Like all apoptotic cell death, T cell receptor (TCR)-mediated death can bedivided into two phases: an inductive phase and an effector phase. The effector phase includes a sequence of steps that are common to apoptosis inmany cell types, which, if not interrupted, will lead to cell death. Theinduction phase, which often requires the expression of new genes, consistsof a set of signals that activate the effector phase. Outside the thymus,most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimesreferred to as activation-induced cell death (AICD)) is induced through thesurface antigen Fas pathway: activation through the TCR induces expressionof the Fas (CD95) ligand (FasL); the expression of FasL on either aneighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas,which then initiates a signal-transduction cascade, leading to apoptosis of the Fas-bearing cell. This commitment stage requires the activation of keydeath-inducing enzymes, termed caspases, which act by cleaving proteins that are essential for cell survival and proliferation[, ].Fas is also known to be essential in the death of hyperactivated peripheralCD4+ cells: in the absence of Fas, mature peripheral T cells do not die, butthe activated cells continue to proliferate, producing cytokines that leadto grossly enlarged lymph nodes and spleen. Fas belongs to the tumournecrosis factor receptor (TNFR) family of cysteine-rich type I membranereceptors; its ligand (FasL) is expressed on activated lymphocytes, NK cells,platelets, certain immune-privileged cells and some tumour cells [, ].Defects in the Fas-FasL system are associated with various disease syndromes.Mice with non-functional Fas or FasL display characteristics of lympho-proliferative disorder, such as lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. These mice also secrete anti-DNA autoantibodiesand rheumatoid factor [].
This entry represents the death domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS [, ]. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity [].DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes [, ].
FAIM1 (Fas apoptotic inhibitory molecule 1) plays a role as an inducible effector molecule that mediates Fas resistance produced by surface Ig engagement in B cells [].
Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as Fas cell surface death receptor (FasR), Fas, APT1, CD95, FAS1, APO-1, FASTM, or ALPS1A, contains a death domain and plays a central role in the physiological regulation of programmed cell death [, ]. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system [, ]. The receptor interacts with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells [, , ].This entry represents the N-terminal domain of FasR. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
This entry consists of proteins related to the eukaryotic Fas-activated serine/threonine (FAST) kinases that contain several conserved leucine residues. FAST kinase is rapidly activated during Fas-mediated apoptosis, when it phosphorylates TIA-1, a nuclear RNA-binding protein that has been implicated as an effector of apoptosis []. However, a critical active site residues are not conserved within the family and its kinase activity has been questioned. FASTK localizes to nucleus, cytosol and mitochondria. In mitochondria, FASTK concentrates in mitochondrial RNA granules, where it interacts with the G-rich se-quence factor 1 (GRSF1) and MT-ND6 mRNA [].
RNA-binding protein 5 (RBM5), also known as LUCA15, is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, c-FLIP []and caspase 2 []. In the case of FAS, it promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis [, ]. In the case of CASP2/caspase-2, it promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis [].
This entry represents the RNA recognition motif 1 (RRM1) of RNA-binding protein 5.RNA-binding protein 5 (RBM5), also known as LUCA15, is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, c-FLIP []and caspase 2 []. In the case of FAS, it promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis [, ]. In the case of CASP2/caspase-2, it promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis [].
This entry represents the RNA recognition motif 2 (RRM2) of RNA-binding protein 5.RNA-binding protein 5 (RBM5), also known as LUCA15, is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, c-FLIP []and caspase 2 []. In the case of FAS, it promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis [, ]. In the case of CASP2/caspase-2, it promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis [].
This entry represents the Fas-associated death domain protein FADD. This is an apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate, called the death-inducing signalling complex (DISC), performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. For further information see [, , , , ].
The OCtamer REpeat (OCRE) has been annotated as a 42-residue sequence motif with 12 tyrosine residues in the spliceosome trans-regulatory elements RBM5 and RBM10 (RBM [RNA-binding motif]), which are known to regulate alternative splicing of Fas and Bcl-x pre-mRNA transcripts []. The structure of the domain consists of an anti-parallel arrangement of six beta strands.
FAIM1 (Fas apoptotic inhibitory molecule 1) plays a role as an inducible effector molecule that mediates Fas resistance produced by surface Ig engagement in B cells [].FAIM1 contains two independently folding domains []. The C-terminal domain folds as a non-conventional β-sandwich, and the N-terminal domain has a similar conformation containing eight antiparallel β-strands []. This superfamily recognizes both of them.
This entry represents the RNA recognition motif 2 (RRM2) of RNA-binding protein 10.RBM10, also known as S1-1, is a nuclear RNA-binding protein with domains characteristic of RNA processing proteins. Similar to RBM5, it promotes exon skipping of Fas pre-mRNA as well as selection of an internal 5'-splice site in Bcl-x pre-mRNA []. It preferentially binds to G- and U-rich RNA sequences [].
RBM10, also known as S1-1, is a nuclear RNA-binding protein with domains characteristic of RNA processing proteins. Similar to RBM5, it promotes exon skipping of Fas pre-mRNA as well as selection of an internal 5'-splice site in Bcl-x pre-mRNA []. It preferentially binds to G- and U-rich RNA sequences [].
This domain is found in the fatty acid synthase (FAS) type I complex found in Actinobacteria such as Mycobacterium smegmatis and fungal species such as Thermomyces lanuginosus. FAS is a homo-hexameric enzyme that catalyzes synthesis of fatty acid precursors of mycolic acids. This domain is composed of dimerization module 1 (DM1) and four-helix bundle (4HB), both of which are conserved parts of the acetyl transferase [].
This entry includes human E3 ubiquitin-protein ligase MARCH proteins (MARCH1/2/3/4/5/8/9/11), and virus proteins (MIR1, MIR2, LAP and VIE1) that share homology with the MARCH proteins [, ]. Human MARCH1 mediates ubiquitination of TFRC, CD86, FAS and MHC class II proteins, such as HLA-DR alpha and beta, and promotes their subsequent endocytosis and sorting to lysosomes via multivesicular bodies []. Virus MIR1 has been shown to function as an E3 ubiquitin ligase for immune recognition-related molecules [].
This is the acyl carrier domain (ACP) found in fatty acid synthase subunit alpha (FAS2). The fungal type I fatty acid synthase (FAS) is a 2.6 MDa multienzyme complex, catalyzing all necessary steps for the synthesis of long acyl chains. To be catalytically competent, the FAS must be activated by a posttranslational modification of the central acyl carrier domain (ACP) by an intrinsic phosphopantetheine transferase (PPT) [].
Fatty acid synthesis (FAS) is a vital aspect of cellular physiology which can occur by two distinct pathways. The FAS I pathway, which generally only produces palmitate, is found in eukaryotes and is performed either by a single polypeptide which contains all the reaction centres needed to form a fatty acid, or by two polypeptides which interact to form a multifunctional complex. The FAS II pathway, which is capable of producing many different fatty acids, is found in mitochondria, bacteria, plants and parasites, and is performed by many distinct proteins, each of which catalyses a single step within the pathway. The large diversity of products generated by this pathway is possible because the acyl carrier protein (ACP) intermediates are diffusible entities that can be diverted into other biosynthetic pathways [].3-Oxoacyl-[acyl carrier protein (ACP)]synthase III catalyses the first condensation step within the FAS II pathway, using acetyl-CoA as the primer and malonyl-ACP as the acceptor, as shown below.Acyl-[ACP]+ malonyl-[ACP]= 3-oxoacyl-[ACP]+ CO(2) + [ACP]The oxoacyl-ACP formed by this reaction subsequently enters the elongation cycle, where the acyl chain is progressively lengthened by the combined activities of several enzymes.The enzymes studied so far are homodimers, where each monomer consists of two domains (N-terminal and C-terminal) which are similar in structure, but not in sequence [, ].This entry represents a conserved region within the N-terminal domain.
Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as Fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, contains a death domain and plays a central role in the physiological regulation of programmed cell death [, ]. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system [, ]. The receptor interacts with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells [, , ].In channel catfish and the Japanese rice fish medaka, homologues of Fas receptor (FasR), as well as FADD and caspase 8, have been identified and characterized, and likely constitute the teleost equivalent of the death-inducing signaling complex (DISC) [, ]. FasL/FasR are involved in the initiation of apoptosis and suggest that mechanisms of cell-mediated cytotoxicity in teleosts are similar to those used by mammals; presumably, the mechanism of apoptosis induction via death receptors was evolutionarily established during the appearance of vertebrates.This entry represents the N-terminal domain of TNFRSF6/Fas from teleosts. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
Beta-ketoacyl-ACP synthase (EC 2.3.1.41) (KAS) []is the enzyme that catalyses the condensation of malonyl-ACP with the growing fatty acid chain. It is found as a component of the following enzymatic systems:Fatty acid synthase (FAS), which catalyses the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. Bacterial and plant chloroplast FAS are composed of eight separate subunits which correspond to different enzymatic activities; beta-ketoacyl synthase is one of these polypeptides. Fungal FAS consists of two multifunctional proteins, FAS1 and FAS2; the beta-ketoacyl synthase domain is located in the C-terminal section of FAS2. Vertebrate FAS consists of a single multifunctional chain; the beta-ketoacyl synthase domain is located in the N-terminal section []. The multifunctional 6-methysalicylic acid synthase (MSAS) from Penicillium patulum []. This is a multifunctional enzyme involved in the biosynthesis of a polyketide antibiotic and which has a KAS domain in its N-terminal section.Polyketide antibiotic synthase enzyme systems. Polyketides are secondary metabolites produced by microorganisms and plants from simple fatty acids. KAS is one of the components involved in the biosynthesis of the Streptomyces polyketide antibiotics granatacin [], tetracenomycin C []and erythromycin. Emericella nidulans multifunctional protein Wa. Wa is involved in the biosynthesis of conidial green pigment. Wa is protein of 216 Kd that contains a KAS domain.Rhizobium nodulation protein nodE, which probably acts as a beta-ketoacyl synthase in the synthesis of the nodulation Nod factor fatty acyl chain. Yeast mitochondrial protein Cem1.The condensation reaction is a two step process: the acyl component of anactivated acyl primer is transferred to a cysteine residue of the enzyme andis then condensed with an activated malonyl donor with the concomitant releaseof carbon dioxide.This entry represents the active site of beta-ketoacyl-ACP synthases [].
Prostate apoptosis response 4 (Par-4) induced apoptosis of selective prostate cancer cells PC-3, DU-145, and TSU-Pr and caused tumor regression by inhibition of NF-kappaB activity and cell membrane trafficking of Fas and FasL that leads to the activation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway []. It modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. It down-regulates the anti-apoptotic protein BCL2 via its interaction with WT1 []. Par-4 also regulates the amyloid precursor protein (APP) cleavage activity of BACE1 [].
RBM10 contains two N-terminal RNA recognition motifs (RRMs) and an OCtamer REpeat (OCRE) domain, two C2H2-type zinc fingers, and a G-patch/D111 domain. This entry represents the OCRE domain.RBM10, also known as S1-1, is a nuclear RNA-binding protein with domains characteristic of RNA processing proteins.Similar to RBM5, it promotes exon skipping of Fas pre-mRNA as well as selection of an internal 5'-splice site in Bcl-x pre-mRNA []. It preferentially binds to G- and U-rich RNA sequences [].The OCRE (OCtamer REpeat) domain contains five repeats of an 8-residue motif, which were shown to form β-strands. Based on the architectures of proteins containing OCRE domains, a role in RNA metabolism and/or signalling has been proposed [].
This family consists of adenovirus E1B 19kDa protein or small t-antigen. The E1B 19kDa protein inhibits E1A induced apoptosis and hence prolongs the viability of the host cell []. It can also inhibit apoptosis mediated by tumour necrosis factor alpha and Fas antigen []. E1B 19kDa blocks apoptosis by interacting with and inhibiting the p53-inducible and death-promoting Bax protein []. The E1B region of adenovirus encodes two proteins E1B 19kDa the small t-antigen as found in this family and E1B 55kDa thelarge t-antigen which is not found in this family; bothof these proteins inhibit E1A induced apoptosis [].
This entry includes chromatin assembly factor 1 subunit CHAF1B (also known as p60 subunit) from animals, and its homologues such as Cac2 from yeasts and FAS from Arabidopsis. They are a component of the chromatin assembly factor complex (CAF-1), an evolutionarily conserved heterotrimeric chaperone comprised of p150, p60 and p48 subunits, mediates DNA synthesis-coupled chromatin assembly in S-phase. It is also involved in chromatin assembly following DNA repair [, ]. In plants, the loss of activity of the CAF1 pathway causes delay and arrest of the cell cycle during pollen development []. The CAF1 complex is also required for stable maintenance of telomeres and 45S rDNA in Arabidopsis [].
Like all apoptotic cell death, T cell receptor (TCR)-mediated death can bedivided into two phases: an inductive phase and an effector phase. The effector phase includes a sequence of steps that are common to apoptosis inmany cell types, which, if not interrupted, will lead to cell death. Theinduction phase, which often requires the expression of new genes, consistsof a set of signals that activate the effector phase. Outside the thymus,most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimesreferred to as activation-induced cell death (AICD)) is induced through thesurface antigen Fas pathway: activation through the TCR induces expressionof the Fas (CD95) ligand (FasL); the expression of FasL on either aneighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas,which then initiates a signal-transduction cascade, leading to apoptosis of the Fas-bearing cell. This commitment stage requires the activation of keydeath-inducing enzymes, termed caspases, which act by cleaving proteins thatare essential for cell survival and proliferation[, ]. However whathappens to FasL itself remains unknown. It is possible that it is cleavedfrom the effector cells and internalised into the target cells; it may bedownregulated in the effector cells; or it may be phagocytosed by the targetcells.Fas is also known to be essential in the death of hyperactivated peripheralCD4 cells: in the absence of Fas, mature peripheral T cells do not die, butthe activated cells continue to proliferate, producing cytokines that leadto grossly enlarged lymph nodes and spleen. Defects in the Fas-FasL systemare associated with various disease syndromes. Mice with non-functional Fasor FasL display characteristics of lymphoproliferative disorder, such as lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. Thesemice also secrete anti-DNA autoantibodies and rheumatoid factor [].FasL (also known as tumor necrosis factor ligand superfamily member 6) is a 40kDa type II membrane protein belonging to the tumour necrosisfactor (TNF) family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. It is expressed on activated lymphocytes, NK cells,platelets, certain immune-privileged cells and some tumour cells[, ]. The cell death-inducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL [].Human and mouse FasL induce apoptosis in cells expressing either mouse orhuman Fas with the same specificity. Although the amino acid sequence ofFasL is highly conserved between human and mouse, the similarity betweenhuman and murine Fas is much less pronounced. Greater conservation of theligand than the receptor is also observed in other members of the TNF family.By comparison with other TNF family members, FasL has a long N-terminal intracellular region rich in proline residues, which is known tobind to the SH3 domain. SH3 domains play important roles in mediating specificprotein-protein interactions, specifically in the cytoskeleton.
This entry represents the RNA recognition motif (RRM) of SPF45. SPF45, also termed RNA-binding motif protein 17 (RBM17), is an RNA-binding protein consisting of an unstructured N-terminal region, followed by a G-patch motif and a C-terminal U2AF (U2 auxiliary factor) homology motifs (UHM) that harbours a RNA recognition motif (RRM) and an Arg-Xaa-Phe sequence motif. SPF45 is a bifunctional protein that functions in splicing and DNA repair. It is involved in regulating alternative splicing of the apoptosis regulatory gene FAS (also called CD95). Its UHM binds UHM-ligand motifs (ULMs) present in the 3' splice site-recognizing factors U2AF65, SF1 and SF3b155 []. It binds to the Holliday junction, which is a key DNA intermediate in the homologous-recombination pathway [, ].
Adenoviruses are medium-sized, non-enveloped viruses containing double-stranded DNA. They can cause a variety of diseases including pneumonia, cystitis, conjunctivitis and diarrhoea, all of which can be fatal to patients who are immunocompromised []. These viruses have many mechanisms to evade the host immune response, including several proteins which are expressed as part of the early transcription unit 3 (E3) []. One of the regions of E3, known as the E3B region, encodes three proteins known as 10.4K, 14.5K and 14.7K. Two of these proteins, 10.4K and 14.5K, formthe RID complex (receptor internalisation and degradation) which protects the infected cell from host-induced lysis by clearing the the TNF and Fas receptors from the cell surface []. Other receptors, such as the epidermal growth factor receptor, are also known to be cleared by RID []. This entry represents the E3B region 10.4K protein, also known as the RID alpha subunit.
The yeast fatty acid synthase (FAS) is a hexameric complex (alpha 6 beta 6) of two multifunctional proteins, alpha and beta []. The alpha subunit contains two of the seven enzymatic activities required for the synthesis of fatty acids, together with the site for attachment of the prosthetic group 4'-phosphopantetheine. The beta subunit contains the remaining five enzyme domains: acetyltransferase and malonyltransferase, s-acyl fatty acid synthase thioesterase, enoyl-[acyl-carrier protein]reductase, and 3-hydroxypalmitoyl-[acyl-carrier protein]dehydratase.The sequential order of the five FAS1-encoded enzyme domains is co-linear in Yarrowia lipolytica (Candida lipolytica) and Saccharomyces cerevisiae (Baker's yeast), which observation is consistent with evidence that the functional organisation of FAS genes is similar in related organisms but differs between unrelated species [].Sterigmatocystin (ST) and the aflatoxins (AFs) (related fungal secondary metabolites) are among the most toxic, mutagenic and carcinogenic natural products known []. In Emericella nidulans (Aspergillus nidulans), the ST biosynthetic pathway is believed to involve at least 15 enzymatic activities; some Aspergillus parasiticus, Aspergillus flavus and Aspergillus nomius strains contain additional activities that convert ST to AF. A 60kb region of the A. nidulans genome has been characterised and found to contain virtually all of the genes needed for ST biosynthesis []. The deduced polypeptide sequences of regions within this cluster share a high degree of similarity with enzymes that have activities predicted for ST/AF biosynthesis, including a polyketide synthase, a fatty acid synthase (alpha and beta subunits), five monooxygenases, four dehydrogenases, an esterase, an 0-methyltransferase, a reductase, an oxidase and a zinc cluster DNA binding protein [].
A number of proteins, some of which are known to be receptors for growth factors, have been found to contain a cysteine-rich domain of about 110 to 160 amino acids in their N-terminal part, that can be subdivided into four (or in some cases, three) modules of about 40 residues containing 6 conserved cysteines. Some of the proteins containing this domain are listed below [, , ]:Tumor Necrosis Factor type I and type II receptors (TNFR). Both receptors bind TNF-alpha and TNF-beta, but are only similar in the cysteine-rich region. TNFR contains four cysteine-rich domain modules (CRDs), termed CRD1 through CRD4. CRD2 and CRD3 are known as TNF-binding domains [].Shope fibroma virus soluble TNF receptor (protein T2)Lymphotoxin alpha/beta receptorLow-affinity nerve growth factor receptor (LA-NGFR) (p75)CD40 (Bp50), the receptor for the CD40L (or TRAP) cytokineCD27, the receptor for the CD27L cytokineCD30, the receptor for the CD30L cytokineT-cell protein 4-1BB, the receptor for the 4-1BBL putative cytokine FAS antigen (or APO-1), the receptor for FASL, a protein involved in apoptosis (programmed cell death)T-cell antigen OX40, the receptor for the OX40L cytokineWsl-1, a receptor (for a yet undefined ligand) that mediates apoptosisVaccinia virus protein A53 (SalF19R)It has been shown []that the six cysteines all involved in intrachaindisulphide bonds. A schematic representation of the structure of the 40 residuemodule of these receptors is shown below:+-------------+ +--------------+| | | |xCxxxxxxxxxxxxxCxCxxCxxxxxxxxxCxxxxCxx| |+------------+'C': conserved cysteine involved in a disulphide bond.
Tumor necrosis factor receptor superfamily member 10 (TNFRSF10) family contains TNFRSF10A (also known as DR4, Apo2, TRAIL-R1, CD261), TNFRSF10B (also known as DR5, KILLER, TRICK2A, TRAIL-R2, TRICKB, CD262), TNFRSF10C (also known as DcR1, TRAIL-R3, LIT, TRID, CD263), and TNFRSF10D (also known as DcR2, TRUNDD, TRAIL-R4, CD264). Tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL) binds to all 4 receptors.DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are membrane-bound and contain a death domain in their intracellular portion, which is able to transmit an apoptotic signal, thus often called death receptors. In contrast, DcR1 (TRAIL-R3), which lacks the complete intracellular portion and DcR2 (TRAIL-R4), which has a truncated cytoplasmic death domain, do not transmit an apoptotic signal, thus known as decoy receptors [, ]. Apoptosis mediated by DR4 and DR5 requires Fas (TNFRSF6)-associated via death domain (FADD), a death domain containing adaptor protein []. DcR1 appears to function as an antagonistic receptor that protects cells from TRAIL-induced apoptosis; DcR2 has been shown to play an inhibitory role in TRAIL-induced cell apoptosis []. The membrane expression of all of these receptors (DR4, DR5, DcR1, and DcR2) is greater in normal endometrium (NE) than in endometrioid adenocarcinoma (EAC) [, ]. In EAC patients, membrane expression of these receptors are not independent predictors of survival. DcR1 and DcR2 expression is critical in cell growth and apoptosis in cutaneous or uveal melanoma []; DcR1 and DcR2 are frequently methylated in both, leading to loss of gene expression and melanomagenesis. On the other hand, DR4 and DR5 methylation is rare in cutaneous melanoma and frequent in uveal melanoma; their expression is wholly independent of the promoter methylation status. DcR1 and DcR2 genes are also reported to be hyper-methylated in prostate cancer []. The TRAIL ligand, a potent and specific inducer of apoptosis in cancer cells, has been explored as a therapeutic drug; experimental data has shown that DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer [].This entry represents the N-terminal domain of TNFRSF10. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
This family contains thioesterases involved in non-ribosomal peptide biosynthesis or polyketide biosynthesis, as well as those involved in vertebrate fatty acid biosynthesis (medium-chain S-acyl fatty acid synthase thioesterases, ). Based on domain architecture, they belong to type II (stand-alone, non-integrated) thioesterases (TEII). Based on the structural fold, they belong to the thioesterases of the α/β hydrolase fold. This group of thioesterases is distantly related to the integrated (type I) thioeterases that are intrinsic components of animal fatty acid synthase and in this context serve to terminate chain elongation.Prokaryotic members of this family are involved in non-ribosomal peptide biosynthesis or polyketide biosynthesis. Type I polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are organised into modules, each adding one fatty acid or amino acid substrate to a growing chain []. Synthetic intermediates are covalently tethered by thioester linkages to a carrier protein domain in each module. Cyclization and release of the product is catalysed by the type I thioesterase (TEI) which is usually fused C-terminally to the last module (integrated) [, , , , ]. In most systems, another component, type II thioesterase, represented by this family, is also present.For example, SrfTE is a TEI domain embedded at the downstream end of the final subunit, SrfC [], and SrfA-TE is a stand-alone TEII []. These enzymes are not essential; however, they are important for effective synthesis, because deletion of the genes leads to a drastic reduction in product yields []. TEII enzymes that are associated with the synthetases of the peptide antibiotics surfactin (TEIIsrf) and bacitracin (TEIIbac) were shown to efficiently regenerate miss-acylated thiol groups of 4 -phosphopantetheine (4 PP) cofactors attached to the peptidyl carrier proteins (PCPs) of NRPSs []. Therefore, the role of TEIIs in non-ribosomal peptide synthesis is the regeneration of miss-acylated NRPSs, which result from the apo to holo conversion of NRPS enzymes because of the promiscuity of dedicated 4 PP transferases that use not only free CoA, but also acyl-CoAs as 4 PP donors [].Members of this family from vertebrates are medium-chain S-acyl fatty acid synthase thioesterases (TEII, ). They are tissue-specific (found in mammary glands of nonruminants and uropygial glands of waterfowl) chain-terminating enzymes of the fatty acid biosynthesis pathway for the synthesis of shorter chain fatty acids instead of palmitic acid as the major product. TEIIs are stand-alone enzymes that interact with the fatty acid synthase complex and catalyse premature release of the growing acyl chain [, ].Thioesterases are classified into two structural classes: those with a classical α/β hydrolase fold, containing a classic Ser-His-Asp triad in the active site [], and those with a "hot dog"fold [](e.g., , , etc). Typically, those of the former class act on acylated proteins (Acyl-ACP etc), while those of the latter class act on CoA thioesters. Members of this family, as well as related integrated non-ribosomal peptide/polyketide biosynthesis thioesterases and FAS thioesterases, belong to the α/β hydrolase fold class [].Nomenclature note: In the Escherichia coli nomenclature, there are thioesterase I (TesA) and thioesterae II (TesB, ) enzymes. This nomenclature is not derived from the type I and type II classification based on domain architecture (note that both TesA and TesB are stand-alone thioesterases). Therefore, the term TEII is being used by different authors either as a reference to the stand-alone type TE or as a reference to the TesB group, or both.
This domain includes the C-terminal domain from the fungal alpha aminoadipate reductase enzyme (also known as aminoadipate semialdehyde dehydrogenase) which is involved in the biosynthesis of lysine [], as well as the reductase-containing component of the myxochelin biosynthetic gene cluster, MxcG []. The mechanism of reduction involves activation of the substrate by adenylation and transfer to a covalently-linked pantetheine cofactor as a thioester. This thioester is then reduced to give an aldehyde (thus releasing the product) and a regenerated pantetheine thiol []; in myxochelin biosynthesis this aldehyde is further reduced to an alcohol or converted to an amine by an aminotransferase. This is a fundamentally different reaction than beta-ketoreductase domains of polyketide synthases which act at a carbonyl two carbons removed from the thioester and forms an alcohol as a product. The majority of bacterial sequences containing this domain are non-ribosomal peptide synthetases in which this domain is similarly located proximal to a thiolation domain. In some cases this domain is found at the end of a polyketide synthetase enzyme, but is unlike ketoreductase domains which are found before the thiolase domains. Exceptions to this observed relationship with the thiolase domain include three proteins which consist of stand-alone reductase domains (from Mycobacterium leprae, Anabaena and from Streptomyces coelicolor) and one protein (from Nostoc) which contains N-terminal homology with a small group of hypothetical proteins but no evidence of a thiolation domain next to the putative reductase domain.This family consists of a short-chain dehydrogenase/reductase (SDR) module of multidomain proteins identified as putative polyketide sythases fatty acid synthases (FAS), and nonribosomal peptide synthases, among others. However, unlike the usual ketoreductase modules of FAS and polyketide synthase, these domains are related to the extended SDRs, and have canonical NAD(P)-binding motifs and an active site tetrad. Extended short-chain dehydrogenases/reductases (SDRs) are distinct from classical SDRs. In addition to the Rossmann fold (alpha/beta folding pattern with a central β-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids. Extended SDRs are a diverse collection of proteins, and include isomerases, epimerases, oxidoreductases, and lyases; they typically have a TGXXGXXG cofactor binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Classical SDRs have an TGXXX[AG].XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif [, , , , , , , ].
