note=A chromosomal aberration involving NFKB2 is found in a cutaneous T-cell leukemia (C-TCL) cell line. This rearrangement produces the p80HT gene which encodes for a truncated 80 kDa protein (p80HT). Note=In B-cell leukemia (B-CLL) cell line, LB40 and EB308, can be found after heterogeneous chromosomal aberrations, such as internal deletions. Function[NFKB2_HUMAN] NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. In a non-canonical activation pathway, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65.[1] Publication Abstract from PubMedDegradation of I kappaB (kappaB) inhibitors is critical to activation of dimeric transcription factors of the NF-kappaB family. There are two types of IkappaB inhibitors: the prototypical IkappaBs (IkappaBalpha, IkappaBbeta, and IkappaBepsilon), which form low-molecular-weight (MW) IkappaB:NF-kappaB complexes that are highly stable, and the precursor IkappaBs (p105/IkappaBgamma and p100/IkappaBdelta), which form high-MW assemblies, thereby suppressing the activity of nearly half the cellular NF-kappaB [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-kappaB inhibition are unknown. Using the X-ray crystal structure of the C-terminal domain of p100/IkappaBdelta and functional analysis of structure-guided mutants, we show that p100/IkappaBdelta forms high-MW (IkappaBdelta)4:(NF-kappaB)4 complexes, referred to as kappaBsomes. These IkappaBdelta-centric "kappaBsomes" are distinct from the 2:2 complexes formed by IkappaBgamma. The stability of the IkappaBdelta tetramer is enhanced upon association with NF-kappaB, and hence the high-MW assembly is essential for NF-kappaB inhibition. Furthermore, weakening of the IkappaBdelta tetramer impairs both its association with NF-kappaB subunits and stimulus-dependent processing into p52. The unique ability of p100/IkappaBdelta to stably interact with all NF-kappaB subunits by forming kappaBsomes demonstrates its importance in sequestering NF-kappaB subunits and releasing them as dictated by specific stimuli for developmental programs. p100/IkappaBdelta sequesters and inhibits NF-kappaB through kappaBsome formation.,Tao Z, Fusco A, Huang DB, Gupta K, Young Kim D, Ware CF, Van Duyne GD, Ghosh G Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):15946-51. doi:, 10.1073/pnas.1408552111. Epub 2014 Oct 27. PMID:25349408[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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