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A Structural Guide to Proteins of the NF-Kb Signaling Module

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A Structural Guide to Proteins of the NF-Kb Signaling Module Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press A Structural Guide to Proteins of the NF-kB Signaling Module Tom Huxford1 and Gourisankar Ghosh2 1Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, California 92182-1030 2Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0375 Correspondence: [email protected] The prosurvival transcription factor NF-kB specifically binds promoter DNA to activate target gene expression. NF-kB is regulated through interactions with IkB inhibitor proteins. Active proteolysis of these IkB proteins is, in turn, under the control of the IkB kinase complex (IKK). Together, these three molecules form the NF-kB signaling module. Studies aimed at charac- terizing the molecular mechanisms of NF-kB, IkB, and IKK in terms of their three-dimen- sional structures have lead to a greater understanding of this vital transcription factor system. F-kB is a master transcription factor that from the perspective of their three-dimensional Nresponds to diverse cell stimuli by activat- structures. ing the expression of stress response genes. Multiple signals, including cytokines, growth factors, engagement of the T-cell receptor, and NF-kB bacterial and viral products, induce NF-kB Introduction to NF-kB transcriptional activity (Hayden and Ghosh 2008). A point of convergence for the myriad NF-kB was discovered in the laboratory of of NF-kB inducing signals is the IkB kinase David Baltimore as a nuclear activity with bind- complex (IKK). Active IKK in turn controls ing specificity toward a ten-base-pair DNA transcription factor NF-kB by regulating pro- sequence 50-GGGACTTTCC-30 present within teolysis of the IkB inhibitor protein (Fig. 1). the enhancer of the immunoglobin k light This nexus of three factors, IKK, IkB, and chain gene in mature antibody-producing B NF-kB, forms the NF-kB signaling module—a cells (Sen and Baltimore 1986). The biochemi- molecular relay switch mechanism that is con- cally purified activity was found to be composed served across diverse species (Ghosh et al. of 50 and 65 kilodalton (kDa) subunits. Cloning 1998; Hoffmann et al. 2006). In this article, of the p50 subunit revealed significant amino- we introduce the human NF-kB, IkB, and acid sequence homology between its amino- IKK proteins, and discuss how they function terminal 300 amino acids and the oncogene Editors: Louis M. Staudt and Michael Karin Additional Perspectives on NF-kB available at www.cshperspectives.org Copyright # 2009 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a000075 Cite this article as Cold Spring Harb Perspect Biol 2009;1:a000075 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press T. Huxford and G. Ghosh Inducing a Rel Homology Region Structure g signal b The first glimpse at the structure of the RHR was IKK afforded by the successful determination of two x-ray crystal structures of the NF-kB p50:p50 IkB IkB homodimer in complex with related kBDNA proteolysis (Ghosh et al. 1995; Mu¨ller et al. 1995). The structures uncovered a symmetrical protein: Inactive DNA complex structure reminiscent of a but- Cytoplasm NF-kB terfly with double-stranded DNA comprising Nucleus the “body” and two-protein subunit “wings” (Fig. 2B,C). These structures revealed a com- Transcription pletely novel DNA binding motif in which one entire 300 amino acid RHR from each p50 Active NF-kB subunit in the dimer are involved in contacting one whole turn along the major groove of Figure 1. The NF-kB signaling module. NF-kB exists double-stranded DNA (Baltimore and Beg in the cytoplasm of resting cells by virtue of its 1995; Mu¨ller et al. 1996). noncovalent association with an IkB inhibitor protein. The IkB kinase (IKK) responds to diverse As revealed by the NF-kB p50:DNA com- stimuli by catalyzing the phosphorylation-dependent plex structures, the RHR consists of two folded 26 S proteasome-mediated degradation of complex- domains. The amino-terminal domain (or associated IkB. Active NF-kB accumulates in the Rel-N) is approximately 160–210 amino acids nucleus where it binds with DNA sequence specificity in length and exhibits a variant of the immu- in the promoter regions of target genes and activates noglobulin fold. The carboxy-terminal dimer- their transcription. ization domain (referred to as Rel-C) spans roughly 100 amino acids and also adopts an immunoglobulin-like fold. The five RHR- from the reticuloendotheliosis virus of turkeys containing NF-kB subunits assemble to form and shared by v-Rel and its cellular proto- various homo- and heterodimer combinations oncogene c-Rel. This portion of conserved to form active NF-kB transcription factors. amino acid sequence was termed the Rel ho- The two domains are joined by a short flexible mology region (RHR). As is discussed later, linker approximately 10 amino acids in length. the mRNA responsible for producing the A carboxy-terminal flexible region in which p50 subunit was found to encode a longer pre- is embedded the nuclear localization signal cursor protein of 105 kDa in size that possesses terminates the conserved RHR portion of the entire p50 amino-acid sequence at its the NF-kB subunits. Besides dimerization, this amino-terminal end and its own inhibitor RHR is responsible for sequence-specific DNA within its carboxy-terminal region. Once the binding, nuclear localization, and interaction cDNA encoding the p65 subunit (also known with IkB proteins. as RelA) was sequenced, it was also found to Outside of the conserved RHR, three NF-kB contain an amino-terminal RHR. Two subunits, p65/RelA, c-Rel, and RelB, contain a additional NF-kB family subunits, RelB and transcription activation domain (TAD) at p52 (the processed product of a longer their extreme carboxy-terminal ends. This 100-kDa precursor), were also discovered to region, which is poorly understood in protein harbor the conserved RHR within their amino- structural terms, is responsible for the increase terminal regions. These five polypeptides, p50, in target gene expression that results from p65/RelA, c-Rel, p52, and RelB, constitute the induction of NF-kB and, consequently, NF-kB entire family of NF-kB subunits encoded by dimers that possess at least one of these sub- the human genome (Fig. 2A). units function as activators of transcription. 2 Cite this article as Cold Spring Harb Perspect Biol 2009;1:a000075 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Proteins of the NF-kB Signaling Module A B Rel Homology Region (RHR) C Class I p50 433 NTD DimD LG Dimerization p52 NTD DimD L G 447 domain Linker Class II p65 NTD DimD L TAD 551 N c-Rel NTD DimD L TAD 619 Amino-terminal domain ReIB LZ NTD DimD L TAD 557 CDE C C C C D256 N200 Y269 F213 p50 p65 p50 p65 RHR RHR F GGG5´ N N N kB N R56 DNA R58 H66 Y59 Figure 2. The NF-kB family. (A) The human genome encodes five polypeptides that assemble in various dimer combinations to form active NF-kB transcription factors. Each of the subunits contains the Rel homology region (RHR) near its amino terminus. The RHR consists of two folded domains, the amino-terminal domain (NTD) and the dimerization domain (DimD), that are joined by a short flexible linker and a carboxy-terminal flexible region that contains the nuclear localization signal (L). Three of the subunits, p65, c-Rel, and RelB, also contain a transcription activation domain (TAD) at their carboxy-terminal ends. RelB contains a predicted leucine zipper motif (LZ) amino-terminal to its RHR. The NF-kB subunits p50 and p52 lack transactivation domains and have glycine-rich regions (G). (B) A ribbon diagram representation of the RHR from p50 in its DNA-bound conformation. (C) The NF-kB p50:p65/RelA heterodimer bound to kBDNA.(D) Another view of the complex. (E) The NF-kB p50:p65/RelA heterodimer dimerization domains with key amino acid side chains labeled. (F) kB DNA from the NF-kB:DNA complex with key base-contacting amino acid residues labeled. RelB also contains a predicted leucine zipper binding and activating target gene expression motif amino-terminal to its RHR. The NF- is mediated entirely by the dimerization kB subunits p50 and p52 lack transactivation domain. In theory, a total of 15 unique homo- domains. Rather, their extreme carboxy- and heterodimers are possible from combinato- terminal ends are rich in glycine. Consequently, rial dimerization of the five NF-kB subunits NF-kB dimers consisting exclusively of p50 (Hoffmann et al. 2006). Of these, 12 have and p52 subunits are capable of nuclear locali- been identified in vivo. Three that are not zation and DNA binding but fail to activate known to exist are the RelB:RelB, RelB:c-Rel, target gene expression and, in fact, function and p52:c-Rel. However, of these three, only both in vitro and in vivo as repressors of tran- RelB homodimer fails to exist in vivo, and the scription (Franzoso et al. 1992). status of the other two dimers is uncertain; they could exist under specialized conditions such as the p65/RelA:RelB heterodimer k NF- B Dimerization (Marienfeld et al. 2003). Assembly of individual NF-kB subunits into The homo- and heterotropic interactions dimers capable of sequence-specific DNA between NF-kB family subunits follow the Cite this article as Cold Spring Harb Perspect Biol 2009;1:a000075 3 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press T.
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