This entry represents RelA, also known as nuclear factor NF-kappa-B p65 subunit. RelA and p50 is the mostly commonly found heterodimer complex among NF-kappaB homodimers and heterodimers, and is the functional component participating in nuclear transclocation and activation of NF-kappaB [].NF-kappaB is a pleiotropic transcription factor present in almost all cell types. It 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-kappaB is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RelA/p65, RelB, NFKB1/p50, c-Rel and NFKB2/p52 []. Each individual NF-kappaB subunit, and perhaps each dimer, carries out unique functions in regulating transcription. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins [].The prototypical NF-kB complex is a p50/RelA heterodimer. NF-kB is largely sequestered in the cytoplasm through its association with an IkB inhibitor []. Cytoplasmic events culminating in the phosphorylation of IkB-alpha lead to its polyubiquitylation and proteasome-mediated degradation. The liberated NF-kB complex translocates to the nucleus. In the nucleus, site-specific acetylation and phosphorylation of RelA regulates the actions of the NF-kB complex [, ].
RelA/SpoT homologue (RSH) proteins play a central role in bacterial stringent response. RelA (also referred to as ppGpp hydrolase/synthetase) and SpoT are activated during stress conditions and synthesize transcriptional modulators (p)ppGpp that allow bacteria to adapt to this condicions. They contain a TGS domain, named after the Threonyl-tRNA Synthetase, GTPase, and SpoT proteins where it occurs []. This domain of RelA binds the CCA tail to orient the free 3' hydroxyl group of the terminal adenosine towards a β-strand, thus an aminoacylated tRNA at this position would be sterically impeded. This association suppresses auto-inhibition and activates the synthesis of (p)ppGpp and initiates the stringent response. [, ].
SET domain methyltransferases can be involved both in translational and transcriptional roles. N-lysine methyltransferase SETD6 is a SET domain protein that specifically monomethylates 'Lys-310' of the RELA subunit of NF-kappa-B complex, leading to down-regulation of NF-kappa-B transcription factor activity []. Homologues in yeast monomethylate 60S ribosomal protein L42 (RPL42A and RPL42B) at 'Lys-55' [, ].
This entry represents the SET domain found in SETD6 and related proteins.SET domain methyltransferases can be involved both in translational and transcriptional roles. N-lysine methyltransferase SETD6 is a SET domain protein that specifically monomethylates 'Lys-310' of the RELA subunit of NF-kappa-B complex, leading to down-regulation of NF-kappa-B transcription factor activity []. Homologues in yeast monomethylate 60S ribosomal protein L42 (RPL42A and RPL42B) at 'Lys-55' [, ].
CDK5RAP3 (also known as C53 or LZAP) serves as a probable tumour suppressor initially identified as a CDK5R1 interactor controllingcell proliferation [, ]. It negatively regulates NF-kappa-B-mediated gene transcription through the control of RELA phosphorylation [, ]. It also regulates mitotic G2/M transition checkpoint and mitotic G2 DNA damage checkpoint [, ]. It has been shown to bind Wip1 and stimulates its phosphatase activity [].
RelA/SpoT-homologue proteins (RHS) mediate the stringent response in bacteria which enables its metabolic adaptation under stress conditions. These enzymes synthesize the second messenger (p)ppGpp, a small molecule also known as 'alarmone', which is a regulatory metabolite of the stringent response, characterised by growth arrest and the modulation of gene expression in response to various nutritional stresses [, , ]. Including in this group of proteins are RelA and SpoT, whose functions differ somewhat. RelA () produces pppGpp (or ppGpp) from ATP and GTP (or GDP), while SpoT () is a bifunctional enzyme that degrades ppGpp, but can also act as a ppGpp synthetase. In many species, a single homologue to SpoT and RelA , Rsh, appears responsible for both ppGpp synthesis and ppGpp degradation [, , ]. ppGpp together with c-di-GMP play an important role to control biofilm formation in response to translational stress [].These enzymes consist of a N-terminal domain which harbor (p)ppGpp hydrolase and synthetase activity and a stress-perceiving and regulatory C-terminal domain, which comprising four sub-domains: the TGS (ThrRS, GTPase, and SpoT), AH (alpha helical), RIS (ribosome inter-subunit), and ACT (aspartate kinase, chorismate mutase, TyrA) [, ].
This entry represents the alpha helical (AH) and Ribosome-InterSubunit (RIS) domains found in RelA/SpoT proteins, adjacent to the ACT domain [, ]. AH interacts with A/R tRNA and connects the RIS domain with the TGS domain. RIS domain is part of the binding interface between the C-terminal region and the ribosome, bridging the largeand the small ribosomal subunits. RIS contains a four-stranded β-sheet and a short α-helix.RelA/SpoT-homologue proteins (RHS) mediate the stringent response in bacteria which enables its metabolic adaptation under stress conditions. These enzymes synthesize the second messenger (p)ppGpp, a small molecule also known as 'alarmone', which is a regulatory metabolite of the stringent response, characterised by growth arrest and the modulation of gene expression in response to various nutritional stresses [, , ]. Including in this group of proteins are RelA and SpoT, whose functions differ somewhat. RelA () produces pppGpp (or ppGpp) from ATP and GTP (or GDP), while SpoT () is a bifunctional enzyme that degrades ppGpp, but can also act as a ppGpp synthetase. In many species, a single homologue to SpoT and RelA , Rsh, appears responsible for both ppGpp synthesis and ppGpp degradation [, , ]. ppGpp together with c-di-GMP play an important role to control biofilm formation in response to translational stress [].These enzymes consist of a N-terminal domain which harbor (p)ppGpp hydrolase and synthetase activity and a stress-perceiving and regulatory C-terminal domain, which comprising four sub-domains: the TGS (ThrRS, GTPase, and SpoT), AH (alpha helical), RIS (ribosome inter-subunit), and ACT (aspartate kinase, chorismate mutase, TyrA) [, ].
Histone-lysine N-methyltransferase EHMT1, () mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin []. H3K9me is a specific tag for repression of epigenetic transcription, recruiting HP1 proteins to methylated histones. EHMT1 also methylates 'Lys-27' of histone H3 (H3K27me), but weakly []. EHMT1 also dimethylates other proteins, including 'Lys-373' of p53 []. EHMT1 forms a heterodimer with EHMT2 [], and is a component of the E2F6.com-1 complex in G0 phase []. EHMT1 contains eight ankyrin repeats which bind the monomethylated RELA subunit of NF-kappa-B, a SET domain which interacts with WIZ [], and a pre-SET domain that binds three zinc ions via cysteine residues [].
Histone-lysine N-methyltransferase EHMT1, () mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin []. H3K9me is a specific tag for repression of epigenetic transcription, recruiting HP1 proteins to methylated histones. EHMT1 also methylates 'Lys-27' of histone H3 (H3K27me), but weakly []. EHMT1 also dimethylates other proteins, including 'Lys-373' of p53 []. EHMT1 forms a heterodimer with EHMT2 [], and is a component of the E2F6.com-1 complex in G0 phase []. EHMT1 contains eight ankyrin repeats which bind the monomethylated RELA subunit of NF-kappa-B, a SET domain which interacts with WIZ [], and a pre-SET domain that binds three zinc ions via cysteine residues [].
This entry includes the catalytic domains of Escherichia coli ppGpp synthetase (RelA), ppGpp synthetase/hydrolase (SpoT), and related proteins. The functions of Escherichia coli RelA and SpoT differ somewhat. RelA () produces pppGpp (or ppGpp) from ATP and GTP (or GDP) in response to amino-acid starvation and in association with ribosomes []. SpoT () degrades ppGpp, but may also act as a secondary ppGpp synthetase under carbon limitation in a ribosome-independent manner [, ]. Gram-negative bacteria have two enzymes involved in (p)ppGpp metabolism while most Gram-positive organisms have a single Rel-Spo enzyme (Rel), which both synthesizes and degrades (p)ppGpp [, ]. The Arabidopsis thaliana Rel-Spo proteins, At-RSH1, At-RSH2, and At-RSH3 appear to regulate a rapid (p)ppGpp-mediated response to pathogens and other stresses []. This catalytic domain is found in association with an N-terminal HD domain and a C-terminal metal dependent phosphohydrolase domain (TGS). Some Rel-Spo proteins also have a C-terminal regulatory ACT domain. This subgroup belongs to the Pol beta-like NT superfamily [, ]. (p)ppGpp is a regulatory metabolite of the stringent response [], but appears also to be involved in antibiotic biosynthesis in some species []. In the Pol beta-like NT superfamily [, ], the majority of enzymes have two carboxylates, Dx[D/E], together with a third more distal carboxylate, which coordinate two divalent metal cations involved in a two-metal ion mechanism of nucleotide addition. These carboxylate residues are fairly well conserved in this family.
Histone-lysine N-methyltransferase EHMT2 () mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin []. H3K9me is a specific tag for repression of epigenetic transcription, recruiting HP1 proteins to methylated histones. EHMT2 also monomethylates 'Lys-56' of histone H3 (H3K56me1) during the G1 phase of the cell cycle [], and methylates 'Lys-27' of histone H3 (H3K27me) []. EHMT2 also dimethylates other proteins [], including 'Lys-373' of p53 []. EHMT2 forms a heterdimer with EHMT1 [], and is a component of the E2F6.com-1 complex in G0 phase []. EHMT2 contains seven ankyrin repeats which bind the monomethylated RELA subunit of NF-kappa-B, a SET domain which interacts with WIZ [], and a pre-SET domain that binds three zinc ions via cysteine residues [].
This entry represents ribosomal protein S6 kinase II []. This enzyme acts as a serine/threonine kinase required for the mitogen or stress-induced phosphorylation of the transcription factors CREB (cAMP response element-binding protein) and ATF1 (activating transcription factor-1). It plays an essential role in the control of RELA transcriptional activity in response to TNF. It directly represses transcription via phosphorylation of Ser-1 of histone H2A. It phosphorylates Ser-10 of histone H3 in response to mitogenics, stress stimuli and epidemal growth-factor (EGF), which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. It mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 14 (HMG-14). It requires magnesium ions as a cofactor.
This entry represents a family of proteins from bacteria, archaea and animals, including Interleukin-1 receptor-associated kinase 1-binding protein 1 from mouse, which has been named SIMPL (signalling molecule that associates with mouse pelle-like kinase). SIMPL is a component of the IRAK1-dependent TNFRSF1A signaling pathway that leads to NF-kappa-B activation and is required for cell survival. It functions by enhancing RelA transcriptional activity [, ]. Separate experiments demonstrate that a mouse family member (named LaXp180) binds the Listeria monocytogenes surface protein ActA, which is a virulence factor that induces actin polymerisation. It may also bind stathmin, a protein involved in signal transduction and in the regulation of microtubule dynamics []. In bacteria its function is unknown, but it is thought to be located in the periplasm or outer membrane.
Terpenes are among the largest groups of natural products and include compounds such as vitamins, cholesterol and carotenoids. The biosynthesis of all terpenoids begins with one or both of the two C5 precursors of the pathway: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). In animals, fungi, and certain bacteria, the synthesis of IPP and DMAPP occurs via the well-known mevalonate pathway, however, a second, nonmevalonate terpenoid pathway has been identified in many eubacteria, algae, malaria parasite and the chloroplasts of higher plants [, , ].LytB(IspH) is the last enzyme in the biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) in the 1-deoxy-d-xylulose-5-phosphate (DOXP, the nonmevalonate pathway, also known as MEP) pathway []. This enzyme contains a [4Fe-4S]cluster and forms a stable complex with ferredoxin, which suggests that ferredoxin/ferredoxin-NADP+ reductase redox system serves as the physiological electron donor for LytB []. Escherichia coli LytB protein had been found to regulate the activity of RelA (guanosine 3',5'-bispyrophosphate synthetase I), which in turn controls the level of a regulatory metabolite. It is involved in penicillin tolerance and the stringent response [].
