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Crystal structure of a NF-kB heterodimer bound to an IFNb-kB
Structural highlights
FunctionTF65_MOUSE 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 and the heterodimeric p65-p50 complex appears to be most abundant one. 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. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression (By similarity). The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedWe have determined the x-ray crystal structure of the transcription factor NF-kappaB p50.p65 heterodimer complexed to kappaB DNA from the cytokine interferon beta enhancer (IFNbeta-kappaB). To better understand how the binding modes of NF-kappaB on its two best studied DNA targets might contribute to promoter-specific transcription, this structure is compared with the previously determined complex crystal structure containing NF-kappaB bound to the Ig kappa light chain gene enhancer as well as to a second NF-kappaB.Ig kappa light chain gene enhancer complex also reported in this paper. The global binding modes of all NF-kappaB.DNA complex structures are similar, although crystal-packing interactions lead to differences between identical complexes of the same crystallographic asymmetric unit. An extensive network of stacked amino acid side chains that contribute to base-specific DNA contacts is conserved among the three complexes. Consistent with earlier reports, however, the IFNbeta-kappaB DNA is bent significantly less by NF-kappaB than is the Ig kappa light chain gene enhancer. This and other small structural changes may play a role in explaining why NF-kappaB-directed transcription is sensitive to the context of specific promoters. The precise molecular mechanism behind the involvement of the high mobility group protein I(Y) in interferon beta enhanceosome formation remains elusive. The x-ray crystal structure of the NF-kappa B p50.p65 heterodimer bound to the interferon beta -kappa B site.,Berkowitz B, Huang DB, Chen-Park FE, Sigler PB, Ghosh G J Biol Chem. 2002 Jul 5;277(27):24694-700. Epub 2002 Apr 22. PMID:11970948[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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