The Rel homology domain (RHD) is composed of two structural domains, an N-terminal DNA-binding domain () and a C-terminal dimerisation domain. This is the dimerisation domain [].This domain can be found in both nuclear factor of activated T cells (NFAT) and nuclear factor kappa-B (NFkB), which are RHD-containing transcription factors [].
Members of the Rel family share a highly conserved 300 amino acids domain termed Rel homology domain (RHD) which is located towards the amino terminus. The unique C terminus is thought to be involved in gene activation and cytoplasmic anchoring functions.For several proteins it has been demonstrated []that the Rel homology domain includes:a DNA-binding domain, which binds to the consensus DNA sequence motif5'-GGGRNNYYCC-3' (except for dorsal, which recognises the related motif5'-GRGAAAANCC-3');a dimerisation domain, which is located in the C-terminal part of theRHD;a PKA phosphorylation site (except in RelB);a nuclear localization signal (NLS), which consists of a stretch of fouror five basic residues.This entry represents a conserved site located at theN terminus of the RHD. It includes a conserved cysteine that seems tobe essential for DNA-binding in p50 [].
The Rel homology domain (RHD) is found in a family of eukaryotic transcription factors, which includes NF-kappaB, Dorsal, Relish, NFAT, among others. The RHD is composed of two structural domains: the N-terminal DNA binding domain that is similar to that found in P53, the C-terminal domain has an immunoglobulin-like fold (See ) that functions as a dimerisation domain. This entry represents the N-terminal DNA binding domain []. Some of these transcription factors appear to form multi-protein DNA-bound complexes []. Phosphorylation of the RHD appears to play a role in the regulation of some of these transcription factors, acting to modulate the expression of their target genes []. The RHD is composed of two immunoglobulin-like β-barrel subdomains that grip the DNA in the major groove. The N-terminal specificity domain resembles the core domain of the p53 transcription factor, and contains a recognition loop that interacts with DNA bases; the C-terminal dimerisation domain contains the site for interaction with I-kappaB [].
The Rel homology domain (RHD) is found in a family of eukaryotic transcription factors, which includes NF-kappaB, Dorsal, Relish, NFAT, among others. The RHD is composed of two structural domains: the N-terminal DNA binding domain that is similar to that found in P53, the C-terminal domain has an immunoglobulin-like fold (See ) that functions as a dimerisation domain. This entry represents the N-terminal DNA binding domain superfamily []. Some of these transcription factors appear to form multi-protein DNA-bound complexes []. Phosphorylation of the RHD appears to play a role in the regulation of some of these transcription factors, acting to modulate the expression of their target genes []. The RHD is composed of two immunoglobulin-like β-barrel subdomains that grip the DNA in the major groove. The N-terminal specificity domain resembles the core domain of the p53 transcription factor, and contains a recognition loop that interacts with DNA bases; the C-terminal dimerisation domain contains the site for interaction with I-kappaB [].
This entry represents the C-terminal 200 residues of the cactin protein, which is necessary for the association of cactin with the IkappaB protein cactus, as one of the intracellular members of the Rel complex. The Rel (NF-kappaB) pathway is conserved in invertebrates and vertebrates. In mammals, it controls the activities of the immune and inflammatory response genes as well as viral genes, and is critical for cell growth and survival. In Drosophila, the Rel pathway functions in the innate cellular and humoral immune response, in muscle development and in the establishment of dorsal-ventral polarity in the early embryo []. Most members of the family also have the conserved mid region of cactin () further upstream.
This entry represents the conserved central domain of cactin. It contains two of three predicted coiled-coil motifs. Most proteins containing this domain also have at the C-terminal end. Upstream of this domain in Drosophila proteins are a serine-rich region, some non-typical RD motifs and three predicted bipartite nuclear localisation signals, none of which are well-conserved.Cactin associates with IkappaB-cactus as one of the intracellular members of the Rel (NF-kappaB) pathway which is conserved in invertebrates and vertebrates. In mammals, this pathway controls the activities of the immune and inflammatory response genes as well as viral genes, and is critical for cell growth and survival. In Drosophila, the Rel pathway functions in the innate cellular and humoral immune response, in muscle development, and in the establishment of dorsal-ventral polarity in the early embryo [].
Protein tamozhennic (means 'customs officer' in Russian, also known as Tamo) has an essential role during oogenesis and embryogenesis. Tamo interacts with Dorsal and proteins of the nuclear import machinery. Translocation of the Rel protein Dorsal from the cytoplasm to the nucleus in a graded manner directs the development of the dorsal-ventral axis in Drosophila. Tamo is likely to have a role in nuclear import of Dorsal and other proteins [].
This family of bacterial metallo-peptidases is thought to compromise the inflammatory response by degrading p65, thereby down-regulating the NF-kappaB signalling pathway []. NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in 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.
C19orf12 codes for a transmembrane glycine zipper-containing mitochondrial protein of unknown function. Mutations of C19orf12 cause inability to respond to oxidative stress and increased mitochondrial Ca2+ []. Mutations in C19orf12 have been identified in patients affected by Neurodegeneration with Brain Iron Accumulation (NBIA), a condition characterised by iron accumulation in the basal ganglia []. Transgenic flies with impaired C19orf12 homologues also show the neurodegenerative phenotype []. This family also includes protein Nazo from Drosophila melanogaster, an orthologue of human C190rf12 which functions as an antiviral effector protein expressed downstream of Sting and Rel (Relish) signalling in response to viral infection [].
The Dorsal morphogen directs formation of the Drosophila dorsoventral axis by both activating and repressing transcription. It contains an N-terminal Rel homology domain (RHD), which is responsible for DNA binding and regulated nuclear import, and a C-terminal domain (CTD) that contains activation and repression motifs []. In wild-type embryos, the dorsal protein is found in the cytoplasm during cleavage. After the nuclei migrate to the periphery of the embryo, a ventral-to-dorsal gradient of nuclear dorsal protein is established [].Dorsal-related immunity factor Dif does not appear to participate in dorsoventral patterning, but instead mediates an immune response in Drosophila larvae. Dif is normally localised in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury. Once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes [].
NF-kappa B proteins are part of a protein complex that acts as a transcription factor, which is responsible for regulating a host of cellular responses to a variety of stimuli. This complex tightly regulates the expression of a large number of genes, and is involved in processes such as adaptive and innate immunity, stress response, inflammation, cell adhesion, proliferation and apoptosis. The cytosolic NF-kappa B complex is activated via phosphorylation of the ankyrin-repeat containing inhibitory protein I-kappa B, which dissociates from the complex and exposes the nuclear localization signal of the heterodimer (NF-kappa B and Rel) [, ]. c-Rel plays an important role in B cell proliferation and survival [].Proteins containing the Rel homology domain (RHD) are metazoan transcription factors. The RHD is composed of two structural sub-domains. This entry represents the N-terminal RHD sub-domain of the c-Rel family of transcription factors, categorized as a class II member of the NF-kappa B family. In class II NF-kappa Bs, the RHD domain co-occurs with a C-terminal transactivation domain (TAD) [, ].
Toll proteins or Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R) superfamily areboth involved in innate antibacterial and antifungalimmunity in insects as well as in mammals. These receptors share a conserved cytoplasmic domain of approximately 200 amino acids, known as the Toll/IL-1R homologous region (TIR). The similarity between TLRs and IL-1Rs is not restricted to sequence homology since these proteins also share a similar signalling pathway. They both induce the activation of a Rel type transcription factor via an adaptor protein and a protein kinase []. Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain [, , ]. Besides the mammalian and Drosophila proteins, a TIR domain is also found in a number of plant cytoplasmic proteins implicated in host defense [].Site directed mutagenesis and deletion analysis have shown that the TIR domain is essential for Toll and IL-1R activities. Sequence analysis have revealed the presence of three highly conserved regions among the different members of the family: box 1 (FDAFISY), box 2 (GYKLC-RD-PG), and box 3 (a conserved W surrounded by basic residues). It has been proposed that boxes 1 and 2 are involved in the binding of proteins involved in signalling, whereas box 3 is primarily involved in directing localization of receptor, perhaps through interactions with cytoskeletal element [].Resolution of the crystal structures of the TIR domains of human Toll-like receptors 1 and 2 has shown that they contain a central five-stranded parallel β-sheet that is surrounded by a total of five helices on both sides, with connecting loop structures []. The loop regions appear to play an important role in mediating the specificity of protein-proteininteractions [, ].
This entry represents the Toll/interleukin-1 receptor (TIR) domain, which is the conserved cytoplasmic domain of approximately 200 amino acids, found in Toll-like receptors (TLRs) and their adaptors. Proteins containing this domain can also be found in plants, where they mediate disease resistance [], and in bacteria, where they have been associated with virulence. Interestingly, the TIR domains from proteins present in all three major domains of life have been shown to cleave nicotinamide adenine dinucleotide (NAD+). In plants, TIR domains require self-association interfaces and a putative catalytic glutamic acid that is conserved in both bacterial TIR NAD+-cleaving enzymes (NADases) and the mammalian SARM1 (sterile alpha and TIR motif containing 1) NADase for cell death induction and NAD+ cleavage activity [, ]. It has been suggested that the primordial function of the TIR domain is the enzymatic cleavage of NAD+ and that the scaffolding function, which is best characterised in mammalian TIR domains involved in innate immunity, may be a more recent evolutionary adaptation [].Toll proteins or Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R) superfamily are both involved in innate antibacterial and antifungalimmunity in insects as well as in mammals. These receptors share a conserved cytoplasmic domain of approximately 200 amino acids, known as the Toll/IL-1R homologous region (TIR). The similarity between TLRs and IL-1Rs is not restricted to sequence homology since these proteins also share a similar signalling pathway. They both induce the activation of a Rel type transcription factor via an adaptor protein and a protein kinase []. Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain [, , ]. Besides the mammalian and Drosophila proteins, a TIR domain is also found in a number of plant cytoplasmic proteins implicated in host defense [].Site directed mutagenesis and deletion analysis have shown that the TIR domain is essential for Toll and IL-1R activities. Sequence analysis have revealed the presence of three highly conserved regions among the different members of the family: box 1 (FDAFISY), box 2 (GYKLC-RD-PG), and box 3 (a conserved W surrounded by basic residues). It has been proposed that boxes 1 and 2 are involved in the binding of proteins involved in signalling, whereas box 3 is primarily involved in directing localization of receptor, perhaps through interactions with cytoskeletal element [].Resolution of the crystal structures of the TIR domains of human Toll-like receptors 1 and 2 has shown that they contain a central five-stranded parallel β-sheet that is surrounded by a total of five helices on both sides, with connecting loop structures []. The loop regions appear to play an important role in mediating the specificity of protein-protein interactions [, ].
