Members of this family are involved in cobalamin synthesis. The gene encoded by Swiss:P72862 has been designated cbiH but in fact represents a fusion between cbiH and cbiG. As other multi-functional proteins involved in cobalamin biosynthesis catalyse adjacent steps in the pathway, including CysG, CobL (CbiET), CobIJ and CobA-HemD, it is therefore possible that CbiG catalyses a reaction step adjacent to CbiH. In the anaerobic pathway such a step could be the formation of a gamma lactone, which is thought to help to mediate the anaerobic ring contraction process [1]. Within the cobalamin synthesis pathway CbiG catalyses the both the opening of the lactone ring and the extrusion of the two-carbon fragment of cobalt-precorrin-5A from C-20 and its associated methyl group (deacylation) to give cobalt-precorrin-5B [2]. The N-terminal of the enzyme is conserved in this family, and the C-terminal and the mid-sections are conserved independently in other families, CbiG_C and CbiG_mid, although the distinct function of each region is unclear.
This entry includes family members such as EarP enzymes which are essential for post-translational activation of elongation factor P(EF-P). It was identified as EF-P arginine R32 specific rhamnosyl transferase in Shewanella oneidensis using dTDP-beta-L-rhamnose as donor substrate [1]. This was further confirmed for Pseudomonas aeruginosa [2], Pseudomonas putida [3] and Neisseria meningitidis [4]. As for S. oneidensis [5] and P. aeruginosa [6], EarP enzyme acts as an inverting glycosyltransferase, thus mediating the formation of an alpha-L-rhamnosidic linkage. Structural analysis show that EarP is composed of two opposing domains with Rossmann folds, thus constituting a B pattern-type glycosyltransferase (GT-B) and provide basis for arginine glycosylation by EarP [3]. Mutational analysis of efp and earP genes, resulted in a substantial decrease in the production of rhamnolipids and pyocyanin (important factors for colonization and invasion during infection) of P. aeruginosa. Collectively this indicates that EarP and EF-P are essential for P. aeruginosa pathogenicity [1].The protein family is also annotated in the CaZy Database as GT104.
This family includes the toxic component HepT of a type II toxin-antitoxin (TA) system, which has RNase activity. These proteins contain a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain and are neutralised through tri-AMPylation by the cognate antitoxin MntA, containing a MNT (minimal nucleotidyltransferase) domain [1, 2, 3]. HepT-MnA form an heterooctamer (at a 2:6 ratio), a rare organisation for this kind of TA systems. HepT dimerises and enables the formation of a deep cleft at the HEPN-domain interface, containing the RX4-6H motif (where X is any amino acid and the residue immediately after the conserved R is typically a polar amino acid) as the active site that functions as an RNA-cleaving RNase. This type II TA system regulates cell motility and confers plasmid stability [2]. Due to the prevalence of these HEPN/MNT modules in bacteria and archaea, it has been suggested that these TA systems may also play a role in the environmental adaptation to extreme habitats [3].
Hydrogen gas-evolving membrane-bound hydrogenase (MBH) is a respiratory complex homologous to the quinone-reducing Complex I. Like Complex I, MBH has peripheral and membrane arms. MBH is made of 14 subunits (MbhA-N). MbhJ, K, L, N and M form the Membrane-anchored hydrogenase module. MbhJ, K, L, N are predicted to be exposed to the cytoplasm and form the peripheral arm. The remaining 10 subunits are predicted to be integral membrane proteins forming the membrane arm, made of 44 transmembrane helices (TMH) [2, 3]. MbhA, B, C and F form the Sodium translocation module. MbhD, E, G and H form the Proton translocation module. MbhI is the linker between the hydrogenase module and the proton-translocating membrane module. It anchors the discontinuous TMH7 of MbhH via its middle lateral helix and the C-terminal of TMH2, found in MbhE. MbhD and MbhE together are equivalent to Nqo10 of Complex I [1]. MbhD has three TM helices.
MqsA_antitoxin is a family of prokaryotic proteins that act as antidotes to the mRNA interferase MqsR. It has a zinc-binding at the very N-terminus indicating its DNA-binding capacity. MqsR is the gene most highly upregulated in E. Colo MqsR_toxin is a family of bacterial toxins that act as an mRNA interferase. MqsR is the gene most highly upregulated in E. coli persister cells [2] and it plays an essential role in biofilm regulation [3] and cell signalling [4]. It forms part of a bacterial toxin-antitoxin TA system, and as expected for a TA system, the expression of the MqsR toxin leads to growth arrest, while co-expression with its antitoxin, MqsA, rescues the growth arrest phenotype. In addition, MqsR associates with MqsA to form a tight, non-toxic complex and both MqsA alone and the MqsR:MqsA2:MqsR complex bind and regulate the mqsR promoter. The structure of MqsR shows that is is a member of the RelE/YoeB family of bacterial RNases that are structurally and functionally characterised bacterial toxins [1].
This family, many of whose members are YcbG, organises the macrodomain Ter of the chromosome of bacteria such as E coli. In these bacteria, insulated macrodomains influence the segregation of sister chromatids and the mobility of chromosomal DNA. Organisation of the Terminus region (Ter) into a macrodomain relies on the presence of a 13 bp motif called matS repeated 23 times in the 800-kb-long domain. MatS sites are the main targets in the E. coli chromosome of YcbG or MatP (macrodomain Ter protein). MatP accumulates in the cell as a discrete focus that co-localises with the Ter macrodomain. The effects of MatP inactivation reveal its role as the main organiser of the Ter macrodomain: in the absence of MatP, DNA is less compacted, the mobility of markers is increased, and segregation of the Ter macrodomain occurs early in the cell cycle. A specific organisational system is required in the Terminus region for bacterial chromosome management during the cell cycle. This entry represents the C-terminal ribbon-helix-helix domain.
This is the second domain on the N-terminal region found on the alpha C protein (ACP). ACP is found in Streptococcus and acts as an invasin which plays a role in the internalisation and translocation of the organism across human epithelial surfaces [1]. Group B Streptococcus is the leading cause of diseases including bacterial pneumonia, sepsis and meningitis. ACP consists of an N-terminal domain (NtACP; 170 amino acids) followed by a variable number of tandem repeats (82 amino acids each) and a C-terminal domain (45 amino acids) containing an LPXTG peptidoglycan-anchoring motif. The NtACP, contains two structural domains, D1 and D2. D1, the more distal (amino-terminal) portion Pfam:PF08829 and consists of a beta sandwich with strong structural homology to fibronectin's integrin-binding region (FnIII10). This entry, D2 (connects distally to Domain 1 and proximally to the repeat region) [1] consists of three antiparallel alpha helix coils [2]. It is suggested that the GAG-binding region of ACP may extend from Domain 2 into the repeat region [3].
Hydrogen gas-evolving membrane-bound hydrogenase (MBH) is a respiratory complex homologous to the quinone-reducing Complex I. Like Complex I, MBH has peripheral and membrane arms. MBH is made of 14 subunits (MbhA-N). MbhJ, K, L, N and M form the Membrane-anchored hydrogenase module. MbhJ, K, L, N are predicted to be exposed to the cytoplasm and form the peripheral arm. The remaining 10 subunits are predicted to be integral membrane proteins forming the membrane arm, made of 44 transmembrane helices (TMH) [2, 3]. MbhA, B, C and F form the Sodium translocation module. MbhD, E, G and H form the Proton translocation module. MbhI is the linker between the hydrogenase module and the proton-translocating membrane module. It anchors the discontinuous TMH7 of MbhH via its middle lateral helix and the C-terminal of TMH2, found in MbhE. MbhD and MbhE together are equivalent to Nqo10 of Complex I [1]. MbhE has two transmembrane helices: TMH1 and TMH2.
Pullulanases (pullulan 6-glucanohydrolase, EC 3.2.1.41) are debranching enzymes that are able to hydrolyze the alpha-1,6-glycosidic linkage in pullulan, starch, amylopectin, and related oligosaccharides. Type I pullulanases specifically cleave the alpha-1,6-glycosidic linkages in pullulan and branched oligosaccharides to produce maltotriose and linear oligosaccharides, respectively [1]. Structural analysis of Klebsiella lipoprotein pullulanase (PulA) illustrates that the catalytic core is composed of two major regions: the TIM-barrel domain A and beta-sandwich fold domain C. PulA contains an extra domain, a highly mobile Ins subdomain of unknown function which is inserted into the catalytic TIM-barrel domain A of Klebsiella pullulanases. The Ins subdomain is rich in helical and loop secondary structure. A disulfide bond between Cys491 and Cys506 and two Ca2+ ions presumably stabilizes this domain.This insertion is also found in pullulanases from other Gram-negative genera that have a functional T2SS, such as Vibrio, Aeromonas, and Photorhabdus. Functional analysis indicate that this domain is required for PulA secretion via the T2SS [2].
This is a thrombospondin type I repeat (TSR) found in properdin. Properdin, also known as factor P (fP), is a glycoprotein constructed from a common pool of structure units or modules, which are homologous to the thrombospondin type 1 repeat, TSR. It is positive regulator of the complement system that stabilises the alternative pathway C3-convertase C3bBb. Properdin also inhibits the factor H-mediated cleavage of C3b by factor I. In addition, properdin acts as a pattern recognition molecule capable of identifying and interacting with microbial surfaces, apoptotic cells, and necrotic cells [1]. However this role of pattern recognition is controversial [2]. Studies indicate that this domain is a TSR variants. It is present at the N-terminal of properdin and has been denoted as TSR-0. It is suggested that the TSR-0 domain of properdin which possesses only the six Cys residues and no CWR-layered motif (which is usually found in other TSR domains) may constitute a truncated TSR domain [3].
This family, many of whose members are YcbG, organises the macrodomain Ter of the chromosome of bacteria such as E coli. In these bacteria, insulated macrodomains influence the segregation of sister chromatids and the mobility of chromosomal DNA. Organisation of the Terminus region (Ter) into a macrodomain relies on the presence of a 13 bp motif called matS repeated 23 times in the 800-kb-long domain. MatS sites are the main targets in the E. coli chromosome of YcbG or MatP (macrodomain Ter protein). MatP accumulates in the cell as a discrete focus that co-localises with the Ter macrodomain. The effects of MatP inactivation reveal its role as the main organiser of the Ter macrodomain: in the absence of MatP, DNA is less compacted, the mobility of markers is increased, and segregation of the Ter macrodomain occurs early in the cell cycle. A specific organisational system is required in the Terminus region for bacterial chromosome management during the cell cycle. This entry represents the N-terminal domain of MatP.
This family comprises of several D-Tyr-tRNA(Tyr) deacylase proteins. Cell growth inhibition by several d-amino acids can be explained by an in vivo production of d-aminoacyl-tRNA molecules. Escherichia coli and yeast cells express an enzyme, d-Tyr-tRNA(Tyr) deacylase, capable of recycling such d-aminoacyl-tRNA molecules into free tRNA and d-amino acid. Accordingly, upon inactivation of the genes of the above deacylases, the toxicity of d-amino acids increases. Orthologues of the deacylase are found in many cells [1].The D-aminoacyl-tRNA deacylase (DTD) enzyme is homodimeric with two active sites located at the dimeric interface. Each active site carries an invariant Gly-cisPro dipeptide motif in each monomer. The interaction between the dipeptide motifs from each monomer ensures substrate stereospecificity. This family also includes a subclass of DTDs which is present in Chordata and harbors a Gly-transPro motif. The cis to trans switch is the key to Animal DTDs (ATD) gaining of L-chiral selectivity. This 'gain of function' through relaxation of substrate chiral specificity underlies ATD's capability of correcting the error in tRNA selection [2].
ThrE_2 is a family of membrane proteins involved in the export of threonine and serine. L-threonine, L-serine are both substrates for the exporter. The exporter exhibits nine-ten predicted transmembrane-spanning helices with long charged C and N termini and an amphipathic helix present within the N terminus [1]. L-Threonine can be made by the amino acid-producing bacterium Corynebacterium glutamicum, but the potential for amino acid formation can be considerably improved by reducing its intracellular degradation into glycine and increasing its export by this exporter [2]. Members of the family are found in Bacteria, Archaea, and the fungal kingdoms, and the family can exist either as a single long polypeptide chain or as two short polypeptides [2]. All family members show an extended hydrophilic N-terminal domain with weak sequence similarity to portions of hydrolases (proteases, peptidases, and glycosidases); this suggests that since this region is cytoplasmic to the membrane it may be generating the transport substrate, so may imply that threonine may not be the primary substrate and the ThrE has a subsidiary function [3].
Fibroblast growth factors are a family of proteins involved in growth and differentiation in a wide range of contexts. They are found in a wide range of organisms, from nematodes to humans [2]. Most share an internal core region of high similarity, conserved residues in which are involved in binding with their receptors. On binding, they cause dimerisation of their tyrosine kinase receptors leading to intracellular signalling. There are currently four known tyrosine kinase receptors for fibroblast growth factors. These receptors can each bind several different members of this family. Members of this family have a beta trefoil structure. Most have N-terminal signal peptides and are secreted. A few lack signal sequences but are secreted anyway; still others also lack the signal peptide but are found on the cell surface and within the extracellular matrix. A third group remain intracellular [2]. They have central roles in development, regulating cell proliferation, migration and differentiation. On the other hand, they are important in tissue repair following injury in adult organisms [2].
This domain family is found in eukaryotes, and is typically between 117 and 132 amino acids in length. PRAS domain family is found in eukaryotes, and is typically between 117 and 132 amino acids in length. It is a proline-rich family that can be phosphorylated by AKT, and in the phosphorylated state binds to 14-3-3. The AKT signalling pathway contributes to regulation of apoptosis after a variety of cell death stimuli, and PRAS is found to be a substrate [1]. PRAS plays an important role in regulating cell survival downstream of the PI3-K/Akt pathway after re-perfusion injury after transient focal cerebral ischemia. Copper/zinc-SOD (SOD1), a cytosolic isoenzyme of superoxide dismutase, SOD, is highly protective against ischemia and re-perfusion injury after transient focal cerebral ischemia, and SOD1 thus contributes to the inhibition of direct oxidation of PRAS and the activation of its signalling pathway [2]. PRAS is also a mTOR binding partner, and PRAS phosphorylation by AKT and its association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mTOR (mammalian target of rapamycin) [3].
This is the second domain (C2) located in the C-terminal region found in antigen I/II type adhesin protein AspA from S. pyogenes. Together with C3, these two domains form an elongated structure, each domain adopts the DEv-IgG fold. Similar to the classical IgG folds, it is comprised of two major antiparallel beta-sheets, designated ABED and CFG. For the C2-domain, there are two additional strands on the CFG sheet. Furthermore, sheets ABED and CFG are interconnected by several cross-connecting loops and one alpha-helix (DH1). The side chains of D982 and N996 in the C2-domain are involved in hydrogen bonding with the side chains of R1264 and N1295 in the C3 domain. Main chain hydrogen bonding can also be observed between S992 in C2 and N1189/G1191 in C3, furthermore stabilizing the interaction between the domains. The C2 domain contains one bound metal ion, modeled as Ca2+, and both the C2- and C3-domains are stabilized by conserved isopeptide bonds, which connect the beta-sheets of the central DEv-IgG motifs [1].Other members of this family include Major cell-surface adhesin PAc from Streptococcus mutans and SspB from Streptococcus gordonii.
This is the C-terminal domain secreted by Mycobacterium tuberculosis (Mtb). It induces necrosis of infected cells to evade immune responses. Mtb utilizes the protein CpnT to kill human macrophages by secreting its C-terminal domain (CTD), named tuberculosis necrotizing toxin (TNT) that induces necrosis. It acts as a NAD+ glycohydrolase which hydrolyzes the essential cellular coenzyme NAD+ in the cytosol of infected macrophages resulting in necrotic cell death [1]. CpnT transports its toxic CTD from the cell surface of M. tuberculosis by proteolytic cleavage, where the toxin is cleaved to induce host cell death [2]. Structural analysis determined that the TNT core contains only six beta-strands as opposed to seven found in all known NAD+-utilizing toxins, and is significantly smaller, with only two short alpha-helices and two 3/10 helices. Furthermore, the putative NAD+ binding pocket identified Q822, Y765 and R757 as residues possibly involved in NAD+-binding and hydrolysis based on similar positions of catalytic amino acids of ADP-ribosylating toxins. While glutamine 822 residue was detected to be highly conserved among TNT homologs [1].
Mediator is a large complex of up to 33 proteins that is conserved from plants to fungi to humans - the number and representation of individual subunits varying with species [1-2]. It is arranged into four different sections, a core, a head, a tail and a kinase-active part, and the number of subunits within each of these is what varies with species. Overall, Mediator regulates the transcriptional activity of RNA polymerase II but it would appear that each of the four different sections has a slightly different function [4]. The overall function of the full-length Med25 is efficiently to coordinate the transcriptional activation of RAR/RXR (retinoic acid receptor/retinoic X receptor) in higher eukaryotic cells. Human Med25 consists of several domains with different binding properties, the N-terminal, VWA domain, an SD1 - synapsin 1 - domain from residues 229-381, a PTOV(B) or ACID domain from 395-545, an SD2 domain from residues 564-645 and a C-terminal NR box-containing domain (646-650) from 646-747. This family is the combined PTOV and SD2 domains. the PTOV domain being the domain through which Med25 co-operates with the histone acetyltransferase CBP, but the function of the SD2 domain is unclear [3].
The WIF domain is found in the RYK tyrosine kinase receptors Swiss:P34925 and WIF the Wnt-inhibitory- factor. The domain is extracellular and contains two conserved cysteines that may form a disulphide bridge. This domain is Wnt binding in WIF, and it has been suggested that RYK may also bind to Wnt [1]. The WIF domain is a member of the immunoglobulin superfamily, and it comprises nine beta-strands and two alpha-helices, with two of the beta-strands (6 and 9) interrupted by four and six residues of irregular secondary structure, respectively. Considering that the activity of Wnts depends on the presence of a palmitoylated cysteine residue in their amino-terminal polypeptide segment, Wnt proteins are lipid-modified and can act as stem cell growth factors, it is likely that the WIF domain recognises and binds to Wnts that have been activated by palmitoylation and that the recognition of palmitoylated Wnts by WIF-1 is effected by its WIF domain rather than by its EGF domains. A strong binding affinity for palmitoylated cysteine residues would further explain the remarkably high affinity of human WIF-1 not only for mammalian Wnts, but also for Wnts from Xenopus and Drosophila [2].
The role of the cell surface D-galactose (Gal)/N-Acetyl-D-galactosamine (GalNAc), lectin in the adhesion process has been demonstrated in Entamoeba histolytica, a protozoan parasite that causes amebiasis in humans [1]. The Gal/GalNAc lectin is a heterotrimeric protein complex. It is composed of a 260 kDa heterodimer of trans-membrane disulphide-linked heavy 170 kDa subunit and glycosylphosphatidylinositol (GPI)-anchored light 31 kDa/35 kDa subunits. The light subunits are non-covalently associated with an intermediate subunit of 150 kDa [1] [2]. Inhibition of expression of 35 kDa subunit of Gal/GalNAc lectin inhibits the cytotoxic and cytopathic activity of E. histolytica, but no decrease in adherence capacity to mammalian cells was evident. Interestingly, a carbohydrate-binding activity has been reported for the 35 kDa light subunit of the lectin molecules of the closely related Entamoeba invadens. This entry is related to the light subunit where this domain of unknown function is present. The light subunit consists of several polypeptide chains with considerable antigenic homology. The two light (31/35 kDa) subunits of the lectin are present in two isoforms: the 31 kDa isoform is glycerolphosphatidylinositol (GPI) anchored; and the 35 kDa isoform is more highly glycosylated [2].
This domain is found in human cytoplasmic dynein-2 proteins. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport and is associated with human skeletal ciliopathies. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement. Structural analysis reveal that the motor's ring consists of six AAA+ domains (ATPases associated with various cellular activities: AAA1-AAA6) [1]. This is the first site (out of four nucleotide binding sites in the dynein motor) where the movement depends on ATP hydrolysis [2]. When this site is nucleotide free or bound to ADP, the microtubule binding domain (MTBD) binds to the microtubule and the linker adopts the straight post-power-stroke conformation. Upon ATP binding and hydrolysis, the MTBD detaches from the microtubule and the linker is primed into the pre-power-stroke conformation. Dynein's AAA+ domains are each divided into an alpha/beta large subdomain designated with an L and and alpha small subdomains designated with an S. This is the AAA1 large (AAA1L) subdomain with the accompanying small subdomain (AAA1S). AAA1L, AAA1S and AAA2L enclose ADP.vanadate (ADP.Vi, ATP-hydrolysis transition state analogue). The AAA1L sensor-I loop, which varies in position depending on dynein's nucleotide state, swings in to contact AAA2L forming the important AAA1 nucleotide-binding site [1].
Endolysins are bacteriophage encoded proteins synthesized at the end of the lytic infection cycle. They degrade the peptidoglycan (PG) of the host bacterium to allow viral progeny release. This domain family is found in bacteria and viruses. It is also found associated with Pfam:PF01471. One of the family members is the modular Gp110 endolysin found in the Salmonella phage. This domain represents the catalytic region found in the C-terminal of Gp110. It has been demonstrated to have N-acetylmuramidase (lysozyme) activity cleaving the beta-(1,4) glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine residues in the sugar backbone of the PG. Furthermore, sequence alignments containing this domain show that the Gp110 E101 residue is conserved (suggesting that is is the catalytic residue), and followed by serine (a common feature in lysozymes). The structure of endolysins varies depending on their origin. In general, most of the endolysins from phages infecting Gram-positive bacteria have a modular structure consisting of one or two N-terminal enzymatic active domains (EADs) and a C-terminal cell wall binding domain (CBD) separated by a short linker. In silico analysis indicate that this endolysin has a modular structure harboring this EAD family at the C terminus and a PG_binding_1 CBD at the N terminus [1].
IFT20 is subunit 20 of the intraflagellar transport complex B [1]. The intraflagellar transport complex assembles and maintains eukaryotic cilia and flagella. IFT20 is localised to the Golgi complex and is anchored there by the Golgi polypeptide, GMAP210, whereas all other subunits except IFT172 localise to cilia and the peri-basal body or centrosomal region at the base of cilia [1,2,3]. IFT20 accompanies Golgi-derived vesicles to the point of exocytosis near the basal bodies where the other IFT polypeptides are present, and where the intact IFT particle is assembled in association with the inner surface of the cell membrane. Passage of the IFT complex then follows, through the flagellar pore recognition site at the transition region, into the ciliary compartment. There also appears to be a role of intraflagellar transport (IFT) polypeptides in the formation of the immune synapse in non ciliated cells. The flagellum, in addition to being a sensory and motile organelle, is also a secretory organelle [5]. A number of IFT components are expressed in haematopoietic cells, which have no cilia, indicating an unexpected role of IFT proteins in immune synapse-assembly and intracellular membrane trafficking in T lymphocytes; this suggests that the immune synapse could represent the functional homologue of the primary cilium in these cells [6,7].
The DOMON (named after dopamine beta-monooxygenase N-terminal) domain is 110-125 residues long. It is predicted to form an all beta fold with up to 11 strands and is secreted to the extracellular compartment. The beta-strand folding produces a hydrophobic pocket which appears to bind soluble haem. This is consistent with the predominant architectures where the protein is associated with cytochromes or enzymatic domains whose activity involves redox or electron transfer reactions potentially as a direct participant in the electron transfer process. The DOMON domain superfamily, of which this is just one member, shows (1) multiple hydrophobic residues that contribute to the hydrophobic core of the strands of the beta-sandwich, and small residues found at the boundaries of strands and loops, (2) a strongly conserved charged residue (usually arginine/lysine) at the end of strand 9, which possibly stabilises the loop between 9 and 10, and (3) a polar residue (usually histidine, lysine or arginine), that interacts or coordinates with ligands [1]. The suggested superfamily includes both haem- and sugar-binding members: the haem-binding families being the ethyl-Benzoate dehydrogenase family EB_dh, Pfam:PF09459, the cellobiose dehydrogenase family CBDH and this family, and the sugar-binding families being the xylanases, CBM_4_9, Pfam:PF02018. The common feature of the superfamily is the 11-beta-strand structure, although the first and eleventh strands are not well conserved either within families or between families.
This is the 2B and 2B-like sub-domain found in TraI (EC:5.99.1.2) a relaxase of F-family plasmids. It contains four domains; a trans-esterase domain that executes the nicking and covalent attachment of the T-strand to the relaxase, a vestigial helicase domain (carrying the 2B/2B-like sub-domain) that operates as an ssDNA-binding domain, an active 5' to 3' helicase domain, and a C-terminal domain that functions as a recruitment platform for relaxosome components. The 2B sub-domains in TraI are formed by residues 625-773 in the vestigial helicase domain and residues 1255-1397 in the active helicase domain. The 2B/2B-like sub-domain interacts with ssDNA where it contributes to the surface area where ssDNA bind. In other words the ssDNA-binding site is located in a groove between the 2B and 2B-like parts of the sub-domain. The sub-domain parts appear to act as clamps holding the ssDNA in place, resulting in the ssDNA being completely surrounded by protein. In previous studies, the 2B/2B-like sub-domain of the TraI vestigial helicase domain has been identified as translocation signal A (TSA) since it contains sequences essential for the recruitment of TraI to the T4S system. Thus, the 2B/2B-like sub-domain plays two major roles in relaxase function: (1) interacting with the DNA and possibly promoting high processivity and (2) mediating recruitment of the relaxosome to the T4S system [1].
The SWR1 complex is involved in chromatin-remodeling by promoting the the ATP-dependent exchange of histone H2A for the H2A variant HZT1 in Saccharomyces cerevisiae or H2AZ in mammals. The SWR1 chromatin-remodeling complex is composed of at least 14 subunits and has a molecular mass of about 1.2 to 1.5 MDa. In S. cerevisiae there are core conserved subunits (ATPase; Swr1,RuvB-like; Rvb1 and Rvb2, Actin; Act1, Actin-related: Arp4 and Arp6, YEATS protein; [1]) and non-conserved subunits (Vps71 (Swc6), Vps72 (Swc2), Swc3, Swc4, Swc5, Swc7, Bdf1 [2]). Seven of the SWR1 subunits are involved in maintaining complex integrity and H2AZ histone replacement activity: Swr1, Swc2, Swc3, Arp6, Swc5, Yaf9 and Swc6. Arp4 is required for the association of Bdf1, Yaf9, and Swc4 and Arp4 is also required for SWR1 H2AZ histone replacement activity in vitro. Furthermore the N-terminal region of the ATPase Swr1 provides the platform upon which Bdf1, Swc7, Arp4, Act1, Yaf9 and Swc4 associate [3]. It also contains an additional H2AZ-H2B specific binding site, distinct from the binding site of the Swc2 subunit [4]. In eukaryotes the deposition of variant histones into nucleosomes by the chromatin-remodeling complexes such as the SWR1 and INO80 complexes have many crucial functions including the control of gene regulation and expression, checkpoint regulation, DNA replication and repair, telomere maintenance and chromosomal segregation and as such represent critical components of pathways that maintain genomic integrity. This entry represents the subunit Swc7; the smallest subunit of the SWR1 complex. Swc7 is not required for H2AZ binding. It associates with the N terminus of Swr1, and the association of Bdf1 requires Swc7, Yaf9, and Arp4 [3].
This family is found in alpha and beta proteobacteria. Family members include anti-sigma factor CnrY from Cupriavidus metallidurans. Sigma factors are multi-domain sub-units of bacterial RNA polymerase (RNAP) that play critical roles in transcription initiation, including the recognition and opening of promoters as well as the initial steps in RNA synthesis. They also control a wide variety of adaptive responses such as morphological development and the management of stress. A recurring theme in sigma factor control is their sequestration by anti-sigma factors that occlude their RNAP-binding determinants [1]. CnrH, controls cobalt and nickel resistance in Cupriavidus metallidurans. CnrH is regulated by a complex of two transmembrane proteins: the periplasmic sensor CnrX and the anti-sigma CnrY. At rest, CnrH is sequestered by CnrY whose 45-residue-long cytosolic domain is one of the shortest anti-sigma domains. Upon Ni(II) or Co(II) ions detection by CnrX in the periplasm, CnrH is released between CnrH and the cytosolic domain of CnrY (CnrYc). The CnrH/CnrYC complex displays an unexpected structural similarity to the anti-sigma NepR in complex with its antagonist PhyR, whereas NepR shares no sequence similarity with CnrY. Crystal structure of CnrH/CnrY shows that CnrYC residues 3-19 are folded as a well-defined alpha-helix. The peptide further extends along the hydrophobic groove of sigma 2 with no canonical structure except for a short helical turn spanning residues 24-28. CnrY has a hydrophobic knob made of V4, W7 and L8 side chains protruding into sigma 4 hydrophobic pocket and contributing to the interface. In vivo investigation of CnrY function pinpoints part of the hydrophobic knob as a hotspot in CnrH inhibitory binding [2].
CNDH2_N is the N-terminal domain of the H2 subunit of the condensing II complex, found in eukaryotes but not in fungi. Eukaryotes carry at least two condensin complexes, I and II, each made up of five subunits. The functions of the two complexes are collaborative but non-overlapping. CI appears to be functional in G2 phase in the cytoplasm beginning the process of chromosomal lateral compaction while the CII is concentrated in the nucleus, possibly to counteract the activity of cohesion at this stage. In prophase, CII contributes to axial shortening of chromatids while CI continues to bring about lateral chromatid compaction, during which time the sister chromatids are joined centrally by cohesins. There appears to be just one condensin complex in fungi. CI and CII each contain SMC2 and SMC4 (structural maintenance of chromosomes) subunits, then CI has non-SMC CAP-D2 (CND1), CAP-G (CND3), and CAP-H (CND2). CII has, in addition to the two SMCs, CAP-D3, CAPG2 and CAP-H2. All four of the CAP-D and CAP-G subunits have degenerate HEAT repeats, whereas the CAP-H are kleisins or SMC-interacting proteins (ie they bind directly to the SMC subunits in the complex). The SMC molecules are each long with a small hinge-like knob at the free end of a longish strand, articulating with each other at the hinge. Each strand ends in a knob-like head that binds to one or other end of the CAP-H subunit. The HEAT-repeat containing D and G subunits bind side-by-side between the ends of the H subunit. Activity of the various parts of the complex seem to be triggered by extensive phosphorylations, eg, entry of the complex, in Sch.pombe, into the nucleus during mitosis is promoted by Cdk1 phosphorylation of SMC4/Cut3; and it has been shown that Cdk1 phosphorylates CAP-D3 at Thr1415 in He-La cells thus promoting early stage chromosomal condensation by CII.
CNDH2_C is the C-terminal domain of the H2 subunit of the condensin II complex, found in eukaryotes but not fungi. Eukaryotes carry at least two condensin complexes, I and II, each made up of five subunits. The functions of the two complexes are collaborative but non-overlapping. CI appears to be functional in G2 phase in the cytoplasm beginning the process of chromosomal lateral compaction while the CII are concentrated in the nucleus, possibly to counteract the activity of cohesion at this stage. In prophase, CII contributes to axial shortening of chromatids while CI continues to bring about lateral chromatid compaction, during which time the sister chromatids are joined centrally by cohesins. There appears to be just one condensin complex in fungi. CI and CII each contain SMC2 and SMC4 (structural maintenance of chromosomes) subunits, then CI has non-SMC CAP-D2 (CND1), CAP-G (CND3), and CAP-H (CND2). CII has, in addition to the two SMCs, CAP-D3, CAPG2 and CAP-H2. All four of the CAP-D and CAP-G subunits have degenerate HEAT repeats, whereas the CAP-H are kleisins or SMC-interacting proteins (ie they bind directly to the SMC subunits in the complex). The SMC molecules are each long with a small hinge-like knob at the free end of a longish strand, articulating with each other at the hinge. Each strand ends in a knob-like head that binds to one or other end of the CAP-H subunit. The HEAT-repeat containing D and G subunits bind side-by-side between the ends of the H subunit. Activity of the various parts of the complex seem to be triggered by extensive phosphorylations, eg, entry of the complex, in Sch.pombe, into the nucleus during mitosis is promoted by Cdk1 phosphorylation of SMC4/Cut3; and it has been shown that Cdk1 phosphorylates CAP-D3 at Thr1415 in He-La cells thus promoting early stage chromosomal condensation by CII.
CNDH2_M is the middle domain of the H2 subunit of the condensin II complex, found in eukaryotes but not fungi. Eukaryotes carry at least two condensin complexes, I and II, each made up of five subunits. The functions of the two complexes are collaborative but non-overlapping. CI appears to be functional in G2 phase in the cytoplasm beginning the process of chromosomal lateral compaction while the CII are concentrated in the nucleus, possibly to counteract the activity of cohesion at this stage. In prophase, CII contributes to axial shortening of chromatids while CI continues to bring about lateral chromatid compaction, during which time the sister chromatids are joined centrally by cohesins. There appears to be just one condensin complex in fungi. CI and CII each contain SMC2 and SMC4 (structural maintenance of chromosomes) subunits, then CI has non-SMC CAP-D2 (CND1), CAP-G (CND3), and CAP-H (CND2). CII has, in addition to the two SMCs, CAP-D3, CAPG2 and CAP-H2. All four of the CAP-D and CAP-G subunits have degenerate HEAT repeats, whereas the CAP-H are kleisins or SMC-interacting proteins (ie they bind directly to the SMC subunits in the complex). The SMC molecules are each long with a small hinge-like knob at the free end of a longish strand, articulating with each other at the hinge. Each strand ends in a knob-like head that binds to one or other end of the CAP-H subunit. The HEAT-repeat containing D and G subunits bind side-by-side between the ends of the H subunit. Activity of the various parts of the complex seem to be triggered by extensive phosphorylations, eg, entry of the complex, in Sch.pombe, into the nucleus during mitosis is promoted by Cdk1 phosphorylation of SMC4/Cut3; and it has been shown that Cdk1 phosphorylates CAP-D3 at Thr1415 in He-La cells thus promoting early stage chromosomal condensation by CII [1,2]. This region represents the disordered section of CNDH2 between the N- and the C-termini.
This family consists exclusively of streptococcal competence stimulating peptide precursors, which are generally up to 50 amino acid residues long. In all the members of this family, the leader sequence is cleaved after two conserved glycine residues; thus the leader sequence is of the double- glycine type [2]. Competence stimulating peptides (CSP) are small (less than 25 amino acid residues) cationic peptides. The N-terminal amino acid residue is negatively charged, either glutamate or aspartate. The C-terminal end is positively charged. The third residue is also positively charged: a highly conserved arginine [2]. A few COMC proteins and their precursors (not included in this family) do not fully follow the above description. In particular: the leader sequence in the CSP precursor from Streptococcus sanguis NCTC 7863 Swiss:O33758 is not of the double-glycine type; the CSP from Streptococcus gordonii NCTC 3165 Swiss:O33645 does not have a negatively charged N-terminus residue and has a lysine instead of arginine at the third position. Functionally, CSP act as pheromones, stimulating competence for genetic transformation in streptococci. In streptococci, the (CSP mediated) competence response requires exponential cell growth at a critical density, a relatively simple requirement when compared to the stationary-phase requirement of Haemophilus, or the late-logarithmic- phase of Bacillus [1]. All bacteria induced to competence by a particular CSP are said to belong to the same pherotype, because each CSP is recognised by a specific receptor (the signalling domain of a histidine kinase ComD). Pherotypes are not necessarily species-specific. In addition, an organism may change pherotype. There are two possible mechanisms for pherotype switching: horizontal gene transfer, and accumulation of point mutations. The biological significance of pherotypes and pherotype switching is not definitively determined. Pherotype switching occurs frequently enough in naturally competent streptococci to suggest that it may be an important contributor to genetic exchange between different bacterial species [2]. The family Antibacterial16, streptolysins from group A streptococci, has been merged into this family.
