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Regulation of DNA Binding by Rel/NF-Kb Transcription Factors: Structural Views

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Regulation of DNA Binding by Rel/NF-Kb Transcription Factors: Structural Views Oncogene (1999) 18, 6845 ± 6852 ã 1999 Stockton Press All rights reserved 0950 ± 9232/99 $15.00 http://www.stockton-press.co.uk/onc Regulation of DNA binding by Rel/NF-kB transcription factors: structural views Frances E Chen1 and Gourisankar Ghosh*,2 1Department of Biology, University of California ± San Diego, 9500 Gilman Drive, MC 0359, La Jolla, California, CA 92093-0359, USA; 2Department of Chemistry and Biochemistry, University of California ± San Diego, 9500 Gilman Drive, MC 0359, La Jolla, California, CA 92093-0359, USA Rel/NF-kB transcription factors form homo- and nuclear localization and IkB binding. Additional Rel/ heterodimers with dierent DNA binding site speci®cities NF-kB family members include the v-Rel oncoprotein and DNA binding anities. Several intracellular path- of the avian Rev-T retrovirus, and the Drosophila ways evoked by a wide range of biological factors and Dorsal, Dif and Relish proteins. Rel/NF-kB proteins environmental conditions can lead to the activation of bind to DNA segments with a consensus sequence of Rel/NF-kB dimers by signaling degradation of the 5'-GGGRNYYYCC-3' collectively referred to as kB inhibitory IkB protein. In the nucleus Rel/NF-kB dimers elements or kB sites. For the NF-kB p50/RelA modulate the expression of a variety of genes including heterodimer alone, there are a large number of those encoding cytokines, growth factors, acute phase dierent kB sites that display varying degrees of response proteins, immunoreceptors, other transcription consensus (Figure 1). factors, cell adhesion molecules, viral proteins and Rel/NF-kB regulation can occur at multiple levels: regulators of apoptosis. The primary focus of this review (1) dimerization, (2) inhibition by IkB (and thus is on structural and functional aspects of Rel/NF- control of its nuclear translocation), (3) DNA kB:DNA complexes and their formation. The salient binding, (4) interaction with other transcriptional co- features of the Rel/NF-kB dimer:DNA structure are activators, and (5) interaction with the basal transcrip- described, as are modes of transcriptional regulation by tional machinery. This review describes common phosphorylation, altered DNA binding properties, vary- stereochemical features of several crystallographic ing protein conformations, and interactions with IkB Rel/NF-kB:DNA complexes, and, in the context of proteins. these models, provides some insights into how phosphorylation, protein sequence variation, DNA Keywords: Rel; NF-kB; IkB; DNA; structure; tran- sequence variation, and IkB modulation can aect scription the DNA binding characteristics of NF-kB. Other more general reviews of NF-kB are also available (Baeuerle and Henkel, 1994; Baldwin, 1996; Ghosh et al., 1998; Siebenlist et al., 1994). Introduction Rel/NF-kB transcription factors form homo- and Structure of NF-kB/DNA complexes heterodimers with dierent DNA binding site specifi- cities and DNA binding anities. Various intracellular Three-dimensional structures have been solved of pathways evoked by a wide range of biological factors several Rel/NF-kB Rel homology (RH) domain and environmental conditions can activate the Rel/NF- dimers complexed to DNA, including those of the kB dimer by signaling degradation of the Rel/NF-kB p50, RelA, p52 and c-Rel homodimers, and the p50/ inhibitor IkB proteins. IkB degradation uncovers a RelA heterodimer (NF-kB) (Chen et al., 1998a,b; nuclear localization sequence (NLS) in each subunit of Cramer et al., 1997; Ghosh et al., 1995; MuÈ ller et al., the Rel/NF-kB dimer and allows the dimer to 1995). All models of Rel/NF-kB protein dimer translocate from its inactive cytoplasmic location into straddling DNA demonstrate a tertiary structure that the nucleus. In the nucleus it modulates the expression has been likened to that of a butter¯y and is unlike of a variety of genes including those encoding that of other observed transcription factors (Figure 2). cytokines, growth factors, acute phase response Each dimer subunit contains two sets of b sheet proteins, immunoreceptors, other transcription fac- immunoglobulin folds that form an N' terminal tors, cell adhesion molecules, viral proteins and domain (NTD) that contacts DNA both base regulators of apoptosis (see Pahl, 1999, this issue). speci®cally and backbone non-speci®cally, and a C' The mammalian Rel/NF-kB protein family mem- terminal domain (CTD) that mediates dimerization bers, which include p50, p52, c-Rel, RelA (p65), and and non-speci®c DNA contacts. Unlike most tran- RelB, share an N-terminal domain called the Rel scription factors which use alpha helices to bind homology (RH) domain. The RH domain contains DNA, the Rel/NF-kB proteins use ten ¯exible loops sequences responsible for dimerization, DNA binding, extending from the secondary structure of these immunoglobulin folds to mediate DNA contacts. These structures support numerous biochemical results that indicate the N' region of the RH domain is important for DNA binding (Coleman et al., 1993; *Correspondence: G Ghosh Toledano et al., 1993). Rel/NF-kBstructure FE Chen and G Ghosh 6846 Figure 1 Various kB sites DNA binding on kB site DNA occurs via loops on lysine electrostatically interacts with the pyrimidines the edges of immunoglobulin folds and loosely re¯ects opposite of the guanine-rich strand. The nonspeci®c the twofold symmetry of the subunits in the dimer. phosphate backbone contacts, which contribute to the These contacts delineate two subsites within a kB site. high overall DNA anity of the Rel/NF-kB dimer, The numerous base-speci®c contacts on a subsite are are mediated by residues in all ®ve loops of each made via residues in the long loop L1 of the protein subunit. which reaches into the major groove of the DNA and After solving both the p50 and the RelA homodimer contacts the distal end of the subsites. Two arginine crystal structures (Chen et al., 1998b; Ghosh et al., residues in this loop make bidentate contacts with 1995; MuÈ ller et al., 1995), it was determined that kB conserved guanines and this is stabilized by hydrogen sequences are pseudosymmetric with a 5 base pair long bonds from a glutamate that binds the cytosines in the p50 subsite, a 4 base pair long RelA subsite, and a 1 opposite strand. A tyrosine residue makes van der base pair spacer between them. The structure of the Waals contacts while a positively-charged arginine or DNA-bound p50/RelA heterodimer con®rms this Rel/NF-kB structure FE Chen and G Ghosh 6847 Figure 2 The secondary structure of a Rel/NF-kB dimer bound to a space ®lling model of the target DNA model and exhibits the expected directional binding in a biphasic manner, with the protein either bound or light of the subsites de®ned above and the observed unbound and transcription on or o, but in a ®nely biochemical experiments (Chen et al., 1998a; Zabel et tuned manner that can incorporate dierent levels of al., 1991). However, other experiments have indicated regulation. Four points of regulation that aect Rel/ that there is some ¯exibility in the size of the subsites NF-kB proteins include phosphorylation, variations in especially if it is localized to one side. Chen et al. the primary sequence, tertiary conformational changes, (1998b) showed that a RelA dimer given only one and interaction with IkB proteins. optimal subsite can still bind to the length of the kB site DNA by making base-speci®c contacts to that Phosphorylation subsite and only maintaining phosphate backbone contacts to the other. Additional work on the RelA Rel/NF-kB proteins have been observed to be homodimer also shows that given longer optimal positively regulated by phosphorylation events both subsites, a RelA subunit can utilize additional residues constitutively and inducibly in vivo (Li et al., 1994b). to bind a 5 base pair subsite in a manner similar to Hyperphosphorylation of p50 is required for phorbol that of p50 (Y-Q Chen, unpublished). ester and hemagglutinin induced nuclear translocation in Jurkat cells, and phosphorylated p50 accounts for most of the observed nuclear p50 population (Li et Regulation of DNA binding by Rel/NF-kB transcription al., 1994a). Phosphorylation of p50 has also been factors shown to increase the anity of formation and stability of p50:DNA complexes in vitro (Li et al., There is much experimental evidence to support the 1994a), whereas hypophosphorylation has been found hypothesis that transcriptional activation occurs not in to decrease stability of p50:DNA complexes in Ad12 Rel/NF-kBstructure FE Chen and G Ghosh 6848 E1-transformed Hooded Lister rat cells (Kushner and in determining dimerization anity. The particularly Ricciardi, 1999). The adenovirus Ad12 exploits favorable juxtaposition in the p50/RelA heterodimer of hypophosphorylation of p50 to downregulate the Asp-254 in the p50 subunit and Asn-200 in RelA helps transcription of the major histocompatability complex to overcome the loss of hydrogen bonds resulting from I gene allowing the cell to evade cytotoxic T cell- juxtaposing Tyr-267 in p50 with its analog, Phe-214, in mediated lysis. While preliminary phosphoamino RelA. The RelA homodimer, however, forgoes analysis indicates that p50 is phosphorylated on favorable hydrogen bonding interactions by facing serine residues (Hayashi et al., 1993; Li et al., two Phe-214 residues and also by not providing 1994b), it still remains to be determined which additional energy with two opposing Asn-200. phosphorylated residues of p50 are responsible for The dierential and oncogenic activity of v-Rel the observed eects on DNA binding. Nevertheless, it arises, at least in part, from an altered DNA-binding is apparent that phosphorylation cannot be enhancing anity (see Gilmore, 1999, this issue). The cause of this DNA binding by a direct mechanism since the altered anity originates from numerous mutations additional negative charge resulting from a phosphor- that v-Rel has acquired, which include substitution of ylation can only provide repulsive forces when binding the ®rst two N-terminal and last 118 C-terminal to a negatively-charged DNA molecule.
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