The protein superfamily represented by this entry, YggX, serves to protect Fe-S clusters from oxidative damage []. The effect is two-fold: proteins that rely on Fe-S clusters do not become inactivated, and the release of free iron and hydrogen peroxide--a DNA damaging agent--is prevented. These observations are consistent with the hypothesis that YggX chelates free iron, and recent experiments show that YggX can indeed bind Fe(II) in vitro and in vivo []. Furthermore, YggX has a positive effect on the action of at least one Fe(II)-responsive protein. The combined actions of YggX is reminiscent of iron trafficking proteins [], and YggX is therefore proposed to play a role in Fe(II) trafficking []. In Escherichia coli, YggX was shown to be under the transcriptional control of the redox-sensing SoxRS system [].Structurally, YggX has a beta(2)-alpha(3) fold and contains a zinc-less 'zinc finger'-like fold.
This entry represents IMP cyclohydrolase, which catalyses the cyclisation of 5-formylamidoimidazole-4-carboxamide ribonucleotide to inosine monophosphate (IMP), a reaction which is important in de novo purine biosynthesis in archaeal species []. This single domain protein is arranged to form an overall fold that consists of a four-layered α-β-beta-alpha core structure. The two antiparallel β-sheets pack against each other and are covered by α-helices on one face of the molecule. The protein is structurally similar to members of the N-terminal nucleophile (NTN) hydrolase superfamily. A deep pocket was in fact found on the surface of IMP cyclohydrolase in a position equivalent to that of active sites of NTN-hydrolases, but an N-terminal nucleophile could not be found. Therefore, it is thought that this enzyme is structurally but not functionally similar to members of the NTN-hydrolase family [].In bacteria this step is catalysed by a bifunctional enzyme (purH).
Kinase A inhibitor KipI was first identified as a potent inhibitor of the autophosphorylation reaction of kinase A (KipA) and its reverse reaction, but does not inhibit phosphate transfer to the Spo0F response regulator once kinase A is phosphorylated. KipI is an inhibitor of the catalytic domain of kinase A affecting the ATP/ADP reactions and not the phosphotransferase functions of this domain. The inhibition is noncompetitive with respect to ATP [].KipI forms a complex with KipA. The KipI-KipA complex shares protein structure and sequence similarity with the carboxyltransferase (CT) domain of urea amidolyase from K. lactis, but residues that are important for CT catalysis are not conserved in KipA and KipI. Therefore, the KipA-KipI complex is unlikely to have CT activity [].
The SUZ-C domain is a conserved motif found in one or more copies in several RNA-binding proteins []. It is always found at the C terminus of the protein and appears to be required for localization of the protein to specific subcellular structures. The domain was first characterised in the C.elegans protein SZY-20, a centrosome-associated RNA-binding protein that negatively regulates centrosome assembly. SZY-20 and its animal orthologs share three prominent blocks of conservation. The N-terminal block is a short element, which is found exclusively in orthologs of SZY-2. The third block, the SUZ-C domain, is at the extreme C terminus and is defined by a characteristic pattern of two highly conserved glycines and one absolutely conserved proline. The SUZ and SUZ-C domains occur independently in proteins outside of the SZY-20 family. Many of these proteins contain known RNA-binding domains. The SUZ-C domain is a putative RNA-binding domain [, ].
The class III basic helix-turn-helix (bHLH) transcription factors have proliferative and apoptotic roles and are characterised by the presence of a leucine zipper adjacent to the bHLH domain. The myc oncogene gene was first discovered in small-cell lung cancer cell lines where it is found to be deregulated []. Although the biochemical function of the gene product is unknown, as a nuclear protein with a short half-life it may play a direct or indirect role in controlling gene expression []. Myc forms a heterodimer with Max, and this complex regulates cell growth through direct activation of genes involved in cell replication [].This entry represents the N-terminal domain found adjacent to the basic helix-loop-helix (bHLH) region ().
This domain is called PHR as it was originally found in the E3 ubiquitin-protein ligase proteins PAM (), highwire () and RPM-1 () [].PHR proteins are conserved, large multi-domain E3 ubiquitin ligases with modular architecture. PHR proteins presynaptically control synaptic growth and axon guidance and postsynaptically regulate endocytosis of glutamate receptors. Dysfunction of neuronal ubiquitin-mediated proteasomal degradation is implicated in various neurodegenerative diseases. PHR proteins are characterised by the presence of two PHR domains near the N terminus, which are essential for proper localisation and function. The domain has a β-sandwich fold composed of 11 anti-parallel β-strands [].The C-terminal region of the protein BTBD1 includes the PHR domain and is known to interact with Topoisomerase I, an enzyme which relaxes DNA supercoils [].
RIN1, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs []. Previous studies showed that RIN1 interacts with EGF receptors via its SH2 domain and regulates trafficking and degradation of EGF receptors via its interaction with STAM, indicating a vital role for RIN1 in regulating endosomal trafficking of receptor tyrosine kinases (RTKs) []. RIN1 was first identified as a Ras-binding protein that suppresses the activated RAS2 allele in S. cerevisiae. RIN1 binds to the activated Ras through its carboxyl-terminal domain and this Ras-binding domain also binds to 14-3-3 proteins as Raf-1 does [].The SH2 domain of RIN1 are thought to interact with the phosphotyrosine-containing proteins, but the physiological partners for this domain are unknown. The proline-rich domain in RIN1 is similar to the consensus SH3 binding regions.
Cytokine-inducible SH2-containing protein (CIS) is a member of the suppressor of cytokine signaling (SOCS) family proteins. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. It inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation [].Suppressor of cytokine signalling (SOCS) was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain [, ].This entry represents the SH2 domain of CIS.
Interleukins (IL) are a group of cytokines that play an important role in the immune system. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells. Interleukin-11 (IL-11) is a pleiotropic cytokine that stimulates megakaryocytopoiesis, resulting in increased production of platelets, as well as activating osteoclasts, inhibiting epithelial cell proliferation and apoptosis, and inhibiting macrophage mediator production. These functions may be particularly important in mediating the hematopoietic, osseous and mucosal protective effects of IL-11 []. The cytokine also possesses anti-inflammatory activity, and has been proposed as a therapeutic agent in the treatment of chronic inflammatory diseases, such as Crohn's disease and rheumatoid arthritis []. Although IL-11 was initially believed to be restricted to mammals, subsequent studies demonstrated it to be expressed in ray-finned fish [, ]. Two fish paralogues have now been identified, designated IL-11A and IL-11B []. This entry represents interleukin-11 found in fish, and covers both fish paralogues IL-11A and IL-11B.
Three transport protein particle (TRAPP) complexes exist in yeast (TRAPPI-TRAPPIII), which share a common core in addition to unique subunits. TRAPPI-TRAPPIII regulate endoplasmic reticulum (ER)-to-Golgi transport, intra-Golgi transport and autophagy, respectively. TRAPPC composition seems to be more complex in higher eukaryotes than in yeast, and its roles are less clear.Mammalian TRAPPC13 is involved in regulating autophagy and survival in response to small molecule compound-induced Golgi stress []. The overall architecture of TRAPPC is not disrupted upon TRAPPC13 depletion. This is also the case for yeast TRAPP II Trs65 subunit, which was previously reported to be specific to yeast. However, Trs65 has been shown to have homology to TRAPPC13 and they are now thought to be orthologues []. This entry consists of high eukaryotes TRAPPC13 and some related yeast proteins, but it does not include S. cerevisiae Trs65 (see ).
Zeste white 10 (ZW10) was initially identified as a mitoticcheckpoint protein involved in chromosome segregation, and then implicated in targeting cytoplasmic dynein and dynactin to mitotic kinetochores, but it is also important in non-dividing cells. These include cytoplasmic dynein targeting to Golgi and other membranes, and SNARE-mediated ER-Golgi trafficking [, , ]. Dominant-negative ZW10, anti-ZW10 antibody, and ZW10 RNA interference (RNAi) cause Golgi dispersal. ZW10 RNAi also disperse endosomes and lysosomes [].Drosophila kinetochore components Rough deal (Rod) and Zw10 are required for the proper functioning of the metaphase checkpoint in flies and mammals [, ]. The eukaryotic spindle assembly checkpoint (SAC) monitors microtubule attachment to kinetochores and prevents anaphase onset until all kinetochores are aligned on the metaphase plate. It is an essential surveillance mechanism that ensures high fidelity chromosome segregation during mitosis. In higher eukaryotes, cytoplasmic dynein is involved in silencing the SAC by removing the checkpoint proteins Mad2 and the Rod-Zw10-Zwilch complex (RZZ) from aligned kinetochores [, , ].
The cystatin superfamily comprises cysteine protease inhibitors that play key regulatory roles in protein degradation processes. This superfamily includes cystatins, cathelicidins, staphopains, kininogens, latexins and Secreted phosphoprotein 24 (Spp-24) []. The progenitor of this superfamily was most probably intracellular and lacked a signal peptide and disulfide bridges, much like the extant Giardia cystatin. A primordial gene duplication produced two ancestral eukaryotic lineages, cystatins and stefins. Stefins remain encoded by a single or a small number of genes throughout the eukaryotes, whereas the cystatins have undergone a more complex and dynamic evolution through numerous gene and domain duplications []. Members of this superfamily differ in amino acid sequence but they share a conserved fold, consisting of a five stranded anti-parallel β-sheet wrapped around a five-turn α-helix [, ].
This entry represents an N-terminal domain of the ABC ATPase, RNase L inhibitor (RLI). RLI is also known as ABCE1, which contains two nucleotide-binding domains (NBDs) typical of the ABC transporter protein superfamily []; however, it lacks the transmembrane domains required for membrane transport functions [, ].RLI is a key enzyme in ribosomal biogenesis, formation of translation pre-initiation complexes, and assembly of HIV capsids [, ]. RLI1 was first identified as an endoribonuclease inhibitor that interacts directly with RNase L to prevent it from binding 2-5A (5'-phosphorylated 2',5'-linked oligo- adenylates) []. Structurally, RLIs have an N-terminal Fe-S domain and two nucleotide binding domains which are arranged to form two composite active sites in their interface cleft []. RLI is one of the most conserved enzymes between archaea and eukaryotes with a sequence identity more than 48%. The high degree of evolutionary conservation suggests that RLI performs a central role in archaeal and eukaryotic physiology.
The FLI-1 protein participates in regulation of cellular differentiation, proliferation, and survival [, ]. The Fli-1 gene was initially described in Friend virus-induced erythroleukemias as a site for virus integration. It is highly expressed in hematopoietic tissues and at lower level in lungs, heart, and ovaries. Fli-1 is a proto-oncogene implicated in Ewing's sarcoma and erythroleukemia [, ]. Members of this subfamily are potential targets for cancer therapy []. The Fli-1 proto-oncogene is a member of the ETS family of winged helix-turn-helix transcription factors that bind a purine-rich consensus sequence GGA(A/T) [].This entry also includes DNA-binding protein D-ETS-3, a drosophila protein which shows very high sequence homology to FLI-1 and contains and almost identical DNA binding domain [].
This entry includes testisin (PRSS21 or esp-1; MEROPS identifier S01.011), also known as tryptase-4 in mice []. Testisin is a serine endopeptidase with predominantly trypsin-like activity []which is bound to the surface of premeiotic spermatocytes via a GPI anchor [, ]. It was first identified in eosinophils but is widely expressed in mononuclear cells and tissues such as testis and prostate []. Knockout of the testisin gene leads to deformed sperm that have reduced motility [], and double knockout of the acrosin and testisin genes reduces fertility in male mice and sperm are unable to cross the zona pellucida of the ovum suggesting a role in fertilization for the peptidases []. Testisin promotes cervical cancer because by binding to the serpin homologue maspin, inhibiting its tumour-suppressing activity [].
Zeste white 10 (ZW10) was initially identified as a mitotic checkpoint protein involved in chromosome segregation as part of the RZZ (Rod-Zwilch-Zw10) complex, and then implicated in targeting cytoplasmic dynein and dynactin to mitotic kinetochores, but it is also important in non-dividing cells. These include cytoplasmic dynein targeting to Golgi and other membranes, andSNARE-mediated ER-Golgi trafficking in the context of Zw10-Rint1-Nag complex which are DSL11, Tip20, and Sec39 orthologues, respectively [, , ]. Yeast DSL1, is a peripheral membrane protein required for transport between the Golgi and the endoplasmic reticulum, part of the Dsl1p complex (Dsl1Tip20-Sec20-Sec39) [, , ]. These proteins are members of the CATCHR (complexes associated with tethering containing helical rods) family which includes subunits of evolutionarily related complex, such as conserved oligomeric Golgi (COG), Golgi-associated retrograde protein (GARP) and exocyst []. This entry represents the C-terminal domain of Zw10 and DSL1 which consists of an α-helical bundle.
Many flagellar proteins are exported by a flagellum-specific export pathway. Attempts have been made to characterise the apparatus responsible for this process, by designing assays to screen for mutants with export defects []. Experiments involving filament removal from temperature-sensitive flagellar mutants of Salmonella typhimurium have shown that, while most mutants were able to regrow filaments, flhA, fliH, fliI and fliN mutants showed no or greatly reduced regrowth. This suggests that the corresponding gene products are involved in the process of flagellum-specific export. The sequences of fliH, fliI and the adjacent gene, fliJ, have been deduced. FliJ was shown to encode a protein of molecular mass 17,302 Da []. It is a membrane-associated protein that affects chemotactic events, mutations in FliJ result in failure to respond to chemotactic stimuli.This subgroup is dominated by FliJ proteins found in Proteobacteria.
Members of the golgin subfamily A were identified as Golgi auto-antigens []. They might be involved in maintaining cis-Golgi structure []. One of the members of this family, member 2 or GM130, is a specific interacting partner of the small GTPase Rab1b []and plays a key role in the disassembly and reassembly of the Golgi apparatus during mitosis. GM130 is also involved in vesicle tethering and fusion at the cis-cisternae to facilitate transit between transport vesicles and the stacked cisternae. It interacts with GRASPs proteins, which mediate the stacking of Golgi cisternae []. Additionally, GM130 was localised to the spindle poles and regulates microtubule organization [].Structurally, GM130 is comprised of six coiled-coil regions in the middle, a Golgi-targeting domain at the C terminus, and a p115-interacting motif at the N terminus [].
Copper homeostasis protein CutC was originally thought to be involved in copper tolerance in Escherichia coli, as mutation in the corresponding gene lead to an increased copper sensitivity []. However, this phenotype has been later reported to depend on the levels of the mRNA-interfering complementary RNA regulator MicL, which is transcribed from a promoter located within the coding sequence of the cutC gene in the enterobacteria []. In the plant pathogen Xylella fastidiosa, this protein has been reported as specific for copper efflux []. The structure of this protein in the bacteria Shigella flexneri showed a monomer structure that adopts a common TIM β/α barrel with 8 β-strands surrounded by 8 α-helices [].The human homologue of this protein, which structure showed a potential copper-binding site, has an important role in intracellular copper homeostasis [, ].
Halocyanins are blue (type I) copper redox proteins found in halophilic archaea such as Natronomonas pharaonis (Natronobacterium pharaonis). Halocyanin from from N. pharaonis has been characterised and shown to be a small blue copper protein with a molecular mass of about 15.5kDa [, ]. This protein, which was named halocyanin, contains one Cu2+, with a copper-binding site containing two His, one Met, and one Cys as probable ligands. It is probable that halocyanin is a peripheral membrane protein, which serves as a mobile electron carrier.This entry represents the copper-binding domain of halocyanins. This domain is present only once in some halocyanins and is duplicated in others. It is not found in plastocyanins or certain divergent paralogs of halocyanin.
Protein containing this domain are highly divergent in their overall sequence, however, they share a common region of roughly 200 amino acids known as the SEC7 domain [[cite27373159], ]. The 3D structure of the domain displays several α-helices []. It was found to be associated with other domains involved in guanine nucleotide exchange (e.g., CDC25, Dbl) in mammalian guanine-nucleotide-exchange factors [].SEC7 domain containing proteins are guanine nucleotide exchange factors (GEFs) specific for the ADP-rybosylation factors (ARF), a Ras-like GTPases which is important for vesicular protein trafficking. These proteins can be divided into five families, based on domain organisation and conservation of primary amino acid sequence: GBF/BIG, cytohesins,eFA6, BRAGs, and F-box []. They are found in all eukaryotes, and are involved in membrane remodeling processes throughout the cell [].
This domain was identified in proteins including Kae1 and Gcp (YgjD), which were originally thought to be endopeptidases belonging to the peptidase M22 family []. However, there is a lack of experimental evidence to support peptidase activity as a general property, and this has not been confirmed in other orthologues [, ]. Recent research indicates that the Kae1 and Gcp proteins are involved in the biosynthesis of N6-threonylcarbamoyl adenosine, a universal modification found at position 37 of tRNAs that read codons beginning with adenine []. This domain is also present in Bacillus subtilis YdiC and Escherichia coli YeaZ. These proteins have been recently renamed as TsaB, and have also been shown to be involved in N6-Threonylcarbamoylad enonsine (t(6)A) biosynthesis [, ].
Ectatomin is a toxin from the venom of the ant Ectatomma tuberculatum. Ectatomin can efficiently insert into the plasma membrane, where it can form channels. Ectatomin was shown to inhibit L-type calcium currents in isolated rat cardiac myocytes []. In these cells, ectatomin induces a gradual, irreversible increase in ion leakage across the membrane, which can lead to cell death.Ectatomin is comprised of two subunits, A and B, which are homologous. The structure of ectatomin reveals that each subunit consists of two alpha helices with a connecting hinge region, which form a hairpin structure that is stabilised by disulphide bridges. A disulphide bridge between the hinge regions of the two subunits links the heterodimer together, forming a closed bundle of four helices with a left-handed twist [].
The PET domain is a ~110 amino acid motif in the N-terminal part of LIM domain proteins. The domain was described in Drosophila proteins involved in cell differentiation and is named after Prickle, Espinas and Testin. PET domain proteins contain about three zinc-binding LIM domains (see , ) and are found among metazoans. The PET domain has been suggested to play a role in protein-protein interactions with proteins involved in planar polarity signalling or organisation of the cytoskeleton []. Some proteins known to contain a PET domain:Mammalian testin protein (), which may function as a tumour suppressor.Mammalian LIM domain only protein 6 (LMO6/Prickle3, ).Fruit fly prickle () and espinas () proteins encoded by the tissue polarity gene prickle (pk), involved in the control of orientation of bristles and hairs. Mammalian prickle-like proteins 1 () and 2 ().
The insulin family of proteins groups together several evolutionarily related active peptides []: these include insulin [, ], relaxin [, ], insect prothoracicotropic hormone (bombyxin) [], insulin-like growth factors (IGF1 and IGF2) [, ], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [, , ]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain.Placenta insulin-like peptide, also known as placentin, was initially identified by cDNA library screening []. Placentin may participate in the cellular proliferation and/or differentiation processes during placental development [].
The PKD (Polycystic Kidney Disease) domain was first identified in the Polycystic Kidney Disease protein, polycystin-1 (PDK1 gene), and contains an Ig-like fold consisting of a β-sandwich of seven strands in two sheets with a Greek key topology, although some members have additional strands []. Polycystin-1 is a large cell-surface glycoprotein involved in adhesive protein-protein and protein-carbohydrate interactions; however it is not clear if the PKD domain mediates any of these interactions. PKD domains are also found in other proteins, usually in the extracellular parts of proteins involved in interactions with other proteins. For example, domains with a PKD-type fold are found in archaeal surface layer proteins that protect the cell from extreme environments [], and in the human VPS10 domain-containing receptor SorCS2 [].
The first characterised member of the Kae1/TsaD family was annotated as Gcp for O-sialoglycoprotein endopeptidase [], but this activity could not be confirmed []. Later, its homologue, Kae1 from Pyrococcus abyssi, has been shown to have DNA-binding properties and apurinic-endonuclease activity []. Members of this family have since been studied in yeast, archaea and bacteria resulting in sometimes conflicting data, several proposed functions and annotations but no definitive characterisation. For instance, some members have been linked to DNA maintenance in bacteria and mitochondria []and transcription regulation and telomere homeostasis in eukaryotes [, ], but their function remained unclear. Recent research indicates that this family is involved in the biosynthesis of N6-threonylcarbamoyl adenosine, a universal modification found at position 37 of tRNAs that read codons beginning with adenine [].
Alkaptonuria (AKU), a rare hereditary disorder, was the first disease to be interpreted as an inborn error of metabolism. The deficiency causes homogentisic aciduria, ochronosis, and arthritis. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGD) (), the enzyme that mediates the conversion of homogentisate to maleylacetoacetate, a step in the catabolism of both tyrosine and phenylalanine. The structure of this protein shows that the enzyme forms a hexamer arrangement comprised of a dimer of trimers. The active site iron ion is coordinated near the interface between the trimers [, ].This group of proteins includes human HDG and homologues from eukaryotes, bacteria and some archaeal species. This entry represents the N-terminal domain of HGD, which forms a jelly roll of β-strands [].
Alkaptonuria (AKU), a rare hereditary disorder, was the first disease to be interpreted as an inborn error of metabolism. The deficiency causes homogentisic aciduria, ochronosis, and arthritis. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGD) (), the enzyme that mediates the conversion of homogentisate to maleylacetoacetate, a step in the catabolism of both tyrosine and phenylalanine. The structure of this protein shows that the enzyme forms a hexamer arrangement comprised of a dimer of trimers. The active site iron ion is coordinated near the interface between the trimers [, ].This group of proteins includes human HDG and homologues from eukaryotes, bacteria and some archaeal species. This entry represents the C-terminal active site domain of HGD.
Villin is an actin-binding protein that is found in a variety of tissues. It is able to bind to the barbed end of actin filaments with high affinity and can sever filaments []. In addition, villin's activity is important for actin bundling in certain cell types []. It was first isolated as a major component of the core of intestinal microvilli [].Five villin proteins (Villin1-5) coexist in Arabidopsis. This entry represents the Villin-3 family. It has been shown that Villin-1 and Villin-3 have distinct and overlapping functions in formation andturnover of actin filament bundles []. While Villin-2 and Villin3 act redundantly to regulate cell elongation and directional organ growth []through bundling of actin filament [].
Villin is an actin-binding protein that is found in a variety of tissues. It is able to bind to the barbed end of actin filaments with high affinity and can sever filaments []. In addition, villin's activity is important for actin bundling in certain cell types []. It was first isolated as a major component of the core of intestinal microvilli [].Villin is a member of the gelsolin family, which includes other actin-binding proteins such as severin and supervillin []. Gelsolin family members contain between three and six evolutionarily conserved domains (called gelsolin-like or G domains) and have a carboxy terminal headpiece []. Villin has 6 gelsolin like domains that form its core domain. The core domain retains actin severing, capping and nucleating activities and also contains actin-binding, PIP2 binding and calcium-binding sites. Villin's headpiece allows it to form actin bundles [].
This entry represents the N-terminal domain of RESA (ring-infected erythrocyte surface antigen) from Plasmodium falciparum, the apicomplexan parasite that causes the most severe form of malaria in humans. The short, four-helical domain first identified in the Plasmodium export proteins PHISTa and PHISTc []has been identified in the P. falciparum-specific RESA-type (Ring-infected erythrocyte surface antigen) proteins in association with the DnaJ domain. Overall, at least 67 proteins have been detected in P. falciparum with complete copies of the PRESAN domain. No versions of this domain were detected in other apicomplexan genera, suggesting that the domain was 'invented' after the divergence of the lineage leading to the genus Plasmodium undergoing a dramatic proliferation only in P. falciparum. The structure of this domain has been solved. It contains a short initial helix (alpha1) followed by an antiparallel bundle of 3 long helices (alpha2-alpha4) [].
This alcohol dehydrogenase domain is located on the C-terminal part of a bifunctional two-domain protein. The N-terminal part of the protein contains an acetaldehyde-CoA dehydrogenase domain. This protein is involved in pyruvate metabolism. Pyruvate is converted to acetyl-CoA and formate by pyruvate formate-lysase (PFL). Under anaerobic condition, acetyl-CoA is reduced to acetaldehyde and ethanol by this two-domain protein []. Acetyl-CoA is first converted into an enzyme-bound thiohemiacetal by the N-terminal acetaldehyde dehydrogenase domain. The enzyme-bound thiohemiacetal is subsequently reduced by the C-terminal NAD+-dependent alcohol dehydrogenase domain. In E. coli, this protein is called AdhE and was shown pyruvate formate-lysase (PFL) deactivase activity, which is involved in the inactivation of PFL, a key enzyme in anaerobic metabolism []. In Escherichia coli and Entamoeba histolytica, this enzyme forms homopolymeric peptides composed of more than 20 protomers associated in a helical rod-like structure [].
A five-stranded β-barrel was first noted as a common structure among four proteins binding single-stranded nucleic acids (staphylococcal nuclease andaspartyl-tRNA synthetase) or oligosaccharides (B subunits of enterotoxin and verotoxin-1), and has been termed the oligonucleotide/oligosaccharide binding motif, or OB fold, a five-stranded β-sheet coiled to form a closed β-barrel capped by an alpha helix located between the third and fourth strands []. Two ribosomal proteins, S17 and S1, are members of this class, and have different variations of the OB fold theme. Comparisons with other OB fold nucleic acid binding proteins suggest somewhat different mechanisms of nucleic acid recognition in each case [].There are many nucleic acid-binding proteins that contain domains with this OB-fold structure, including anticodon-binding tRNA synthetases, ssDNA-binding proteins (CDC13, telomere-end binding proteins), phage ssDNA-binding proteins (gp32, gp2.5, gpV), cold shock proteins, DNA ligases, RNA-capping enzymes, DNA replication initiators and RNA polymerase subunit RBP8 [].This entry represents the RNA-binding domain of translation elongation factor IF5A [].
Ninjurins are novel homophilic cell adhesion proteins involved in different processes such as inflammation, cell death, axonal growth, cell chemotaxis and angiogenesis [, ]. Ninjurin1 was named for its up regulation in Schwann cells following nerve injury [, ]. Ninjurin1 promotes cell adhesion by mediating homophilic interactions via its its extracellular N-terminal adhesion motif (N-NAM) and is involved in the progression of the inflammatory stress by promoting cell-to-cell interactions between immune cells and endothelial cells, being also involved in cell migration [, ]. Ninjurin1 mediates programmed and necrotic cell death [, ], playing a key role in the induction of plasma membrane rupture during programmed and necrotic cell death. It is also involved in striated muscle growth and differentiation [].
The bipartite CS domain, which was named after CHORD-containing proteins and SGT1 [], is a ~100-residue protein-protein interaction module. The CS domain can be found in stand-alone form, as well as fused with other domains, such as CHORD (), SGS (), TPR (), cytochrome b5 () or b5 reductase, in multidomain proteins []. The CS domain has a compact antiparallel β-sandwich fold consisting of seven β-strands [, ]. Some proteins known to contain a CS domain are listed below []: Eukaryotic proteins of the SGT1 family. Eukaryotic Rar1, related to pathogenic resistance in plants, and to development in animals. Eukaryotic nuclear movement protein nudC. Eukaryotic proteins of the p23/wos2 family, which act as co-chaperone. Animal b5+b5R flavo-hemo cytochrome NAD(P)H oxydoreductase type B. Mammalian integrin beta-1-binding protein 2 (melusin).
This family contains the bacterial Sigma factor-binding protein Crl. This is a transcriptional regulator of the csgA curlin subunit gene for curli fibres that are found on the surface of certain bacteria []. These proteins bind to the sigma-S subunit of RNA polymerase, activating expression of sigma-S-regulated genes. It was initially suggested that Crl affects transcription initiation in vitro by other sigmas, such as sigma-70 and sigma-32. However, it is now established that Crl binds specifically to the alternative sigma factor S/RpoS and favors its association with the core RNAP (RNA polymerase), thereby increasing its activity, which in turn regulates general stress response that protects many Gram-negative bacteria from several harmful environmental conditions. Furthermore, sigma S factor/RpoS plays important roles in biofilm formation and virulence of the food-borne pathogen Salmonella enterica serovarTyphimurium [].
The endoplasmic reticulum (ER) of the yeast Saccharomyces cerevisiae (Baker's yeast) contains a proteolytic system able to selectively degrade misfolded lumenal secretory proteins. For examination of the components involved in this degradation process, mutants were isolated. They could be divided into four complementation groups. The mutations led to stabilisation of two different substrates for this process, and the classes were called der for degradation in the ER. DER1 was cloned by complementation of the der1-2 mutation. The DER1 gene codes for a novel, hydrophobic proteinthat is localized to the ER. Deletion of DER1 abolished degradation of the substrate proteins, suggesting that the function of the Der1 protein may be specifically required for the degradation process associated with the ER []. Interestingly this family seems distantly related to the Rhomboid family of membrane peptidases. This family may also mediate degradation of misfolded proteins.
This entry represents the calcium-binding domain found in SPARC (Secreted Protein Acidic and Rich in Cysteine) and Testican (also known as SPOCK; or SParc/Osteonectin, Cwcv and Kazal-like domains) proteins. SPARC proteins are down-regulated in various tumours and may have a tumour-suppressor function [, ]. Testican-3 appears to be a novel regulator that reduces the activity of matrix metalloproteinase (MMP) in adult T-cell leukemia (ATL) [].This cysteine-rich domain is responsible for the anti-spreading activity of human urothelial cells. This extracellular calcium-binding domain is rich in α-helices and contains two EF-hands that each coordinates one Ca2+ ion, forming a helix-loop-helix structure that not only drives the conformation of the protein but is also necessary for biological activity. The anti-spreading activity was dependent on the coordination of Ca2+ by a Glu residue at the Z position of EF-hand 2 [].
This is the neddylation site of cullin proteins, which are a family of structurally related proteins containing an evolutionarily conserved cullin domain. With the exception of APC2, each member of the cullin family is modified by Nedd8 and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S proteasome recognises and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin chains. Cullins are molecular scaffolds responsible for assembling the ROC1/Rbx1 RING-based E3 ubiquitin ligases, of which several play a direct role in tumorigenesis. Nedd8/Rub1 is a small ubiquitin-like protein, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase complex in Saccharomyces cerevisiae (Baker's yeast), and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for cell cycle control and for embryogenesis in metazoans. The only identified Nedd8 substrates are cullins. Neddylation results in covalent conjugation of a Nedd8 moiety onto a conserved cullin lysine residue [].
This entry represents inosine monophosphate (IMP) cyclohydrolase family, found in archaeal species, as well as some bacterial proteins of unknown function.IMP cyclohydrolase catalyses the cyclisation of 5-formylamidoimidazole-4-carboxamide ribonucleotide to IMP, a reaction which is important in de novo purine biosynthesis in archaeal species []. This single domain protein is arranged to form an overall fold that consists of a four-layered α-β-beta-alpha core structure. The two antiparallel β-sheets pack against each other and are covered by α-helices on one face of the molecule. The protein is structurally similar to members of the N-terminal nucleophile (NTN) hydrolase superfamily. A deep pocket was in fact found on the surface of IMP cyclohydrolase in a position equivalent to that of active sites of NTN-hydrolases, but an N-terminal nucleophile could not be found. Therefore, it is thought that this enzyme is structurally but not functionally similar to members of the NTN-hydrolase family [].In bacteria this step is catalysed by a bifunctional enzyme (purH).
The protein represented by this entry, YggX, serves to protect Fe-S clusters from oxidative damage []. The effect is two-fold: proteins that rely on Fe-S clusters do not become inactivated, and the release of free iron and hydrogen peroxide--a DNA damaging agent--is prevented. These observations are consistent with the hypothesis that YggX chelates free iron, and recent experiments show that YggX can indeed bind Fe(II) in vitro and in vivo []. Furthermore, YggX has a positive effect on the action of at least one Fe(II)-responsive protein. The combined actions of YggX is reminiscent of iron trafficking proteins [], and YggX is therefore proposed to play a role in Fe(II) trafficking []. In Escherichia coli, YggX was shown to be under the transcriptional control of the redox-sensing SoxRS system [].
The following proteins of the tesmin/TSO1 family contain two cysteines-richrepeats with the consensus C-X-C-X(4)-C-X(3)-Y-C-X-C-X(6)-C-X(3)-C-X-C-X(2)-Cseparated by a region of variable length containing the short conservedsequence R-N-P-X-A-F-X-P-K:Animal tesmin or MTL5, originally identified by its specific expression in testes, but subsequently it was also detected at specific stages of ovary development.Animal tesmin-like (tesl) or LIN54.Drosophila melanogaster tombola (tomb), a meiotic arrest protein which is expressed specifically in testis.Arabidopsis thaliana TSO1, 'tso' means 'ugly' in Chinese and refers to the appearance of tso1 mutant flowers.Arabidopsis thaliana TSO1-like 1 and 2 (SOL1 and SOL2).Legume Cysteine-rich Polycomb-like Protein 1 (CPP1), a DNA-binding protein acting as a negative regulator of the leghemoglobin gene.This domain has been named the CRC domain (C1-RNPXAFXPK-C2). It binds zinc andis able to bind DNA [, , , , ].The CRC domain shows some similarity to the CXC domain found in the E(z)-typeof Polycomb group proteins []. However, a clear distinctioncan be made, since the CXC domain lacks the RNPXAFXPK motif.
Initiation factor 3 (IF-3) (gene infC) is one of the three factors required for the initiation of protein biosynthesis in bacteria. IF-3 is thought to function as a fidelity factor during the assembly of the ternary initiation complex which consist of the 30S ribosomal subunit, the initiator tRNA and the messenger RNA. IF-3 is a basicprotein that binds to the 30S ribosomal subunit []. The chloroplast initiation factor IF-3(chl) is a protein that enhances the poly(A,U,G)-dependent binding of the initiator tRNA to chloroplast ribosomal30s subunits in which the central section is evolutionary related to the sequence of bacterial IF-3 []. The signature pattern for this entry was made from a highly conserved region located in the central section of bacterial and plant chloroplast IF-3.
Members of this protein family are exclusive to the Bacteroidetes phylum (previously Cytophaga-Flavobacteria-Bacteroides). GldC is a protein linked to a type of rapid surface gliding motility found in certain Bacteroidetes, such as Cytophaga johnsonae (Flavobacterium johnsoniae) and Cytophaga hutchinsonii. GldE was discovered because of its adjacency to GldD in C. johnsonae. Over expression of GldE partially suppresses the effects of a GldB point mutant suggesting that GldB and GldE interact []. Gliding motility appears closely linked to chitin utilization in the model species C. johnsonae. Not all Bacteroidetes with members of this protein family appear to have all of the genes associated with gliding motility and in fact some do not appear to have the gliding phenotype.
Numerous bacterial transcription regulatory proteins bind DNA via a helix-turn-helix (HTH) motif. These proteins are very diverse, but for convenience may be grouped into subfamilies on the basis of sequence similarity. One such family, the lysR family, groups together a range of proteins, including ampR, catM, catR, cynR, cysB, gltC, iciA, ilvY, irgB, lysR, metR, mkaC, mleR, nahR, nhaR, nodD, nolR, oxyR, pssR, rbcR, syrM, tcbR, tfdS and trpI [, , , , ]. The majority of these proteins appear to be transcription activatorsand most are known to negatively regulate their own expression. All possess a potential HTH DNA-binding motif towards their N-termini.The hdfR gene encodes a LysR family protein. HdfR is able to bind to the flhDC promoter, indicating that HdfR is a transcriptional regulator for the flagellar master operon. Furthermore, the expression of the hdfR gene was shown to be negatively regulated by H-NS [].
Numerous bacteria encode systems for producing bacteriocins by extensive modification of ribosomally produced precursors. Members of the TOMM class (thiazole/oxazole-modified microcins) are recognizable by association with cyclodehydratase (and often dehydrogenase) maturation proteins. This family consists of a special subclass, the heterocycloanthracin family, that share a homologous leader peptide region and then a repeat region with Cys as every third residue. In Bacillus anthracis and Bacillus cereus, the RiPP (ribosomally translated and post-translationally modified natural product) precursor is encoded far from its maturase genes, and every strain has the system. In other species (e.g. B. licheniformis, B. sorenensis), precursor and maturase genes are close together. Sonorensin, from B. sonorensis MT93, was shown to have broad spectrum antimicrobial activity, affecting Gram-positive and Gram-negative bacteria [].
Early annotation suggested this family, SepSecS, of several eukaryotic and archaeal proteins, was involved in antigen-antibodies responses in the liver and pancreas [, ]. Structural studies show that the family is O-phosphoseryl-tRNA(Sec) selenium transferase, an enzyme involved in the synthesis of the amino acid selenocysteine (Sec). Sec is the only amino acid whose biosynthesis occurs on its cognate transfer RNA (tRNA). SepSecS catalyses the final step in the formation of the amino acid [, , , ]. The early observation that autoantibodies isolated from patients with type I autoimmune hepatitis targeted a ribonucleoprotein complex containing tRNASec led to the identification and characterisation of the archaeal and the human SepSecS []. SepSecS forms its own branch in the family of fold-type I pyridoxal phosphate (PLP) enzymes that goes back to the last universal common ancestor.This entry also includes O-phosphoseryl-tRNA:Cys-tRNA synthase SepCysS. It is found in Methanogenic archaea, which have an alternative pathway for Cys-tRNACys formation [, ].
Budding yeast Yaf9 is a component of the SWR1 []and NuA4 []complexes. Yaf9 contains a YEATS domain.The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
This entry represents the PLP (pyridoxal 5'-phosphate)-binding barrel that can be found at the N terminus of alanine racemase-like proteins and members of the Orn/Lys/Arg decarboxylase class-II family of proteins.The molecular structure of alanine racemase from Bacillus stearothermophilus was determined by X-ray crystallography to a resolution of 1.9 A []. The alanine racemase monomer is composed of two domains, an eight-stranded alpha/beta barrel at the N terminus, and a C-terminal domain essentially composed of β-strands. The pyridoxal 5'-phosphate (PLP) cofactor lies in and above the mouth of the α/β barrel and is covalently linked via an aldimine linkage to a lysine residue, which is at the C terminus of the first β-strand of the α/β barrel.
This entry represents glia maturation factor beta and gamma (GMFB/GMFG), Aim7 from budding yeasts and Gmf1 from fission yeasts. GMF family proteins do not interact with actin, but instead bind to Arp2/3 complex. They sever actin-Arp2/3 complex branch junctions by a cofilin-like mechanism [, ]. Human GMFB was initially identified as a growth and differentiation factor acting on neurons as well as glia in the vertebrate brain. GMFB is produced predominantly in the thymus, and may have roles in both intracellular signal transduction and T cell development [].Fission yeast Gmf1 is an actin depolymerising factor involved in the control of the disassembly of actin patches []. Aim7 binds Arp2/3 complex to stimulate filament debranching and inhibit actin nucleation [].
The N-Utilization Substance G (NusG) protein and its eukaryotic homologue, Spt5, are involved in transcription elongation and termination. NusG contains an NGN domain at its N terminus and Kyrpides Ouzounis and Woese (KOW) repeats at its C terminus. Spt5 forms an Spt4-Spt5 complex that is an essential RNA polymerase II elongation factor. NusG was originally discovered as an N-dependent antitermination enhancing activity in Escherichia coli, and has a variety of functions such as its involvement in RNA polymerase elongation and Rho-termination in bacteria. Orthologues of the NusG gene exist in all bacteria, but their functions and requirements are different. Spt5-like is homologous to the Spt5 proteins present in all eukaryotes, which is unique as it encodes a protein with an additional long carboxy-terminal extension that contains WG/GW motifs. Spt5-like, or KTF1 (KOW domain-containing Transcription Factor 1), is a RNA-directed DNA methylation (RdDM) pathway effector in plants [, ].
Structurally, ArgK (also known as YgfD) belongs to the G3E family of P-loop GTPases, a family defined by the glutamate residue in the Walker B motif and an intact NKxD, members of which include: UreG, HypB, CobW, and MeaB []. ArgK is involved in the transport of positively charged amino acids (lysine, arginine, and ornithine) and has arginine kinase activity. It is found in a small, but phylogenetically diverse array of bacteria and archaea, and in Caenorhabditis and Leishmania among the eukaryotes []. Although ArgK was characterised as an ATPase originally [], it has been shown to binds and cleaves GTP. Therefore, its actual substrate in vivo is GTP rather than ATP []. This entry also includes methylmalonic aciduria type A (MMAA), which is associated with the fatal disease methylmalonyl aciduria []. Caenorhabditis elegan MMAA may have a role in propionyl-CoA metabolism and adenosylcobalamin synthesis []. The structure of MMAA has been revealed [].
This entry includes PAMP-induced secreted peptide 2 (PIP2) and PAMP-INDUCED PEPTIDE-LIKE 1 (PIPL1, also known as CEP16 or PREPIPL1) from Arabidopsis, which are part of the PIP/PIPL family [, ]. These secreted proteins contain two conserved core SGPS motifs at the C terminus and the GxGH motif at the extreme C terminus []. The double peptide motif might be processed into two different peptides or, alternatively, may act as a functional unit, being able to interact with distinct binding sites resulting in the activation of different pathways. PIP2 is involved in innate immune and stress responses. It also acts as a negative regulator of root growth []. PIPL1 is involved in seed development and was also induced by stress [].
This family of proteins are found in a range of bacteria. The conserved region contains a conserved histidine and cysteine, suggesting that these proteins have an enzymatic activity. Several members of this family contain peptidoglycan binding domains. So these proteins may use peptidoglycan or a precursor as a substrate. The molecular structure of YkuD protein shows this domain has a novel tertiary fold consisting of a β-sandwich with two mixed sheets, one containing five strands and the other, six strands. The two β-sheets form a cradle capped by an α-helix. This domain contains a putative catalytic site with a tetrad of invariant His123, Gly124, Cys139, and Arg141. The stereochemistry of this active site shows similarities to peptidotransferases and sortases, and suggests that the enzymes of this family may play an important role in cell wall biology. This family was formerly called the ErfK/YbiS/YcfS/YnhG family, but is now named after the first protein of known structure [, ].
This entry represents liprin family from vertebrates and invertebrates.Liprin was originally identified as binding partners of the receptor protein tyrosine phosphatase LAR (leukocyte common antigen-related), which functions in axon guidance and mammary gland development []. In vertebrates, there are two families of liprins, liprin-alpha and liprin-beta, which have four (alpha1-4) and two (beta1-2) members. In C. elegans and Drosophila, there are only one liprin-alpha (known as Syd-2 and Dliprin-alpha) and one liprin-beta. Another liprin family member, liprin-gamma, has also been identified in Drosophila []. Liprins contain an N-terminal coiled-coil domain and a C-terminal liprin homology (LH) region comprised of three sterile alpha motif (SAM) domains []. The N-terminal coiled coils of liprin-alpha mediate interactions with adapter proteins at the presynaptic active zone, while the SAM repeats bind proteins such as LAR receptor tyrosine phosphatase [].
Liprin-beta-2 is a member of the LAR (leukocyte common antigen-related) protein tyrosine phosphatase-interacting protein (liprin) family []. Liprin was originally identified as binding partners of the receptor protein tyrosine phosphatase LAR (leukocyte common antigen-related), which functions in axon guidance and mammary gland development []. In vertebrates, there are two families of liprins, liprin-alpha and liprin-beta, which have four (alpha1-4) and two (beta1-2) members. Liprins contain an N-terminal coiled-coil domain and a C-terminal liprin homology (LH) region comprised of three sterile alpha motif (SAM) domains. The N-terminal coiled coils of liprin-alpha act as binding regions for several synaptic protein, while the SAM repeats can bind to both phosphatases and protein kinases []. The autophosphorylation of liprin regulates its association with LAR []. Interestingly, all Liprin-alpha genes are subject to alternative splicing, which is regulated in a developmental manner []. The structure of the human CASK/liprin-alpha/liprin-beta ternary complex has been revealed [].
This superfamily includes EspF(U) and related proteins.Enteropathogenic Escherichia coli O127:H6 attaches to the intestinal mucosa through actin pedestals that are created after it has injected the Type III secretion protein EspF (E. coli secreted protein F-like protein from prophage U) into the cells. EspF recruits the actin machinery by activating the WASP (Wiscott-Aldrich syndrome protein) family of actin nucleating factors []. Subsequent cell-death (apoptosis) is caused by EspF being targeted to the mitochondria as a consequence of its mitochondrial targeting sequence. Import into mitochondria leads to a loss of membrane potential, leakage of cytochrome c and activation of the apoptotic caspase cascade. Mutation of leucine to glutamic at position 16 of EspF (L16E) resulted in the failure of EspF import into mitochondria; mitochondrial membrane potential was not affected and cell death abolished. This suggests that the targeting of EspF to mitochondria is essential for bacterial pathogenesis and apoptosis [, ].
This superfamily represents the N-terminal domain of RESA (ring-infected erythrocyte surface antigen) from Plasmodium falciparum, the apicomplexan parasite that causes the most severe form of malaria in humans.The short, four-helical domain first identified in the Plasmodium export proteins PHISTa and PHISTc []has been identified in the P. falciparum-specific RESA-type (Ring-infected erythrocyte surface antigen) proteins in association with the DnaJ domain. Overall, at least 67 proteins have been detected in P. falciparum with complete copies of the PRESAN domain. No versions of this domain were detected in other apicomplexan genera, suggesting that the domain was 'invented' after the divergence of the lineage leading to the genus Plasmodium undergoing a dramatic proliferation only in P. falciparum. The structure of this domain has been solved. It contains a short initial helix (α1) followed by an antiparallel bundle of 3 long helices (α2-α4) [].
The transport of peptides into cells is a well-documented biological phenomenon which is accomplished by specific, energy-dependent transporters found in a number of organisms as diverse as bacteria and humans. The amino acid/peptide transporter family of proteins is distinct fromthe ABC-type peptide transporters and was uncovered by sequence analysis of a number of recently discovered peptide transport proteins []. This family consists of bacterial proton-dependent oligopeptide transporters, although they are found in yeast, plants and animals. They function by proton symport in a 1:1 stoichiometry, which is variable in different species. Structurally, these transporters present a conserved architecture consisting of 14 transmembrane α-helices with N-terminal and C-terminal six-helix bundles connected by two transmembrane α-helices (HA and HB) [].This entry represents a family of probable proton-dependent permeases that transport dipeptides.
The transport of peptides into cells is a well-documented biological phenomenon which is accomplished by specific, energy-dependent transporters found in a number of organisms as diverse as bacteria and humans. The amino acid/peptide transporter family of proteins is distinct from the ABC-type peptide transporters and was uncovered by sequence analysis of a number of recently discovered peptide transport proteins []. This family consists of bacterial proton-dependent oligopeptide transporters, although they are found in yeast, plants and animals. They function by proton symport in a 1:1 stoichiometry, which is variable in different species. Structurally, these transporters present a conserved architecture consisting of 14 transmembrane α-helices with N-terminal and C-terminal six-helix bundles connected by two transmembrane α-helices (HA and HB) [].This entry represents a family of proton-dependent permeases that transport di- and tripeptides.
The TCP transcription factor family was named after: teosinte branched 1 (tb1, Zea mays (Maize)) [], cycloidea (cyc) (Antirrhinum majus) (Garden snapdragon) []and PCF in rice (Oryza sativa) [, ]. The TCP proteins code for structurally related proteins implicated in the evolution of key morphological traits []. However, the biochemical function of CYC and TB1 proteins remains to be demonstrated. One of the conserved regions is predicted to form a non-canonical basic-Helix-Loop-Helix (bHLP) structure. This domain is also found in two rice DNA-binding proteins, PCF1 and PCF2, where it has been shown to be involved in DNA-binding and dimerization.This family of transcription factors are exclusive to higher plants. They can be divided into two groups, TCP-C and TCP-P, that appear to have separated following an early gene duplication event []. This duplication event may have led to functional divergence and it has been proposed that that the TCP-P subfamily are transcriptional repressors, while the TPC-C subfamily are transcription activators [].
This entry represents the TMEM33/Pom33 family. Budding yeast Pom33 is a transmembrane nucleoporin that contributes to proper distribution and/or efficient assembly of nuclear pores []. Proteins in this entry also include Tts1 from fission yeasts [], Kr-h2 (krueppel homologue 2) from flies []and TMEM33 from vertebrates []. Tts1 is required for the correct positioning of the cellular division plane by delimiting the actomyosin ring assembly at the cell equator [].Kr-h2 is a member of the dosage-dependent hierarchy effective upon white gene expression [].TMEM33 regulates the tubular structure of endoplasmic reticulum by suppressing the membrane-shaping activity of reticulons []. It was also demonstrated that TMEM33 regulates the unfolded protein response which is activated during endoplasmic reticulum stress [].
This domain entry includes the N terminus of the actin-interacting protein sperm-specific antigen 2 (SSFA2), also known as Ki-ras-induced actin-interacting protein (KRAP) []. In this region are found the residues that interact with inositol 1,4,5-trisphosphate receptor (IP3R, also known as ITPR). SSFA2 was first localised as a membrane-bound form with extracellular regions suggesting it might be involved in the regulation of filamentous actin and signals from the outside of the cells []. It has now been shown to be critical for the proper subcellular localisation and function of IP3R. Inositol 1,4,5-trisphosphate receptor functions as the Ca2+ release channel on specialised endoplasmic reticulum membranes, so the subcellular localisation of IP3R is crucial for its proper function [].This entry also recognises a domain in Tespa1 and in uncharacterized coiled-coil protein CCDC129. Tespa1 (thymocyte-expressed positive selection-associated protein 1) is required for the development and maturation of T-cells []. Tespa1 shows sequence homology to SSFA2 and physically associates with IP3R in T and B lymphocytes [].
Solute carrier family 26 member 9 (SLC26A9) has been reported to have both a Cl- channel and a Cl-/HCO3- exchanger activity []. It also seems to exhibit a unique function among the SLC26 members, as its anion transport activity was shown to be coupled to cation transport (Na+/anion transport) [].SLC26A9 is predominantly expressed in the lung and stomach, and to a lower degree in kidney [, , ]. Inactivation of SLC26A9 in mice led to loss of gastric acid secretion []. In the airway, SLC26A9 mediated Cl- secretion in response to airway inflammation induced by IL-13 []. In the kidney, SLC26A9 is required for the regulation of both renal salt excretion and blood pressure [].
Copper homeostasis protein CutC was originally thought to be involved in copper tolerance in Escherichia coli, as mutation in the corresponding gene lead to an increased copper sensitivity []. However, this phenotype has been later reported to depend on the levels of the mRNA-interfering complementary RNA regulator MicL, which is transcribed from a promoter located within the coding sequence of the cutC gene in the enterobacteria []. In the plant pathogen Xylella fastidiosa, this protein has been reported as specific for copper efflux []. The structure of this protein in the bacteria Shigella flexneri showed a monomer structure that adopts a common TIM β/α barrel with 8 β-strands surrounded by 8 α-helices [].The human homologue of this protein, which structure showed a potential copper-binding site, has an important role in intracellular copper homeostasis [, ].
Thf1 protein (also known as Psb29) is found in Cyanobacteria and in the plastids of vascular plants. They may function in the biogenesis of Photosystem II complexes [].In Synechocystis it was isolated and partially sequenced from purified photosystem II (PS II). Deletion of psb29 in Synechocystis 6803 results in slower growth rates under high light intensities, increased light sensitivity, and lower PSII efficiency, without affecting the PSII core electron transfer activities []. In plants Thf1 is localised to the outer plastid membrane and the stroma. Thf1 has a role in sugar signalling. Thf1 is also thought to have a role in chloroplast and leaf development. Thf1 has been shown to play a crucial role in vesicle-mediated thylakoid membrane biogenesis [, ].
The entry describes a hydrophobic sequence region that is duplicated to form the AbrB protein of Escherichia coli (not to be confused with a Bacillus subtilis protein with the same gene symbol). In some species, notably the Cyanobacteria and Thermus thermophilus, proteins consist of a single copy rather than two copies. The member from Pseudomonas putida, PP_1415 (), was suggested to be an ammonia monooxygenase characteristic of heterotrophic nitrifiers, based on an experimental indication of such activity in the organism and a glimmer of local sequence similarity between parts of the P. putida protein and an instance of the AmoA protein () from Nitrosomonas europaea []; we do not believe the sequence similarity to be meaningful. The member from E. coli (b0715, ybgN) appears to be the largely uncharacterised AbrB (aidB regulator) protein of E. coli [], although we did not manage to trace the origin of association of the article to the sequence.
Secretion of protein products occurs by a number of different pathways in bacteria. One of these pathways known as the type V pathway was first described for the IgA1 protease []. The protein component that mediates secretion through the outer membrane is contained within the secreted protein itself, hence the proteins secreted in this way are called autotransporters. This family corresponds to the presumed integral membrane β-barrel domain that transports the protein. This domain is found at the C terminus of the proteins it occurs in. The N terminus contains the variable passenger domain that is translocated across the membrane. Once the passenger domain is exported it is cleaved auto-catalytically in some proteins, in others a different protease is used and in some cases no cleavage occurs [].
The DNA single-strand annealing proteins (SSAPs), such as RecT, Red-beta, ERF and Rad52, function in RecA-dependent and RecA-independent DNA recombination pathways. This superfamily includes proteins related to Rad52. These proteins contain two helix-hairpin-helix motifs [].Rad52 was identified in Saccharomyces cerevisiae (Baker's yeast) as a component of the homologous recombination repair pathway and to play an important role in both meiotic and mitotic recombination. The human protein is highly homologous in both structure and function. Inthe presence of absence of DNA, Rad52 forms ring-shaped oligomers which bind both single and double stranded DNA, stimulating annealing of complimentary DNA strands and promoting ligation of both cohesive and blunt-end fragments. Rad52 may act as a recombination mediator, optimising catalysis of strand exchange by the Rad51 protein.A C-terminal self-association domain has been identified that mediates formation of higher order oligomers of Rad52 rings. Formation of these oligomers may be important for interaction with more than one DNA molecule [].
This entry includes Harmonin-binding protein USHBP1 also known as MCC2) and colorectal mutant cancer protein known as MCC. MCC has been found to suppresses cell proliferation and the Wnt/b-catenin pathway in colorectal cancer cells [, ]. It may works as a scaffold protein regulating cell movement and able to bind Scrib, beta-catenin and NHERF1/2 []. MCC1 inhibits DNA binding of b-catenin/TCF/LEF transcription factors, and it is involved in cell migration independently of RAC1, CDC42 and p21-activated kinase (PAK) activation [, , ].MCC2 protein binds the first PDZ domain of AIE-75 with its C-terminal amino acids -DTFL. A possible role of MCC2 as a tumour suppressor has been put forward. The carboxyl terminus of the predicted protein was DTFL which matched the consensus motif X-S/T-X-phi (phi: hydrophobic amino acid residue) for binding to the PDZ domain of AIE-75 [, ].
This entry represents a widespread protein family known as MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) []. This group of membrane associated proteins with highly divergent functions, such as the metabolism of eicosanoids [, ]. Included are:5-lipoxygenase activating protein (gene FLAP), which seems to be required for the activation of 5-lipoxygenase.Leukotriene C4 synthase (), which catalyses the production of LTC4 from LTA4. The structure of human LTC4S was solved by X-ray crystallography []. Microsomal glutathione S-transferase II () (GST-II), which also produces LTC4 from LTA4. These enzymes play an important role in the resistance to temperature stresses and lipid peroxidation [, ]. Prostaglandin E synthase, which catalyses the synthesis of PGE2 from PGH2 (produced by cyclooxygenase from arachidonic acid). Because of structural similarities in the active sites of FLAP, LTC4 synthase and PGE synthase, substrates for each enzyme can compete with one another and modulate synthetic activity.
This model describes bacterial flagellar biogenesis protein fliP, which is one of the genes within the motility locus on the bacterial chromosome that is involved in structure and function of bacterial flagellum. It was demonstrated that mutants in fliP locus were non-flagellated and non-motile, while revertants were flagellated and motile. In Escherichia coli and related proteins the fliP protein probably []plays a role in the transport of flagellar proteins. FliP is a protein of about 30 Kd which contains three or four transmembrane regions. Proteins evolutionary related to fliP have been found in a wide range of bacteria (mopC, hrcR, hrpW, spaP, yscR, etc.) and are involved in a variety of signal-peptide independent secretion systems.
E or 'early' set domains are associated with the catalytic domain of galactose oxidase at the C-terminal end. Galactose oxidase is an extracellular monomeric enzyme which catalyzes the stereospecific oxidation of a broad range of primary alcohol substrates, and possesses a unique mononuclear copper site essential for catalyzing a two-electron transfer reaction during the oxidation of primary alcohols to corresponding aldehydes. The second redox active centre necessary for the reaction was found to be situated at a tyrosine residue. The C-terminal domain of galactose oxidase may be related to the immunoglobulin and/or fibronectin type III superfamilies. These domains are associated with different types of catalytic domains at either the N-terminal or C-terminal end, and may be involved in homodimeric/tetrameric/dodecameric interactions. Members of this family include members of the alpha amylase family, sialidase, galactose oxidase, cellulase, cellulose, hyaluronate lyase, chitobiase, and chitinase, among others [, , , , ].
This entry represents a domain found in BRCA2 proteins. This domain adopts a helical structure, consisting of a four-helix cluster core (alpha 1, alpha 8, alpha 9, alpha 10) and two successive β-hairpins (beta 1 to beta 4). An approximately 50-amino acid segment that contains four short helices (alpha 2 to alpha 4), meanders around the surface of the core structure. In BRCA2, the alpha 9 and alpha 10 helices pack with BRCA-2_OB1 () through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds. This domain binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome [].
TCF-19, also termed transcription factor SC1, was identified as a putative trans-activating factor with expression beginning at the late G1-S boundary in dividing cells []. It also functions as a novel islet factor necessary for proliferation and survival in the INS-1 beta cell line. It plays an important role in susceptibility to both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM); it has been suggested that it may positively impact beta cell mass under conditions of beta cell stress and increased insulin demand [].TCF-19 contains an N-terminal fork head association domain (FHA), a proline rich region, and a C-terminal plant homeodomain (PHD) finger. The FHA domain may serve as a nuclear signaling domain or as a phosphoprotein binding domain. The proline rich region is a common characteristic of trans-activating factors. The PHD finger may allow TCF-19 to interact with chromatin via methylated histone H3 [].
It has been observed that the identity of N-terminal residues of a protein isrelated to the half life of the protein. This observation yields a rule,called the N-end rule []. Similar but distinct versions of the N-end rule operate in all organisms examined, from mammals to fungi and bacteria. Ineukaryotes, the N-end rule pathway is a part of the ubiquitin degradationsystem. Some proteins that have a very short half life contain a specificmotif at their N terminus, the N-degron. It consists of a destabilisingN-terminal residue and an internal Lys, which is the site of poly-Ub chain[, ].The UBR1 protein was shown to bind specifically to proteins bearing N-terminalresidues that are destabilising according to the N-end rule, but not tootherwise identical proteins bearing stabilising N-terminal residues []. UBR1 contains an N-terminal conserved region (the UBR-type zinc finger) which is also found in various proteins implicated in N-degron recognition. The UBR-type zinc finger defines a unique E3 class, most likely N-degron specific [].
Plexin A1 is found in both the nervous and immune systems. Its external Sema domain is also shared by semaphorin proteins. In the nervous system, Plexin A1 mediates Sema3A axon guidance function by interacting with the Sema3A coreceptor neuropilin, resulting in actin depolarization and cell repulsion [, ]. In the immune system, Plexin A1 mediates Sema6D signaling by binding to the Sema6D-Trem2-DAP12 complex on immune cells and osteoclasts to promote Rac activation and DAP12 phosphorylation []. In gene profiling experiments, Plexin A1 was identified as a CIITA (class II transactivator) regulated gene in primary dendritic cells (DCs) []. The Sema domain is located at the N terminus and contains four disulfide bonds formed by eight conserved cysteine residues. It serves as a ligand-recognition and -binding module.
This entry represents a group of pre-mRNA-processing factors, including Syf1/Clf1 from budding yeasts and protein crooked neck (CRN) from fruit flies. Syf1 acts as a component of the NTC complex (or Prp19-associated complex), associatesto the spliceosome to mediate conformational rearrangement or to stabilize the structure of the spliceosome after U4 snRNA dissociation, which leads to spliceosome maturation [, ]. Clf1 is a splicing factor that are part of at least two multisubunit protein complexes, a small nuclear RNA-free structure similar to what was reported as the Prp19 complex and an RNP structure that contains the U2, U5, and U6 small nuclear RNAs []. Human CRN-like protein is also implicated in pre-mRNA splicing [. The crn mutation in Drosophila has been shown to cause abnormalities in the central and peripheral nervous systems [].
Urease (urea amidohydrolase, ) is a nickel-binding enzyme that catalyses the hydrolysis of urea to carbon dioxide and ammonia []. Historically, it was the first enzyme to be crystallized (in 1926). It is mainly found in plant seeds,microorganisms and invertebrates. In plants, urease is a hexamer of identicalchains. In bacteria [], it consists of either two or three different subunits(alpha, beta and gamma).Urease binds two nickel ions per subunit; four histidine, an aspartate and acarbamated-lysine serve as ligands to these metals; an additional histidine isinvolved in the catalytic mechanism []. The urease domain forms an (alphabeta)(8) barrel structure with structural similarity to other metal-dependent hydrolases, such as adenosine and AMP deaminase and phosphotriesterase.This entry represents a conserved region that contains two histidines that bind one of the nickel ions.
Synonym: dark protochlorophyllide reductaseProtochlorophyllide reductase catalyzes the reductive formation of chlorophyllide from protochlorophyllide during biosynthesis of chlorophylls and bacteriochlorophylls. The light-independent (dark) form of protochlorophyllide reductase plays a key role in the ability of gymnosperms, algae, and photosynthetic bacteria to form chlorophyll in the dark. Genetic and sequence analyses have indicated that dark protochlorophyllide reductase consists of three protein subunits that exhibit significant sequence similarity to the three subunits of nitrogenase, which catalyzes the reductive formation of ammonia from dinitrogen. Dark protochlorophyllide reductase activity was shown to be dependent on the presence of all three subunits, ATP, and the reductant dithionite.This enzyme describes the N subunit of the dark form protochlorophyllide reductase, a nitrogenase-like enzyme[].
Urease (urea amidohydrolase, )is a nickel-binding enzyme that catalyses the hydrolysis of urea to carbon dioxide and ammonia []. Historically, it was the first enzyme to be crystallized (in 1926). It is mainly found in plant seeds,microorganisms and invertebrates. In plants, urease is a hexamer of identicalchains. In bacteria [], it consists of either two or three different subunits(alpha, beta and gamma).Urease binds two nickel ions per subunit; four histidine, an aspartate and acarbamated-lysine serve as ligands to these metals; an additional histidine isinvolved in the catalytic mechanism []. The urease domain forms an (alphabeta)(8) barrel structure with structural similarity to other metal-dependent hydrolases, such as adenosine and AMP deaminase and phosphotriesterase.This entry represents a conserved region that contains the active site histidine.
The Ig-like fold is part of proteins with important roles in different physiological processes []. This entry represents the bacterial Ig-like domain (Big2). This domain is mainly found in a variety of bacterial and phage surface proteins such as intimins, but has also been found in several eukaryote proteins []. Intimin (Eae protein) is a bacterial cell-adhesion molecule that mediates the intimate bacterial host-cell interaction. It contains three domains; two immunoglobulin-like domains and a C-type lectin-like module implying that carbohydrate recognition may be important in intimin-mediated cell adhesion [, ].The structure of this domain was also described in the Tail tube protein of phage lambda (TTP). This protein assembles in hexameric rings that stack on top of each others [, ].Nuclear pore membrane glycoprotein 210 from humans (POM210) also belongs to this group of proteins. This nucleoporin is essential for nuclear pore assembly and fusion, nuclear pore spacing, as well as structural integrity [].
This entry represents the JmjN domain.The JmjN and JmjC domains are two non-adjacent domains which have been identified in the jumonji family of transcription factors. Although it wasoriginally suggested that the JmjN and JmjC domains always co-occur and might form a single functional unit within the folded protein, the JmjC domain was later found without the JmjN domain in organisms from bacteria to human [, ].JmJC domains are predicted to be metalloenzymes that adopt the cupin fold, and are candidates for enzymes that regulate chromatin remodelling. The cupin fold is a flattened β-barrel structure containing two sheets of five antiparallel β-strands that form the walls of a zinc-binding cleft. JmjC domains were identified in numerous eukaryotic proteins containing domains typical of transcription factors, such as PHD, C2H2, ARID/BRIGHT and zinc fingers [, ]. The JmjC has been shown to function in a histone demethylation mechanism that is conserved from yeast to human [].
This domain is found in all 24 mce genes associated with the four mammalian cell entry (mce) operons of Mycobacterium tuberculosis and MlaD proteins from other Actinomycetales [, ]. The archetype (mce1A, Rv0169), was isolated as being necessary for colonisation of, and survival within, the macrophage []. The domain is also found in: Chloroplast Ycf22 and related cyanobacterial homologues, the majority of which have an N-terminal transmembrane domain and are putative ABC transporters.Proteobacterial homologues, which include MlaD, PqiB, YrbD, YebT, VpsC and Ttg2C. MlaD is part of the ABC transporter complex MlaFEDB that actively prevents phospholipid accumulation at the cell surface []. MlaFEDB complex is composed of two ATP-binding proteins (MlaF), two transmembrane proteins (MlaE), two cytoplasmic solute-binding proteins (MlaB) and a probable periplamic solute-binding protein (MlaD). Through the Mla pathway, Gram-negative bacteria maintains lipid asymmetry in the outer membrane by retrograde trafficking of phospholipids from the outer membrane to the inner membrane [].
This entry represents the RING-like U-box domain found in E3 ubiquitin-protein ligase CHIP and LubX.CHIP is a multifunctional protein that functions both as a co-chaperone and an E3 ubiquitin-protein ligase. It couples protein folding and proteasome mediated degradation by interacting with heat shock proteins (e.g. HSC70) and ubiquitinating their misfolded client proteins thereby targeting them for proteasomal degradation [, ]. It is also important for cellular differentiation and survival (apoptosis), as well as susceptibility to stress. It targets a wide range of proteins, such as expanded ataxin-1, ataxin-3, huntingtin, and androgen receptor, which play roles in glucocorticoid response, tau degradation, and both p53 and cAMP signaling [, ]. LubX is an E3 ubiquitin ligase that interferes with host's ubiquitination pathway. LubX contains two U-box domains and was shown to interact with a diverse group of mammalian E2-conjugating enzymes including UBE2W, UBEL6, and members of the UBE2D and UBE2E families to direct ubiquitination of mammalian Cdc2-like kinase 1 (Clk1) [, ].
This 14 amino acid motif has been identified within the C-terminal region of several paired-like homeodomain (HD) containing proteins [, ]. It was named OAR domain after the initials of otp, aristaless, and rax []. Although it has been proposed that this domain could be important for transactivation and be involved in protein-protein interactions or DNA binding [, ], its function is not yet known. Some proteins known to contain a OAR domain include human RIEG, defects in which are the cause of Rieger syndrome []; human OG12X and Mus musculus (Mouse) Og12x, whose function is not yet known []; vertebrate Rax, which plays a role in the proliferation and/or differentiation of retinal cells []; Drosophila DRX, which appears to be important in brain development []; and human SHOX, encoded by the short stature homeobox-containing gene.
The BED finger, which was named after the Drosophila proteins BEAF and DREF, is found in one or more copies in cellular regulatory factors and transposases from plants, animals and fungi. The BED finger is an about 50 to 60 amino acid residues domain that contains a characteristic motif with two highly conserved aromatic positions, as well as a shared pattern of cysteines and histidines that is predicted to form a zinc finger. As diverse BED fingers are able to bind DNA, it has been suggested that DNA-binding is the general function of this domain [].Some proteins known to contain a BED domain are listed below:Animal, fungal and plant AC1 and Hobo-like transposases.Caenorhabditis elegans protein dpy-20, a predicted cuticular-gene transcriptional regulator.Drosophila BEAF (boundary element-associated factor), which is thought to be involved in chromatin insulation.Drosophila DREF, a transcriptional regulator for S-phase genes.Tobacco 3AF1 and tomato E4/E8-BP1, which are light- and ethylene-regulated DNA binding proteins that contain two BED fingers [, ].
Phosphoprotein phosphatase-1 regulatory subunit 1B (PPP1R1B, also known as DARPP-32) was initially discovered as a substrate of dopamine-activated protein kinase A (PKA) in the neostriatum in the brain. It is involved in mediating the biochemical, electrophysiological, and behavioral effects controlled by dopamine and other neurotransmitters in response to drugs of abuse and psychostimulants. Dopamine activates DARPP-32 through the D1 receptor pathway and disables DARPP-32 through the D2 receptor. Glutamate, acting through the N-methyl-d-aspartate receptor, renders DARPP-32 inactive. It can be activated by phosphorylation; while phosphorylation at Thr-34 by PKA converts DARPP-32 into a potent inhibitor of protein phosphatase 1 (PP1), phosphorylation at Thr-75 transforms DARPP-32 into an inhibitor of PKA []. A mutant form of DARPP-32 has been linked with gastric cancers [].
AvrLm4-7 is found in Leptosphaeria maculans, an ascomycete fungus in the dothideomycete group which is responsible for stem canker (blackleg) of Brassica napus (oilseed rape, OSR) and other crucifers. AvrLm4-7 is one of six avirulence genes which encodes a small secreted protein strongly over-expressed at the onset of plant infection. This gene confers a dual recognition specificity by two distinct resistance genes of OSR, Rlm4 and Rlm7 and loss of AvrLm4 avirulence was demonstrated to be associated with a strong fitness cost. Structure and functional analysis of AvrLm4-7 protein show that it contains the motifs RAWG and RYRE, part of a well-structured protein region held together by disulfide bridges. Mutations in the RAWG motif or in the RYRE motif (especially mutations in both motifs) almost abolished the translocation of AvrLm4-7 into cells. Furthermore, loss of recognition of AvrLm4-7 by Rlm4 is caused by the mutation of a single glycine to an arginine residue located in a loop of the protein [].
Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse neurobiological processes including brain development, synaptogenesis, and myelination. The aGPCR GPR56/ADGRG1 regulates both oligodendrocyte and cortical development. The N-terminal domain of GPR56 has low sequence identity and a fold that likely diverged from the PTX and LNS domains. It also has a conserved motif (HphiC91xxWxxxxG) that was identified among canonical PTX domains. Thus, it is termed the Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-Like (PLL) domain. Truncation-based analyses suggest that the regions of GPR56 responsible for binding TG2 and collagen III are within the PLL domain, most likely in the surface-exposed conserved patch. Furthermore, it is suggested that the conserved patch of the PLL domain mediates an essential function in CNS myelination [].
Cortactin is a key regulator of actin polymerisation in response to tyrosine kinase signalling []. It was first identified as a tyrosine-phosphorylated protein in v-Src infected fibroblasts []. It contains several domains: an N-terminal acidic (NTA) domain, a central repeat region and a C-terminal Src homology 3 (SH3) domain. The central repeat region binds to actin filaments, the NTA domain binds to the Arp2/3 complex and the SH3 domain interacts with N-WASp, Arg and WIP []. When activated, cortactin can recruit Arp2/3 complex to existing actin filaments to nucleate a new actin filament. Cortactin is involved in the regulation of cell migration, lamellipodia formation, invadopodia formation and endocytosis []. Cortactin can be phosphorylated by Src at several sites, and also binds directly to the SH2 domain of SRC. The non-receptor kinases, such as Fyn, Syk and Fer may also play a role in cortactin tyrosine phosphorylation. The structure of cortactin has been solved [].
Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types [, , ]. They can also form heteropolymers with each other within and between tight junction strands []. Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 []. They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB [].Claudin-10 was identified through cDNA database searching, pursuingsequences similar to other claudin family members []. Human and mouseisoforms have been cloned. Claudin-10 shares ~20-45% overall similarity withother claudin family members at the amino acid level, displaying highestsimilarity to claudin-15.
Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types [, , ]. They can also form heteropolymers with each other within and between tight junction strands []. Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 []. They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB [].Claudin-14 was identified through cDNA database searching, pursuingsequences similar to other claudin family members []. Human and mouseisoforms have been cloned. Claudin-14 shares ~25-45% overall similarity withother claudin family members at the amino acid level, displaying highestsimilarity to claudin-4.
Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types [, , ]. They can also form heteropolymers with each other within and between tight junction strands []. Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 []. They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB [].Claudin-9 was identified through cDNA database searching, pursuing sequencessimilar to other claudin family members []. Human and mouse isoforms havebeen cloned. Claudin-9 shares ~25-70% overall similarity with other claudinfamily members at the amino acid level, displaying highest similarity toclaudin-6.
The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. Integrin linked kinase (ILK) contains N-terminal ankyrin repeats, a Pleckstrin Homology (PH) domain, and a C-terminal pseudokinase domain. It is a component of the IPP (ILK/PINCH/Parvin) complex that couples beta integrins to the actin cytoskeleton, and plays important roles in cell adhesion, spreading, invasion, and migration []. ILK was initially thought to be an active kinase despite the lack of key conserved residues because of in vitro studies showing that it can phosphorylate certain protein substrates. However, in vivo experiments in Caenorhabditis elegans, Drosophila melanogaster, and mice (ILK-null and knock-in) proved that ILK is not an active kinase []. In addition to actin cytoskeleton regulation, ILK also influences the microtubule network and mitotic spindle orientation [, ]. The pseudokinase domain of ILK binds several adaptor proteins including the parvins and paxillin [, ].
CD47 was originally identified as integrin-associated protein (IAP). It is a transmembrane glycoprotein that possesses an immunoglobulin variable (IgV) like N-terminal domain, five transmembrane domains and an alternatively spliced C terminus. It functions as a marker of self on erythrocytes, and likely also on other cells, by binding to the inhibitory receptor SIRPalpha []. CD47-induces caspase-independent cell death may be mediated by cytoskeleton reorganisation []. The protein can also act as a thrombospondin receptor [].This entry represents the IgV domain of of CD47. The interaction of CD47 with integrins is dependent on its IgV and transmembrane domains. The IgV domain and transmembrane domain of CD47 have also been found to be sufficient for the association with actin [].
This entry represents the ABCE family of ATP-binding cassette (ABC) transporters and solely comprises of the ABCE1 gene product (also known as RNase L inhibitor, RLI1) [, , ]. RLI1 contains 2 nucleotide-binding domains (NBDs) typical of the ABC transporter protein superfamily []; however, it lacks the transmembrane domains required for membrane transport functions [, ]. RLI1 was first identified as an endoribonuclease inhibitor that interacts directly with RNase L to prevent it from binding 2-5A (5'-phosphorylated 2',5'-linked oligo- adenylates) []. RNase L plays a major role in the anti-viral and anti-proliferative activities ofinterferons, and its inhibition by RLI1 occurs in a concentration-dependent manner [, ]. Recently, RLI1 has been shown to be essential for the assembly of immature HIV-1 capsids in insect cells and higher eukaryotic cell types []. RLI1 expression is induced during HIV type I infection, and is understood to bind HIV-1 Gag (p55) polypeptides following their translation, and to promote their assembly into immature HIV-1 capsids [, , ].
Proteins containing this domain include the uncharacterised Sulfolobus tokodaii ST1585 protein []. It belongs to the MBL-fold metallo-hydrolase superfamily which is comprised mainly of hydrolytic enzymes which carry out a variety of biological functions. The class B metal beta-lactamases (MBLs) from which this fold was named are only a small fraction of the activities which are included in this superfamily. Activities carried out by superfamily members include class B beta-lactamases, hydroxyacylglutathione hydrolases, AHL (acyl homoserine lactone) lactonases, persulfide dioxygenases, flavodiiron proteins, cleavage and polyadenylation specificity factors such as the Int9 and Int11 subunits of Integrator, Sdsa1-like and AtsA-like arylsulfatases, 5'-exonucleases human SNM1A and yeast Pso2p, ribonuclease J and ribonuclease Z, cyclic nucleotide phosphodiesterases, insecticide hydrolases, and proteins required for natural transformation competence. Classical members of the superfamily are di-, or less commonly mono-, zinc-ion-dependent hydrolases, however the diversity of biological roles is reflected in variations in the active site metallo-chemistry [, , , , ].
DMRT genes encode a conserved family of transcription factors that share a unique DNA binding motif, the DM domain []. This domain was first discovered in the doublesex proteins of Drosophila melanogaster []. In D. melanogaster the doublesex gene controls somatic sexual differentiation by producing alternatively spliced mRNAs encoding related sex-specific polypeptides []. These proteins are believed to function as transcription factors on downstream sex-determination genes, especially on neuroblast differentiation and yolk protein genes transcription [, ]. The DM domain binds DNA as a dimer, allowing the recognition of pseudopalindromic sequences [, , ]. The NMR analysis of the DSX DM domain []revealed a novel zinc module containing 'intertwined' CCHC and HCCC zinc-binding sites. The recognition of the DNA requires the carboxy-terminal basic tail which contacts the minor groove of the target sequence.
