The ATP-grasp fold is one of several distinct ATP-binding folds, and is found in enzymes that catalyse the formation of amide bonds, catalysing the ATP-dependent ligation of a carboxylate-containing molecule to an amino or thiol group-containing molecule [
]. This fold is found in many different enzyme families, including various peptide synthetases, biotin carboxylase, synapsin, succinyl-CoA synthetase, pyruvate phosphate dikinase, and glutathione synthetase, amongst others []. These enzymes contribute predominantly to macromolecular synthesis, using ATP-hydrolysis to activate their substrates. The ATP-grasp fold shares functional and structural similarities with the PIPK (phosphatidylinositol phosphate kinase) and protein kinase superfamilies. The ATP-grasp domain consists of two subdomains with different alpha+beta folds, which grasp the ATP molecule between them. Each subdomain provides a variable loop that forms part of the active site, with regions from other domains also contributing to the active site, even though these other domains are not conserved between the various ATP-grasp enzymes [
].This entry represents subdomain 1 found at the N-terminal end of the ATP-grasp domain.
Dynein is a multisubunit microtubule-dependent motor enzyme that acts as the force generating protein of eukaryotic cilia and flagella. The cytoplasmic isoform of dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.Dynein is composed of a number of ATP-binding large subunits (see
), intermediate size subunits and small subunits. Among the small subunits, there is a family of highly conserved proteins which make up this family [
,
,
]. Proteins in this family act as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function and may play a role in changing or maintaining the spatial distribution of cytoskeletal structures. In yeast, it was identified as a component of the nuclear pore complex where it may contribute to the stable association of the Nup82 subcomplex with the nuclear pore complex [].Both type 1 (DLC1) and 2 (DLC2) dynein light chains have a similar two-layer α-β core structure consisting of beta-alpha(2)-beta-X-beta(2) [
,
].
This zinc-finger is typical of ubiquitin ligases from eukaryotes [
,
]. This domain can also be found in Tripartite motif-containing proteins (TRIM), including TRIM5 from humans, a capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses [,
].
Carbamoyl-phosphate synthase large subunit, CPSase domain
Type:
Domain
Description:
Carbamoyl phosphate synthase (CPSase) is a heterodimeric enzyme composed of a small and a large subunit (with the exception of CPSase III, see below). CPSase catalyses the synthesis of carbamoyl phosphate from biocarbonate, ATP and glutamine (
) or ammonia (
), and represents the first committed step in pyrimidine and arginine biosynthesis in prokaryotes and eukaryotes, and in the urea cycle in most terrestrial vertebrates [
,
]. CPSase has three active sites, one in the small subunit and two in the large subunit. The small subunit contains the glutamine binding site and catalyses the hydrolysis of glutamine to glutamate and ammonia. The large subunit has two homologous carboxy phosphate domains, both of which have ATP-binding sites; however, the N-terminal carboxy phosphate domain catalyses the phosphorylation of biocarbonate, while the C-terminal domain catalyses the phosphorylation of the carbamate intermediate []. The carboxy phosphate domain found duplicated in the large subunit of CPSase is also present as a single copy in the biotin-dependent enzymes acetyl-CoA carboxylase () (ACC), propionyl-CoA carboxylase (
) (PCCase), pyruvate carboxylase (
) (PC) and urea carboxylase (
).
Most prokaryotes carry one form of CPSase that participates in both arginine and pyrimidine biosynthesis, however certain bacteria can have separate forms. The large subunit in bacterial CPSase has four structural domains: the carboxy phosphate domain 1, the oligomerisation domain, the carbamoyl phosphate domain 2 and the allosteric domain [
]. CPSase heterodimers from Escherichia coli contain two molecular tunnels: an ammonia tunnel and a carbamate tunnel. These inter-domain tunnels connect the three distinct active sites, and function as conduits for the transport of unstable reaction intermediates (ammonia and carbamate) between successive active sites []. The catalytic mechanism of CPSase involves the diffusion of carbamate through the interior of the enzyme from the site of synthesis within the N-terminal domain of the large subunit to the site of phosphorylation within the C-terminal domain.Eukaryotes have two distinct forms of CPSase: a mitochondrial enzyme (CPSase I) that participates in both arginine biosynthesis and the urea cycle; and a cytosolic enzyme (CPSase II) involved in pyrimidine biosynthesis. CPSase II occurs as part of a multi-enzyme complex along with aspartate transcarbamoylase and dihydroorotase; this complex is referred to as the CAD protein [
]. The hepatic expression of CPSase is transcriptionally regulated by glucocorticoids and/or cAMP []. There is a third form of the enzyme, CPSase III, found in fish, which uses glutamine as a nitrogen source instead of ammonia []. CPSase III is closely related to CPSase I, and is composed of a single polypeptide that may have arisen from gene fusion of the glutaminase and synthetase domains []. This entry represents the CPSase domain of the large subunit of carbamoyl phosphate synthase.
The PUA (PseudoUridine synthase and Archaeosine transglycosylase) domain was named after the proteins in which it was first found [
]. PUA is a highly conserved RNA-binding motif found in a wide range of archaeal, bacterial and eukaryotic proteins, including enzymes that catalyse tRNA and rRNA post-transcriptional modifications, proteins involved in ribosome biogenesis and translation, as well as in enzymes involved in proline biosynthesis [,
,
]. The structures of several PUA-RNA complexes reveal a common RNA recognition surface, but also some versatility in the way in which the motif binds to RNA [,
]. This domain has an alpha/beta architecture consisting of six β-strands and two short α-helices []. PUA motifs are involved in dyskeratosis congenita and cancer, pointing to links between RNA metabolism and human diseases [].
This entry represents the PUA (PseudoUridine synthase and Archaeosine transglycosylase) domain found in 60S ribosome subunit biogenesis protein NIP7, some UPF0113 family members, such as KD93, and similar proteins found in eukaryotes and some archaeal species [
,
,
]. PUA domains are predicted to bind RNA molecules with complex folded structures []. NIP7 is required for efficient 60S ribosome subunit biogenesis and has been shown to interact with another essential nucleolar protein, Nop8p, and the exosome subunit Rrp43p. These proteins are required for 60S subunit synthesis and may be part of a dynamic complex involved in this process. Nip7 orthologues share a two-domain architecture with the C-terminal PUA domain mediating interaction with RNA, suggesting that Nip7 is an adaptor protein with the C-terminal domain interacting with RNA targets and the N-terminal domain mediating interaction with protein targets. Structural analyses of the RNA-interacting surfaces of the orthologues from Saccharomyces cerevisiae and Pyrococcus abyssi Nip7 indicate that, in the archaeal PUA domain, C-terminal positively charged residues (arginines and lysines) are involved in RNA interaction while equivalent positions in eukaryotic orthologues are occupied by mostly hydrophobic residues. Both proteins can bind specifically to polyuridine, and RNA interaction requires specific residues of the PUA domain as determined by site-directed mutagenesis [
,
,
].
This entry represents 60S ribosome subunit biogenesis protein Nip7, which is required for proper 27S pre-rRNA processing and 60S ribosome subunit assembly [
]. In yeast, Nip7 interacts with nucleolar proteins such as Nol8 [], and with the exosome subunit Rrp43p. Nip7 contains a PUA domain.
Methylglyoxal synthase (MGS,
), which catalyses the conversion of dihydroxyacetone phosphate (DHAP) to methylglyoxal (MG) and inorganic phosphate, has been found in many organisms, including enteric bacteria, some gram-positive bacteria, a number of archaebacteria, several yeast species and goat liver [
,
].The main core of the MGS-like domain, a modified 'Rossmann' fold, is characterised by a five stranded parallel β-sheet flanked on either side by three and five α-helices, respectively [
,
]. MGS-like domains share a conserved phosphate binding site [,
].
ATP-dependent protease complexes are present in all three kingdoms of life, where they rid the cell of misfolded or damaged proteins and control the level of certain regulatory proteins. They include the proteasome in Eukaryotes, Archaea, and Actinomycetales and the HslVU (ClpQY, clpXP) complex in other eubacteria. Genes homologues to eubacterial HslU (ClpY, clpX) have also been demonstrated in to be present in the genome of trypanosomatid protozoa [
].The proteasome (or macropain) (
) [
,
,
,
,
] is a multicatalytic proteinase complex in eukaryotes and archaea, and in some bacteria, that is involved in an ATP/ubiquitin-dependent non-lysosomal proteolytic pathway. In eukaryotes the 20S proteasome is composed of 28 distinct subunits which form a highly ordered ring-shaped structure (20S ring) of about 700kDa. Proteasome subunits can be classified on the basis of sequence similarities into two groups, alpha (A) and beta (B). The proteasome consists of four stacked rings composed of alpha/beta/beta/alpha subunits. There are seven different alpha subunits and seven different beta subunits []. Three of the seven beta subunits are peptidases, each with a different specificity. Subunit beta1c (MEROPS identifier T01.010) has a preference for cleaving glutaminyl bonds ("peptidyl-glutamyl-like"or "caspase-like"), subunit beta2c (MEROPS identifier T01.011) has a preference for cleaving arginyl and lysyl bonds ("trypsin-like"), and subunit beta5c (MEROPS identifier T01.012) cleaves after hydrophobic amino acids ("chymotrypsin-like") [
]. The proteasome subunits are related to N-terminal nucleophile hydrolases, and the catalytic subunits have an N-terminal threonine nucleophile.The prokaryotic ATP-dependent proteasome is coded for by the heat-shock locus VU (HslVU). It consists of HslV, a peptidase, and HslU (
), the ATPase and chaperone belonging to the AAA/Clp/Hsp100 family. The crystal structure of Thermotoga maritima HslV has been determined to 2.1-A resolution. The structure of the dodecameric enzyme is well conserved compared to those from Escherichia coli and Haemophilus influenzae [
,
].This entry contains threonine peptidases and non-peptidase homologues belong to MEROPS peptidase family T1 (proteasome family, clan PB(T)). The family consists of the protease components of the archaeal and bacterial proteasomes and the alpha and beta subunits of the eukaryotic proteasome.
The proteasome (or macropain) (
) [
,
,
,
,
] is a multicatalytic proteinase complex in eukaryotes and archaea, and in some bacteria, that is involved in an ATP/ubiquitin-dependent non-lysosomal proteolytic pathway. In eukaryotes the 20S proteasome is composed of 28 distinct subunits which form a highly ordered ring-shaped structure (20S ring) of about 700kDa. Proteasome subunits can be classified on the basis of sequence similarities into two groups, alpha (A) and beta (B). The proteasome consists of four stacked rings composed of alpha/beta/beta/alpha subunits. There are seven different alpha subunits and seven different beta subunits []. Three of the seven beta subunits are peptidases, each with a different specificity. Subunit beta1c (MEROPS identifier T01.010) has a preference for cleaving glutaminyl bonds ("peptidyl-glutamyl-like"or "caspase-like"), subunit beta2c (MEROPS identifier T01.011) has a preference for cleaving arginyl and lysyl bonds ("trypsin-like"), and subunit beta5c (MEROPS identifier T01.012) cleaves after hydrophobic amino acids ("chymotrypsin-like") [
]. The proteasome subunits are related to N-terminal nucleophile hydrolases, and the catalytic subunits have an N-terminal threonine nucleophile.Subunits that belong to the A group are proteins of from 210 to 290 amino acids. They are classified as non-peptidase homologues in MEROPS peptidase family T1 (clan PB(T)). This entry represents an N-terminal domain conserved in the A subunits of the proteasome complex.
ATP-dependent protease complexes are present in all three kingdoms of life, where they rid the cell of misfolded or damaged proteins and control the level of certain regulatory proteins. They include the proteasome in Eukaryotes, Archaea, and Actinomycetales and the HslVU (ClpQY, clpXP) complex in other eubacteria. Genes homologues to eubacterial HslU (ClpY, clpX) have also been demonstrated in to be present in the genome of trypanosomatid protozoa [
].The proteasome (or macropain) (
) [
,
,
,
,
] is a multicatalytic proteinase complex in eukaryotes and archaea, and in some bacteria, that is involved in an ATP/ubiquitin-dependent non-lysosomal proteolytic pathway. In eukaryotes the 20S proteasome is composed of 28 distinct subunits which form a highly ordered ring-shaped structure (20S ring) of about 700kDa. Proteasome subunits can be classified on the basis of sequence similarities into two groups, alpha (A) and beta (B). The proteasome consists of four stacked rings composed of alpha/beta/beta/alpha subunits. There are seven different alpha subunits and seven different beta subunits []. Three of the seven beta subunits are peptidases, each with a different specificity. Subunit beta1c (MEROPS identifier T01.010) has a preference for cleaving glutaminyl bonds ("peptidyl-glutamyl-like"or "caspase-like"), subunit beta2c (MEROPS identifier T01.011) has a preference for cleaving arginyl and lysyl bonds ("trypsin-like"), and subunit beta5c (MEROPS identifier T01.012) cleaves after hydrophobic amino acids ("chymotrypsin-like") [
]. The proteasome subunits are related to N-terminal nucleophile hydrolases, and the catalytic subunits have an N-terminal threonine nucleophile.The prokaryotic ATP-dependent proteasome is coded for by the heat-shock locus VU (HslVU). It consists of HslV, a peptidase, and HslU (
), the ATPase and chaperone belonging to the AAA/Clp/Hsp100 family. The crystal structure of Thermotoga maritima HslV has been determined to 2.1-A resolution. The structure of the dodecameric enzyme is well conserved compared to those from Escherichia coli and Haemophilus influenzae [
,
].This family consists of the alpha (or A type) subunits of the eukaryotic proteasome as well as some protease components of the archaeal and bacterial proteasomes.
Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP. There are several different types of transmembrane ATPases, which can differ in function (ATP hydrolysis and/or synthesis), structure (e.g., F-, V- and A-ATPases, which contain rotary motors) and in the type of ions they transport [
,
]. The different types include:F-ATPases (ATP synthases, F1F0-ATPases), which are found in mitochondria, chloroplasts and bacterial plasma membranes where they are the prime producers of ATP, using the proton gradient generated by oxidative phosphorylation (mitochondria) or photosynthesis (chloroplasts).V-ATPases (V1V0-ATPases), which are primarily found in eukaryotes and they function as proton pumps that acidify intracellular compartments and, in some cases, transport protons across the plasma membrane [
]. They are also found in bacteria [].A-ATPases (A1A0-ATPases), which are found in Archaea and function like F-ATPases, though with respect to their structure and some inhibitor responses, A-ATPases are more closely related to the V-ATPases [
,
].P-ATPases (E1E2-ATPases), which are found in bacteria and in eukaryotic plasma membranes and organelles, and function to transport a variety of different ions across membranes.E-ATPases, which are cell-surface enzymes that hydrolyse a range of NTPs, including extracellular ATP.V-ATPases (also known as V1V0-ATPase or vacuolar ATPase) are found in the eukaryotic endomembrane system, and in the plasma membrane of prokaryotes and certain specialised eukaryotic cells. V-ATPases hydrolyse ATP to drive a proton pump, and are involved in a variety of vital intra- and inter-cellular processes such as receptor mediated endocytosis, protein trafficking, active transport of metabolites, homeostasis and neurotransmitter release [
]. V-ATPases are composed of two linked complexes: the V1 complex (subunits A-H) contains the catalytic core that hydrolyses ATP, while the V0 complex (subunits a, c, c', c'', d) forms the membrane-spanning pore. V-ATPases may have an additional role in membrane fusion through binding to t-SNARE proteins [].This entry represents the 116kDa subunit (or subunit a) found in the V0 complex of V-ATPases, respectively. The 116kDa subunit is a transmembrane glycoprotein required for the assembly and proton transport activity of the ATPase complex. Several isoforms of the 116kDa subunit exist, providing a potential role in the differential targeting and regulation of the V-ATPase for specific organelles [
].
Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1,
), a ubiquitin-conjugating enzyme (E2,
), and a ubiquitin ligase (E3,
,
), which work sequentially in a cascade. There are many different E3 ligases, which are responsible for the type of ubiquitin chain formed, the specificity of the target protein, and the regulation of the ubiquitinylation process [
]. Ubiquitinylation is an important regulatory tool that controls the concentration of key signalling proteins, such as those involved in cell cycle control, as well as removing misfolded, damaged or mutant proteins that could be harmful to the cell. Several ubiquitin-like molecules have been discovered, such as Ufm1 (), SUMO1 (
), NEDD8, Rad23 (
), Elongin B and Parkin (
), the latter being involved in Parkinson's disease [
].Ubiquitin is a protein of 76 amino acid residues, found in all eukaryotic cells and whose sequence is extremely well conserved from protozoan to vertebrates. Ubiquitin acts through its post-translational attachment (ubiquitinylation) to other proteins, where these modifications alter the function, location or trafficking of the protein, or targets it for destruction by the 26S proteasome [
]. The terminal glycine in the C-terminal 4-residue tail of ubiquitin can form an isopeptide bond with a lysine residue in the target protein, or with a lysine in another ubiquitin molecule to form a ubiquitin chain that attaches itself to a target protein. Ubiquitin has seven lysine residues, any one of which can be used to link ubiquitin molecules together, resulting in different structures that alter the target protein in different ways. It appears that Lys(11)-, Lys(29) and Lys(48)-linked poly-ubiquitin chains target the protein to the proteasome for degradation, while mono-ubiquitinylated and Lys(6)- or Lys(63)-linked poly-ubiquitin chains signal reversible modifications in protein activity, location or trafficking [
]. For example, Lys(63)-linked poly-ubiquitinylation is known to be involved in DNA damage tolerance, inflammatory response, protein trafficking and signal transduction through kinase activation []. In addition, the length of the ubiquitin chain alters the fate of the target protein. Regulatory proteins such as transcription factors and histones are frequent targets of ubquitinylation [].
Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1,
), a ubiquitin-conjugating enzyme (E2,
), and a ubiquitin ligase (E3,
,
), which work sequentially in a cascade. There are many different E3 ligases, which are responsible for the type of ubiquitin chain formed, the specificity of the target protein, and the regulation of the ubiquitinylation process [
]. Ubiquitinylation is an important regulatory tool that controls the concentration of key signalling proteins, such as those involved in cell cycle control, as well as removing misfolded, damaged or mutant proteins that could be harmful to the cell. Several ubiquitin-like molecules have been discovered, such as Ufm1 (), SUMO1 (
), NEDD8, Rad23 (
), Elongin B and Parkin (
), the latter being involved in Parkinson's disease [
].Ubiquitin is a protein of 76 amino acid residues, found in all eukaryotic cells and whose sequence is extremely well conserved from protozoan to vertebrates. Ubiquitin acts through its post-translational attachment (ubiquitinylation) to other proteins, where these modifications alter the function, location or trafficking of the protein, or targets it for destruction by the 26S proteasome []. The terminal glycine in the C-terminal 4-residue tail of ubiquitin can form an isopeptide bond with a lysine residue in the target protein, or with a lysine in another ubiquitin molecule to form a ubiquitin chain that attaches itself to a target protein. Ubiquitin has seven lysine residues, any one of which can be used to link ubiquitin molecules together, resulting in different structures that alter the target protein in different ways. It appears that Lys(11)-, Lys(29) and Lys(48)-linked poly-ubiquitin chains target the protein to the proteasome for degradation, while mono-ubiquitinylated and Lys(6)- or Lys(63)-linked poly-ubiquitin chains signal reversible modifications in protein activity, location or trafficking []. For example, Lys(63)-linked poly-ubiquitinylation is known to be involved in DNA damage tolerance, inflammatory response, protein trafficking and signal transduction through kinase activation []. In addition, the length of the ubiquitin chain alters the fate of the target protein. Regulatory proteins such as transcription factors and histones are frequent targets of ubquitinylation [].This entry represents the conserved region at the centre of the Ubiquitin sequence.
YLP motif-containing protein 1 plays a role in the reduction of telomerase activity during differentiation of embryonic stem cells by binding to the core promoter of TERT and controlling its down-regulation [
].
This domain includes a range of O-methyltransferases some of which utilise S-adenosyl methionine as substrate [
]. In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. In eukaryotes, DNA methylation has been implicated in the control of several cellular processes, including differentiation, gene regulation, and embryonic development. O-methyltransferases have a common catalytic domain structure, which might be universal among S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases []. Comparative analysis of the predicted amino acid sequences of a number of plant O-methyltransferase cDNA clones show that they share some 32-71% sequence identity, and can be grouped according to the different compounds they utilise as substrates [
].
Proteins in this entry belong to the Class I SAM-dependent methyltransferases superfamily, including caffeic acid O-methyltransferase (COMT), isoflavone-7-O-methyltransferase, inositol 4-methyltransferase and acetylserotonin O-methyltransferase [
].Methyltransferases (EC [intenz:2.1.1.-]) constitute an important class of enzymes present in every life form. They transfer a methyl group most frequently from S-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such as oxygen leading to S-adenosyl-L-homocysteine (AdoHcy) and a methylated molecule [,
,
]. All these enzymes have in common a conserved region of about 130 amino acid residues that allow them to bind SAM []. The substrates that are methylated by these enzymes cover virtually every kind of biomolecules ranging from small molecules, to lipids, proteins and nucleic acids [,
,
]. Methyltransferase are therefore involved in many essential cellular processes including biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing [,
,
]. More than 230 families of methyltransferases have been described so far, of which more than 220 use SAM as the methyl donor.The vast majority of methyltransferases belong to the Rossmann-like fold (Class I) which consists in a seven-stranded β-sheet adjoined by α-helices. Even within the structurally conserved family of Class I methyltransferases, a wide variety of mechanisms have evolved to activate the catalytic nucleophile, dependent on the polarizability of the target atom [
].
This entry includes histone H3 and its variant, CENP-A (Cse4 in budding yeast, Cnp1 in fission yeast, and CID/CenH3 in fruit flies). Two primate-specific forms of H3, known as H3.X and H3.Y, are found in the brain [
].Histone H3 is one of the five histones, along with H1/H5, H2A, H2B and H4. Two copies of each of the H2A, H2B, H3, and H4 histones ensemble to form the core of the nucleosome [
]. The nucleosome forms octameric structure that wraps DNA in a left-handed manner. H3 is a highly conserved protein of 135 amino acid residues [,
]. Histones can undergo several different types of post-translational modifications that affect transcription, DNA repair, DNA replication and chromosomal stability.Eukaryotic centromeres consists of an unique nucleosome in which CENP-A can be found []. Human CENP-A nucleosome forms a histone octamer containing two each of histones H2A, H2B, H4 and CENP-A. Similar to the H3-containing nucleosome, the CENP-A nucleosome wraps DNA in a left-handed orientation [,
]. CENP-A nucleosomes function as a scaffold on which other kinetochore proteins assemble. CENP-A may serves as an epigenetic marker for kinetochore assembly []. Deposition of CENP-A to the centromere requires histone chaperone HJURP (Holliday junction recognition protein) [].
Five major families of histones exist: H1/H5, H2A, H2B, H3, and H4 [
]. Histones H2A, H2B, H3 and H4 are known as the core histones, while histones H1 and H5 are known as the linker histones. The core histones together with some other DNA binding proteins form a superfamily defined by a common fold and distant sequence similarities [,
]. Some proteins contain local homology domains related to the histone fold [].This entry represents a domain found in histones H2A, H2B and H3. This domain can also be found in transcription factors, such as OsNF-YC2 from rice [
].
This entry represents both eukaryotic mitochondrial porins and Tom40 proteins.Eukaryotic mitochondrial porins are voltage-dependent anion-selective channels (VDAC) that behave as general diffusion pores for small hydrophilic molecules [
,
,
,
]. The channels adopt an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The eukaryotic mitochondrial porins are β-barrel proteins, composed of between 12 to 16 β-strands that span the mitochondrial outer membrane. Yeast contains two members of this family (genes POR1 and POR2); vertebrates have at least three members (genes VDAC1, VDAC2 and VDAC3) []. They are related to the mitochondrial import receptor subunit Tom40 proteins, sharing a common evolutionary origin and structure [].Tom40 is a mitochondrion outer membrane protein and a component of the TOM (translocator of the outer mitochondrial membrane) complex, which is essential for import of protein precursors into mitochondria [
]. In Saccharomyces cerevisiae, TOM complex is composed of the subunits Tom70, Tom40, Tom22, Tom20, Tom7, Tom6, and Tom5 [,
]. Tom40 is an integral membrane protein and the main structural component of the protein-conducting channel formed by the TOM complex []. It is stabilised by other components, such as Tom5, Tom6, and Tom7 [].
Porins are found in the outer membranes of Gram-negative bacteria,
mitochondria and chloroplasts, where they form ion-selective channels forsmall hydrophilic molecules (up to ~600 D) [
,
]. X-ray structureanalyses of several bacterial porins [
,
,
] have revealed a large 16-strandedanti-parallel β-barrel structure enclosing the transmembrane pore, by
contrast with all other integral membrane proteins described to date,which are α-helical. Three subunits form a trimer; the 3-fold axis is
approximately parallel to the barrel axes and is assumed to beperpendicular to the membrane plane.
From the range of porins now known, similarities have been observed between
porins from different species, and between porins of different specificitywithin the same species. But most porins cannot be related to each other on
the basis of sequence alone, and this is reflected in the lengths of theknown porin sequences, which range from 282-483 residues/monomer.This superfamily represents the structural domain found in porins.
Helix-turn-helix (HTH) motifs are found in all known DNA binding proteins
that regulate gene expression. The motif consists of approximately 20 residues and is characterised by 2 α-helices, which make intimate
contacts with the DNA and are joined by a short turn. The second helix of the HTH motif binds to DNA via a number of hydrogen bonds and hydrophobic
interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA [
]. Thefirst helix helps to stabilise the structure [
]. The HTH motif is very similar in sequence and structure to the N-terminal
region of the lambda [] and other repressor proteins, and has also been identified in many other DNA-binding proteins on the basis of sequence and
structural similarity []. One of the principal differences between HTH motifs in these different proteins arises from the stereochemical
requirement for glycine in the turn, which is needed to avoid steric interference of the β-carbon with the main chain: for cro and other
repressors the Gly appears to be mandatory, while for many of the homeoticand other DNA-binding proteins the requirement is relaxed.
These proteins are integral membrane proteins with four transmembrane spanning helices. The most conserved region of an alignment of the proteins is a motif HPP. The function of these proteins is uncertain but they may be transporters.
The proteins in this family are a component of the acetyl coenzyme A carboxylase complex(
) and are involved in the first step in long-chain fatty acid synthesis. In
plants this is usually located in the chloroplast. In the first step, biotin carboxylase catalyses the carboxylation of the carrier protein to form an intermediate. Next, the
transcarboxylase complex transfers the carboxyl group from the intermediate to acetyl-CoA forming malonyl-CoA. This protein functions in the transfer of CO
2from one site to another, the biotin binding site locates to the C-terminal of this protein. The biotin is specifically attached to a lysine residue in the sequence AMKM.
The structure of the C-terminal domain of the biotin carboxyl carrier (BCC) protein was shown to be a flattened β-barrel structure comprising two four-stranded beta sheets interrupted by a structural loop forming a thumb structure. The biotinyl-lysine is located on a tight β-turn on the opposite end of the molecule. The thumb structure has been shown to attached biotin, thus stabilising the structure.
The biotin/lipoyl attachment domain has a conserved lysine residue that binds biotin or lipoic acid. The 80 residues surrounding the biotinyl-binding lysine residue display some sequence similarity to that around the lipoyl-binding lysine residue. Biotin plays a catalytic role in some carboxyl transfer reactions and is covalently attached, via an amide bond, to a lysine residue in enzymes requiring this coenzyme [
]. E2 acyltransferases have an essential cofactor, lipoic acid, which is covalently bound via an amide linkage to a lysine group []. The lipoic acid cofactor is found in a variety of proteins that include, H-protein of the glycine cleavage system (GCS), mammalian and yeast pyruvate dehydrogenases and branched-chain 2-oxo acid dehydrogenase complex (BCOADC).The lipoyl domains of 2-oxo acid dehydrogenase multienzyme complexes and the biotinyl domains of biotin-dependent enzymes have been solved, which revealed that they have homologous structures consisting of a flattened 8-stranded -barrel with the target lysine positioned in comparable β-turns. Additional important residues for specificity have been identified, such as the conserved methionine flanking the target lysine that is essential for the recognition of the biotinyl domain by the biotinyl protein ligase [
,
].
Biotin, which plays a catalytic role in some carboxyl transfer reactions, is covalently attached, via an amide bond, to a lysine residue in enzymes requiring this coenzyme [
,
,
,
]. Sequence data reveal that the region around the biocytin (biotin-lysine) residue is well conserved and is evolutionary related to that around the lipoyl-binding lysine residue of 2-oxo acid dehydrogenase acyltransferases.
Structural maintenance of chromosomes protein 2 (Smc2) is a central component of the condensin complex, which is required for conversion of interphase chromatin into mitotic-like condense chromosomes. The condensin complex probably introduces positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases [
,
,
,
].Amino-acid sequence homology of SMC proteins between species is largely confined to the amino- and carboxy-terminal globular domains. The amino-terminal domain contains a 'Walker A' nucleotide-binding domain (GxxGxGKS/T, in the single-letter amino-acid code), which by mutational studies has been shown to be essential in several proteins. The carboxy-terminal domain contains a sequence (the DA-box) that resembles a 'Walker B' motif, and a motif with homology to the signature sequence of the ATP-binding cassette (ABC) family of ATPases [
,
].
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [,
].This family includes a number of eukaryotic and archaebacterial ribosomal proteins; mammalian S19, Drosophila S19, Ascaris lumbricoides S19g (ALEP-1) and S19s, yeast YS16
(RP55A and RP55B), Aspergillus S16 and Haloarcula marismortui HS12.
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].This family includes a number of eukaryotic and archaebacterial ribosomal proteins; mammalian S19, Drosophila S19, Ascaris lumbricoides S19g (ALEP-1) and S19s, yeast YS16 (RP55A and RP55B), Aspergillus S16 and Haloarcula marismortui HS12.
Glutaredoxins [,
,
], also known as thioltransferases (disulphide reductases), are small proteins of approximately one hundred amino-acid residues which utilise glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system [].Glutaredoxin functions as an electron carrier in the glutathione-dependent synthesis of deoxyribonucleotides by the enzyme ribonucleotide reductase. Like thioredoxin (TRX), which functions in a similar way, glutaredoxin possesses an active centre disulphide bond [
]. It exists in either a reduced or an oxidized form where the two cysteine residues are linked in an intramolecular disulphide bond. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH ->GSH reductase ->GSH ->GRX ->protein substrates [
,
,
,
]. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress.Glutaredoxin has been sequenced in a variety of species. On the basis of extensive sequence similarity, it has been proposed [
] that Vaccinia virus protein O2L is most probably a glutaredoxin. Finally, it must be noted that Bacteriophage T4 thioredoxin seems also to be evolutionary related. In position 5 of the pattern T4 thioredoxin has Val instead of Pro.This group of glutaredoxin-like proteins is apparently limited to plants. Multiple isoforms are found in Arabidopsis thaliana (Mouse-ear cress) and Oryza sativa(Rice).
Guanylate-binding protein is a GTPase that is induced by interferon (IFN)-gamma. GTPases induced by IFN-gamma are key to the protective immunity against microbial and viral pathogens. These GTPases are classified into three groups: the small 47-kd GTPases, the Mx proteins, and the large 65- to 67-kd GTPases. Guanylate-binding proteins (GBP) fall into the last class. In humans, there are seven GBPs (hGBP1-7) []. Structurally, hGBP1 consists of two domains: a compact globular N-terminal domain harbouring the GTPase function, and an α-helical finger-like C-terminal domain (). Human GBP1 is secreted from cells without the need of a leader peptide, and has been shown to exhibit antiviral activity against Vesicular stomatitis virus and Encephalomyocarditis virus, as well as being able to regulate the inhibition of proliferation and invasion of endothelial cells in response to IFN-gamma [
].
Guanylate-binding protein is a GTPase that is induced by interferon (IFN)-gamma. GTPases induced by IFN-gamma are key to the protective immunity against microbial and viral pathogens. These GTPases are classified into three groups: the small 47-kd GTPases, the Mx proteins, and the large 65- to 67-kd GTPases. Guanylate-binding proteins (GBP) fall into the last class. In humans, there are seven GBPs (hGBP1-7) []. Structurally, hGBP1 consists of two domains: a compact globular N-terminal domain harbouring the GTPase function (), and an α-helical finger-like C-terminal domain. Human GBP1 is secreted from cells without the need of a leader peptide, and has been shown to exhibit antiviral activity against Vesicular stomatitis virus and Encephalomyocarditis virus, as well as being able to regulate the inhibition of proliferation and invasion of endothelial cells in response to IFN-gamma [
].This entry represents the C-terminal domain of the guanylate-binding protein. Proteins containing this domain also include Atlastin2/3. They are GTPases tethering membranes through formation of trans-homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes [
].
The alpha/beta hydrolase fold is common to several hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is similar: an α/β sheet, not barrel, of eight β-sheets connected by α-helices [
]. This entry represents the N-terminal part of an alpha/beta hydrolase domain found in a number of lipases.
This entry represents a family of eukaryotic lipases, including gastric triacylglycerol lipase [
], lysosomal acid lipase [] and triacylglycerol lipase 1 [].
The α/β hydrolase fold [
] is common to a number of hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is an α/β-sheet (rather than a barrel), containing 8 strands connected by helices []. The enzymes are believed to have diverged from a common ancestor, preserving the arrangement of the catalytic residues. All have a catalytic triad, the elements of which are borne on loops, which are the best conserved structural features of the fold. Esterase (EST) from Pseudomonas putida is a member of the α/β hydrolase fold superfamily of enzymes [].In most of the family members the β-strands are parallel, but some have an inversion of the first strands, which gives it an antiparallel orientation. The catalytic triad residues are presented on loops. One of these is the nucleophile elbow and is the most conserved feature of the fold. Some other members lack one or all of the catalytic residues. Some members are therefore inactive but others are involved in surface recognition. The ESTHER database [
] gathers and annotates all the published information related to gene and protein sequences of this superfamily [].This entry represents fold-1 of alpha/beta hydrolase.
This entry represents a class of homeobox domain that differs substantially from the typical homeobox domain described in
. It is found in both C4 and C3 plants [
].
ATP-NAD kinases (
) catalyse the phosphorylation of NAD to NADP utilizing ATP and other nucleoside triphosphates as well as inorganic polyphosphate as a source of phosphorus. ATP-NAD kinase contains two domains, where the N-terminal domain has an alpha/beta topology that is related in structure to the N-terminal of phosphofructokinase, and the C-terminal domain has an atypical β-sandwich topology made of four structural repeats of beta(3) units [
,
]. This entry represents the α/β N-terminal domain.
Dihydroxyacetone (Dha) kinases are a family of sequence-conserved enzymes that phosphorylate dihydroxyacetone, glyceraldehyde and other short-chain ketoses and aldoses. They can be divided into two groups according to the source of high-energy phosphate that they utilise, either ATP or phosphoenolpyruvate (PEP). The ATP-dependent forms are the two-domain Dha kinases (DAK), which occur in animals, plants and eubacteria. They consist of a Dha binding (K) and an ATP binding (L) domain. The PEP-dependent forms occur only in eubacteria and a few archaebacteria and consist of three subunits. Two subunits, DhaK and DhaL, are homologous to the K and L domains. Intriguingly, the ADP moiety is not exchanged for ATP but remains permanently bound to the DhaL subunit where it is rephosphorylated in situ by the third subunit, DhaM, which is homologous to the IIA domain of the mannose transporter of the bacterial PEP:sugar phosphotransferase system (PTS) [
,
].The DhaL domain consists of eight antiparallel α-helices arranged in an
up-and-down geometry and aligned on a circle. This results in the formation of a helix barrel enclosing a deep pocket. The helices are amphipathic with the hydrophobic side chains directed into the pocket of the barrel and with the polar residues exposed. The nucleotide is bound on the top of the barrel [,
].The DhaL alpha helix barrel fold appears not only as a C-terminal domain in Dha kinases but also as an N-terminal domain in a family of two-domain proteins with unknown function. One representative example is YfhG of Lactococcus lactis
[].
Dihydroxyacetone (Dha) kinases are a family of sequence-conserved enzymes that
phosphorylate dihydroxyacetone, glyceraldehyde and other short-chain ketosesand aldoses. They can be divided into two groups according to the source of
high-energy phosphate that they utilise, either ATP or phosphoenolpyruvate(PEP). The ATP-dependent forms are the two-domain Dha kinases (DAK), which
occur in animals, plants and eubacteria. They consist of a Dha binding (K) andan ATP binding (L) domain. The PEP-dependent forms occur only in eubacteria and a few archaebacteria and consist of three subunits. Two subunits, DhaK and DhaL, are homologous to the K and L domains. Intriguingly, the ADP moiety is not exchanged for ATP but remains permanently bound to the DhaL subunit where it is rephosphorylated in situ by the third subunit, DhaM, which is homologous to the IIA domain of the mannose transporter of the bacterial PEP:sugar phosphotransferase system (PTS) [
,
].The DhaK domain consists of two alpha/β-folds, each containing a six-
stranded mixed β-sheet surrounded by six and three helices, respectively. Dha is bound in hemiaminal linkage to the imidazole nitrogen of an invariant histidine [,
].
The MORN (Membrane Occupation and Recognition Nexus) motif is found in multiple copies in several proteins including junctophilins (
). The function of this motif is unknown.
The panB gene from Escherichia coli encodes the first enzyme of the pantothenate biosynthesis pathway, ketopantoate hydroxymethyltransferase (KPHMT)
. Fungal ketopantoate hydroxymethyltransferase is essential for the biosynthesis of coenzyme A, while the pathway intermediate 4'-phosphopantetheine is required for penicillin production [
].
This entry represents a group of proteins mostly from plants and Cyanobacteria (blue-green algae), including TIC21 from Arabidopsis. TIC21 is Involved in chloroplast protein import across the inner envelope membrane. It can acts as a chloroplast permease regulating the iron transport and homeostasis [
,
].
This entry represents a group of transmembrane proteins, including mammalian lung seven transmembrane receptor GPR107 and GPR108. GPR107 localizes to the trans-Golgi network and is essential for retrograde transport [
]. This entry also includes proteins from fungi and plants []. The plant proteins in this entry, including CAND6 and CAND7, are predicted to be G-protein coupled receptors [].
Eukaryotic translation initiation factor 3 subunit B
Type:
Family
Description:
Eukaryotic translation initiation factor 3 subunit B (EIF3B) is a component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis.
EIF3B is considered to be the major scaffolding subunit and interacts with subunits A, G, I, and J []. It contains an RNA recognition motif (RRM) in its N-terminal region [].
Members of this family are 5-methylthioribose kinases (
) that catalyse phosphorylation of 5-methylthioribose (MTR), a step in the recycling of methionine from 5'-methylthioadenosine, a co-product of polyamine biosynthesis. The preceding step of methylthioadenosine (MTA) hydrolysis to MTR is catalysed by 5'-methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase.
Bacillus subtilis protein MtnK (formerly YkrT) [
] and Klebsiella pneumoniae protein MtrK [] have been experimentally characterised. K. pneumoniae MtrK expression is regulated by methionine [].As this enzyme is absent in mammals, it has been considered a target for rational drug design.
This entry consists of bacterial antibiotic resistance proteins,
which confer resistance to various aminoglycosides they include:-aminoglycoside 3'-phosphotransferase or kanamycin kinase /
neomycin-kanamycin phosphotransferase and streptomycin 3''-kinaseor streptomycin 3''-phosphotransferase. The aminoglycoside
phosphotransferases inactivate aminoglycoside antibiotics via phosphorylation [
]. The proteins are found in a range of taxonomic groups.
Phosphoglycerate dehydrogenases (PGDH) have at least two different structural domains: the nucleotide binding and the substrate binding. There are three types of PGDH: type 3 enzymes are composed only of these two domains, type2 enzymes contain an extra C-terminal regulatory domain (ACT domain), type 1 enzymes contain both the regulatory domain and an extra allosteric domain [
,
]. This entry represents the type 1 enzyme. Interestingly, this type of PGDH is found in bacteria such as Mycobacterium, Bacillus subtilis, Corynebacterium, plants such as Arabidopsis, and higher order eukaryotes, including mammals. The PGDHs from E. coli and some lower eukaryotes, such as yeast and Neurospora, belong to the type2 PGDH and are not included in this entry []. PGDH catalyses an early step in the biosynthesis of L-serine by converting D-3-phosphoglyceric acid to hydroxypyruvic acid phosphate (HPAP), utilising NAD+ as a coenzyme [
,
]. Type 1 PGDH is mostly studied in M. tuberculosis. Both E.coli and M. tuberculosis PGDHs are very sensitive to inhibition by L-serine []. However, the mammalian enzymes are not inhibited by L-serine. The structural difference between human and M. tuberculosis PGDHs may explain the differential sensitivity to serine inhibition [].
D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain
Type:
Domain
Description:
A number of NAD-dependent 2-hydroxyacid dehydrogenases which seem to be specific for the D-isomer of their substrate have been shown to be functionally and structurally related. The catalytic domain contains a number of conserved charged residues which may play a role in the catalytic mechanism [
]. The NAD-binding domain is described in .
Prkrip1, also known as protein C114, is a double-stranded RNA-binding protein [
]. It consists of a fully extended N-terminal loop (residues 51-75) and an 18-turn alpha helix (residues 76-142). It directly links the catalytic centre with the U2 snRNP at the periphery of the spliceosome [].
This family contains several eukaryotic transmembrane proteins which are related to the Caenorhabditis elegans protein UNC-50
. A mammalian homologue, UNCL is a novel inner nuclear membrane protein that associates with RNA and is involved in the cell-surface expression of neuronal nicotinic receptors. UNCL plays a broader role because UNCL homologues are present in two yeast and a plant species, none of which express nicotinic receptors and it is also found in tissues that lack nicotinic receptors.
Glutaredoxins [
,
,
], also known as thioltransferases (disulphide reductases), are small proteins of approximately one hundred amino-acid residues which utilise glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system [].Glutaredoxin functions as an electron carrier in the glutathione-dependent synthesis of deoxyribonucleotides by the enzyme ribonucleotide reductase. Like thioredoxin (TRX), which functions in a similar way, glutaredoxin possesses an active centre disulphide bond [
]. It exists in either a reduced or an oxidized form where the two cysteine residues are linked in an intramolecular disulphide bond. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH ->GSH reductase ->GSH ->GRX ->protein substrates [
,
,
,
]. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress.Glutaredoxin has been sequenced in a variety of species. On the basis of extensive sequence similarity, it has been proposed [
] that Vaccinia virus protein O2L is most probably a glutaredoxin. Finally, it must be noted that Bacteriophage T4 thioredoxin seems also to be evolutionary related. In position 5 of the pattern T4 thioredoxin has Val instead of Pro.This family groups proteins from different organisms which are related to monothiol glutaredoxins. Monothiol glutaredoxins occur in different subcellular compartments; for instance, yeast Grx3 and Grx4 are nuclear proteins, whereas Grx5 is mitochondrially localized [
]. They share a common basic structural motif and biochemical mechanism of action, while participating in a diversity of cellular functions as protein redox regulators.
This entry includes a group of transmembrane proteins, including protein FATTY ACID EXPORT 1 (FAX1) from Arabidopsis and TMEM14 from animals. FAX1 mediates the export of free fatty acid from the plastids and is required for biogenesis of the outer pollen cell wall, in particular for the assembly of exine and pollen coat and for the release of ketone wax components [
]. The Zebrafish TMEM14 is required for normal heme biosynthesis []. The structure of human TMEM14 showed a three helical bundle [].
A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown [
,
,
,
,
] to be present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N terminus of some EGF-like domains []. Calcium-binding may be crucial for numerous protein-protein interactions.For human coagulation factor IX it has been shown [
] that the calcium-ligands form a pentagonal bipyramid. The first, third and fourth conserved negatively charged or polar residues are side chain ligands. The latter is possibly hydroxylated (see aspartic acid and asparagine hydroxylation site) []. A conserved aromatic residue, as well as the second conserved negative residue, are thought to be involved in stabilising the calcium-binding site.As in non-calcium binding EGF-like domains, there are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes [
].+------------------+ +---------+
| | | |nxnnC-x(3,14)-C-x(3,7)-CxxbxxxxaxC-x(1,6)-C-x(8,13)-Cx
| | +------------------+
'n': negatively charged or polar residue [DEQN]'b': possibly beta-hydroxylated residue [DN]
'a': aromatic amino acid'C': cysteine, involved in disulphide bond
'x': any amino acid.
A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown [
,
,
,
,
] to be present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N terminus of some EGF-like domains []. Calcium-binding may be crucial for numerous protein-protein interactions.For human coagulation factor IX it has been shown [
] that the calcium-ligands form a pentagonal bipyramid. The first, third and fourth conserved negatively charged or polar residues are side chain ligands. The latter is possibly hydroxylated (see aspartic acid and asparagine hydroxylation site) []. A conserved aromatic residue, as well as the second conserved negative residue, are thought to be involved in stabilising the calcium-binding site.As in non-calcium binding EGF-like domains, there are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes [
].+------------------+ +---------+
| | | |
nxnnC-x(3,14)-C-x(3,7)-CxxbxxxxaxC-x(1,6)-C-x(8,13)-Cx| |
+------------------+'n': negatively charged or polar residue [DEQN]
'b': possibly beta-hydroxylated residue [DN]'a': aromatic amino acid
'C': cysteine, involved in disulphide bond'x': any amino acid.
This entry represents a domain found in the spoU protein from E. coli that shows strong similarities to previously characterised 2'-O-methyltransferases [
,
]. The Mrm1 protein of Saccharomyces cerevisiae has been shown to be required for ribose methylation at a universally conserved nucleotide in the peptidyl transferase centre of the mitochondrial large ribosomal RNA (21S rRNA). Cells reduced in this activity were deficient in formation of functional large subunits of the mitochondrial ribosome. The Mrm1 protein catalyzes the site-specific formation of 2'-O-methylguanosine on in vitrotranscripts of both mitochondrial 21S rRNA and E. coli 23S rRNA providing evidence for an essential modified nucleotide in rRNA [
].
Tensins constitute an eukaryotic family of lipid phosphatases that are defined by the presence of two adjacent domains: a lipid phosphatase domain and a C2-like domain. The tensin-type C2 domain has a structure similar to the classical C2 domain (see
) that mediates the Ca2+-dependent membrane recruitment of several signalling proteins. However the tensin-type C2 domain lacks two of the three conserved loops that bind Ca2+, and in this respect it is similar to the C2 domains of PKC-type [
,
]. The tensin-type C2 domain can bind phopholipid membranes in a Ca2+ independent manner []. In the tumour suppressor protein PTEN, the best characterised member of the family, the lipid phosphatase domain was shown to specifically dephosphorylate the D3 position of the inositol ring of the lipid second messenger, phosphatydilinositol-3-4-5-triphosphate (PIP3). The lipid phosphatase domain contains the signature motif HCXXGXXR present in the active sites of protein tyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs). Furthermore, two invariant lysines are found only in the tensin-type phosphatase motif (HCKXGKXR) and are suspected to interact with the phosphate group at position D1 and D5 of the inositol ring [,
]. The C2 domain is found at the C terminus of the tumour suppressor protein PTEN (phosphatidyl-inositol triphosphate phosphatase). This domain may include a CBR3 loop, indicating a central role in membrane binding. This domain associates across an extensive interface with the N-terminal phosphatase domain DSPc suggesting that the C2 domain productively positions the catalytic part of the protein on the membrane. The crystal structure of the PTEN tumour suppressor has been solved [
]. The lipid phosphatase domain has a structure similar to the dual specificity phosphatase (see ). However, PTEN has a larger active site pocket that could be important to accommodate PI(3,4,5)P3.
Proteins known to contain a phosphatase and a C2 tensin-type domain are listed below: Tensin, a focal-adhesion molecule that binds to actin filaments. It may be involved in cell migration, cartilage development and in linking signal transduction pathways to the cytoskeleton.Phosphatase and tensin homologue deleted on chromosome 10 protein (PTEN). It antagonizes PI 3-kinase signalling by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 and thus inactivates downstream signalling. It plays major roles both during development and in the adult to control cell size, growth, and survival.Auxilin. It binds clathrin heavy chain and promotes its assembly into regular cages.Cyclin G-associated kinase or auxilin-2. It is a potential regulator of clathrin-mediated membrane trafficking.
The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].Phenylalanyl-tRNA synthetase (
) is an alpha2/beta2 tetramer composed of 2 subunits that belongs to class IIc. In eubacteria, a small subunit (pheS gene) can be designated as beta (E. coli) or alpha subunit (nomenclature adopted in InterPro). Reciprocally the large subunit
(pheT gene) can be designated as alpha (E. coli) or beta (see and
). In all other kingdoms the two subunits have equivalent length in eukaryota, and can be identified by specific signatures. The enzyme from Thermus thermophilus has an alpha 2 beta 2 type quaternary structure and is one of the most complicated members of the synthetase family. Identification of phenylalanyl-tRNA synthetase as a member of class II aaRSs was based only on sequence alignment of the small alpha-subunit with other synthetases [
].
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].This family contains the S24e ribosomal proteins from eukaryotes and archaebacteria. These proteins have 101 to 148 amino acids.
Kynurenine formamidase catalyses the hydrolysis of N-formyl-L-kynurenine to L-kynurenine, the second step in the kynurenine pathway of tryptophan degradation [
]. The proteins contain a conserved motif HXGTHXDXPXH that is likely to form a part of the active site.This family also includes cyclase-like proteins from plants. They are involved in responses to abiotic stress, and could function as polyketide cyclases [
]. Isatin hydrolase (), characterized from the bacterium Labrenzia aggregata, is also a member of this family. It is a manganese-binding enzyme that hydrolyses the cyclic amide bond (lactam) of isatin (1H-indole-2,3-dione) to yield isatinate (2-(2-aminophenyl)-2-oxoacetate), during the degradation of the plant hormone indole-3-acetic acid (IAA) [
].
The Ccr4-Not complex is a global regulator of gene expression that is conserved from yeast to human. It affects genes positively and negatively and is thought to regulate transcription factor IID function. In Saccharomyces cerevisiae, it exists in two prominent forms and consists of at least nine core subunits: the five Not proteins (Not1 to Not5), Caf1, Caf40, Caf130 and Ccr4 [
]. The Ccr4-Not complex regulates many different cellular functions, including RNA degradation and transcription initiation. It may be a regulatory platform that senses nutrient levels and stress []. Caf1 and Ccr4, are directly involved in mRNA deadenylation, and Caf1p is associated with Dhh1, a putative RNA helicase thought to be a component of the decapping complex []. Pop2, a component of the Ccr4-Not complex, functions as a deadenylase [].This entry represents a domain of unknown function found in the Not1 subunit of the CCR4-Not complex.
The 22kDa peroxisomal membrane protein (PMP22) is a major component of peroxisomal membranes. PMP22 seems to be involved in pore-forming activity and may contribute to the unspecific permeability of the organelle membrane. PMP22 is synthesised on free cytosolic ribosomes and then directed to the peroxisome membrane by specific targeting information [
]. SYM1 in yeast and Mpv17 in higher eukaryotes are closely related peroxisomal proteins required to maintain mitochondrial DNA (mtDNA) integrity and stability [,
]. Mpv17 is involved in the development of early-onset glomerulosclerosis [].Woronin sorting complex protein from Neurospora crassa is also included in this family. It is involved in both Woronin bodies (WB) formation and inherence [
].
SBP (for SQUAMOSA-pROMOTER BINDING PROTEIN) domain is a sequence specific DNA-binding domain found in plant proteins [
]. Members of family probably function as transcription factors involved in the control of early flower development []. They share a highly conserved DNA-binding domain that contains two zinc-binding sites. Among the 11 possible ligands for the zinc atoms that are conserved in the SBP zinc finger, only 8 are used. The SBP zinc finger follows the general pattern C-x4-C-x16-C-x2-[HC]-x15-C-x2-C-x3-H-x11-C. Three other histidines are well conserved but not involved in zinc binding [
,
].In vitro experiments show that the SBP zinc finger preferentially binds the
consensus sequence -TNCGTACAA- []. However, little is known of the physiological functions of these putative transcriptional regulators beyond their ability to bind DNA.The solution structure of the SBP zinc finger has been solved
[]. The first four Cys or His coordinate one zinc ion and the last four coordinate the other. It can be viewed as two structural subdomains, each subdomain containing a single zinc-binding pocket. The N-terminal subdomain consists of two short alpha helices whereas the C-terminal one contains a three-stranded antiparallel β-sheet.
The XH (rice gene X Homology) domain is found in a family of plant proteins including Oryza sativa (Rice)
and Arabidopsis FDM1-5/IDN2. These proteins usually contain an XS domain (
) that is also found in the PTGS protein SGS3. As the XS and XH domains are fused in most of these proteins, these two domains may interact. The XH domain is between 124 and 145 residues in length and contains a conserved glutamate residue that may be functionally important [
].FDM1-5 and IDN2 are components of RNA-directed DNA methylation pathway (RdDM) [
,
].
Triosephosphate isomerase (
) (TIM) [
] is the glycolytic enzyme that catalyses the reversible interconversion of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. TIM plays an important role in several metabolic pathways and is essential for efficient energy production, highly conserved in prokaryotes and eukaryotes. In pathogenic organisms, this enzyme plays a crucial role obtaining energy for infection and survival. TIM is a dimer of identical subunits, each of which is made up of about 250 amino-acid residues. A glutamic acid residue is involved in the catalytic mechanism [,
,
].The tertiary structure of TIM has eight beta/alpha motifs folded into a barrel structure. The TIM barrel fold occurs ubiquitously and is found in numerous other enzymes that can be involved in energy metabolism, macromolecule metabolism, or small molecule metabolism [
].The sequence around the active site residue is perfectly conserved in all known TIM's. Deficiencies in TIM are associated with haemolytic anaemia coupled with a progressive, severe neurological disorder [
].This entry represents bacterial and eukaryotic triosephosphate isomerases.
Triosephosphate isomerase (
) (TIM) [
] is the glycolytic enzyme that catalyses the reversible interconversion of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. TIM plays an important role in several metabolic pathways and is essential for efficient energy production, highly conserved in prokaryotes and eukaryotes. In pathogenic organisms, this enzyme plays a crucial role obtaining energy for infection and survival. TIM is a dimer of identical subunits, each of which is made up of about 250 amino-acid residues. A glutamic acid residue is involved in the catalytic mechanism [,
,
].The tertiary structure of TIM has eight beta/alpha motifs folded into a barrel structure. The TIM barrel fold occurs ubiquitously and is found in numerous other enzymes that can be involved in energy metabolism, macromolecule metabolism, or small molecule metabolism [
].The sequence around the active site residue is perfectly conserved in all known TIM's. Deficiencies in TIM are associated with haemolytic anaemia coupled with a progressive, severe neurological disorder [
].
The Origin Recognition Complex (ORC) is a six-subunit ATP-dependent DNA-binding complex encoded by ORC1-6 [
]. ORC is a central component for eukaryotic DNA replication, and binds chromatin at replication origins throughout the cell cycle []. ORC directs DNA replication throughout the genome and is required for its initiation [,
,
]. ORC bound at replication origins serves as the foundation for assembly of the pre-replicative complex (pre-RC), which includes Cdc6, Tah11 (aka Cdt1), and the Mcm2-7 complex [,
,
,
]. Pre-RC assembly during G1 is required for replication licensing of chromosomes prior to DNA synthesis during S phase [,
,
]. Cell cycle-regulated phosphorylation of ORC2, ORC6, Cdc6, and MCM by the cyclin-dependent protein kinase Cdc28 regulates initiation of DNA replication, including blocking reinitiation in G2/M phase [,
,
,
]. In yeast, ORC also plays a role in the establishment of silencing at the mating-type loci Hidden MAT Left (HML) and Hidden MAT Right (HMR) [
,
,
]. ORC participates in the assembly of transcriptionally silent chromatin at HML and HMR by recruiting the Sir1 silencing protein to the HML and HMR silencers [,
,
]. Both ORC1 and ORC5 bind ATP, although only ORC1 has ATPase activity [
]. ORC1 and ORC4 constitute the primary DNA binding site in the ORC ring []. The binding of ATP by ORC1 is required for ORC binding to DNA and is essential for cell viability []. The ATPase activity of ORC1 is involved in formation of the pre-RC [,
,
]. ATP binding by ORC5 is crucial for the stability of ORC as a whole. Only the ORC1-5 subunits are required for origin binding; ORC6 is essential for maintenance of pre-RCs once formed [
]. Interactions within ORC suggest that ORC2-3-6 may form a core complex []. DNA replication origin activation is positively regulated by ORC3 and ORC5 multi-mono-ubiquitylation catalysed by OBI1, which is important for origin firing [].ORC homologues have been found in various eukaryotes, including fission yeast, insects, amphibians, and humans [
].
Elongation factor 4, also known as ribosomal back-translocase LepA, is required for accurate and efficient protein synthesis under certain stress conditions. Its function is not clear. However, it may act as a fidelity factor of the translation reaction, by catalysing a one-codon backward translocation of tRNAs on improperly translocated ribosomes. Back-translocation proceeds from a post-translocation (POST) complex to a pre-translocation (PRE) complex, thus giving elongation factor G a second chance to translocate the tRNAs correctly [
,
]. Elongation factor 4 binds to ribosomes in a GTP-dependent manner. The eukaryotic homologue is known as GUF1 and promotes protein synthesis in chloroplasts and mitochondria [].
The elongation factor 4 (LepA or GUF1 in Saccaromyces) is a GTP-binding membrane protein related to EF-G and EF-Tu. LepA is a noncanonical GTPase that has an unknown function. It is highly conserved and present in bacteria, mitochondria, and chloroplasts [
]. LepA contains domains that are homologous to EF-G domain I, II, III, V. However, it also contains a C-terminal domain (CTD) that is not homologous to any region in EF-G. This entry represents the unique C-terminal region of LepA [
]. The CTD of LepA may play a primary role in back translocation by providing additional binding interactions with a back-translocated tRNA [].
LRP chaperone MESD (also known as mesoderm development candidate 2) represents a set of highly conserved proteins found from nematodes to humans.
It is a chaperone that specifically assists with the folding of β-propeller/EGF modules within the family of low-density lipoprotein receptors (LDLRs). It also acts as a modulator of the Wnt pathway, since some LDLRs are coreceptors for the canonical Wnt pathway and is essential for specification of embryonic polarity and mesoderm induction []. The Drosophila homologue, known as boca, is an endoplasmic reticulum protein required for wingless signaling and trafficking of LDL receptor family members [].The final C-terminal residues, KEDL, are the endoplasmic reticulum retention sequence as it is an ER protein specifically required for the intracellular trafficking of members of the low-density lipoprotein family of receptors (LDLRs) [
]. The N- and C-terminal sequences are predicted to adopt a random coil conformation, with the exception of an isolated predicted helix within the N-terminal region, The central folded domain flanked by natively unstructured regions is the necessary structure for facilitating maturation of LRP6 (Low-Density Lipoprotein Receptor-Related Protein 6 Maturation) [].
The crotonase superfamily is comprised of mechanistically diverse proteins that share a conserved trimeric quaternary structure (sometimes a hexamer consisting of a dimer of trimers), the core of which consists of 4 turns of a (β/β/α)n superhelix. Some enzymes in the superfamily have been shown to display dehalogenase, hydratase, and isomerase activities, while others have been implicated in carbon-carbon bond formation and cleavage as well as the hydrolysis of thioesters [
]. However, these different enzymes share the need to stabilise an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two structurally conserved peptidic NH groups that provide hydrogen bonds to the carbonyl moieties of the acyl-CoA substrates and form an "oxyanion hole". The CoA thioester derivatives bind in a characteristic hooked shape and a conserved tunnel binds the pantetheine group of CoA, which links the 3'-phosphate ADP binding site to the site of reaction [
]. Enzymes in the crotonase superfamily include:Enoyl-CoA hydratase (crotonase;
), which catalyses the hydration of 2-trans-enoyl-CoA into 3-hydroxyacyl-CoA []. 3-2 trans-enoyl-CoA isomerase (or dodecenoyl-CoA isomerise;
), which shifts the 3-double bond of the intermediates of unsaturated fatty acid oxidation to the 2-trans position [
].3-hydroxybutyryl-CoA dehydratase (crotonase;
), a bacterial enzyme involved in the butyrate/butanol-producing pathway.
4-Chlorobenzoyl-CoA dehalogenase (
), a Pseudomonas enzyme which catalyses the conversion of 4-chlorobenzoate-CoA to 4-hydroxybenzoate-CoA [
].Dienoyl-CoA isomerase, which catalyses the isomerisation of 3-trans,5-cis-dienoyl-CoA to 2-trans,4-trans-dienoyl-CoA [
].Naphthoate synthase (MenB, or DHNA synthetase;
), a bacterial enzyme involved in the biosynthesis of menaquinone (vitamin K2) [
]. Carnitine racemase (gene caiD), which catalyses the reversible conversion of crotonobetaine to L-carnitine in Escherichia coli [
]. Methylmalonyl CoA decarboxylase (MMCD;
), which has a hexameric structure (dimer of trimers) [
].Carboxymethyl Proline synthase (CarB), which is involved in carbapenem biosynthesis [
].6-oxo camphor hydrolase, which catalyses the desymmetrization of bicyclic beta-diketones to optically active keto acids [
].The alpha subunit of fatty oxidation complex, a multi-enzyme complex that catalyses the last three reactions in the fatty acid beta-oxidation cycle [
].AUH protein, a bifunctional RNA-binding homologue of enoyl-CoA hydratase [
].
This entry represents the C-terminal domain found in enoyl-CoA hydratase and related proteins. This domain has an α-helical structure, and may be involved in trimerisation.
Actin [
,
] is a ubiquitous protein involved in the formation of filaments that are major components of the cytoskeleton. These filaments interact with myosin to produce a sliding effect, which is the basis of muscular contraction and many aspects of cell motility, including cytokinesis. Each actin protomer binds one molecule of ATP and has one high affinity site for either calcium or magnesium ions, as well as several low affinity sites. Actin exists as a monomer in low salt concentrations, but filaments form rapidly as salt concentration rises, with the consequent hydrolysis of ATP. Actin from many sources forms a tight complex with deoxyribonuclease (DNase I) although the significance of this is still unknown. The formation of this complex results in the inhibition of DNase I activity, and actin loses its ability to polymerise. It has been shown that an ATPase domain of actin shares similarity with ATPase domains of hexokinase and hsp70proteins [
,
].In vertebrates there are three groups of actin isoforms: alpha, beta and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exists in most cell types as components of the cytoskeleton and as mediators of internal cell motility. In plants there are many isoforms which are probably involved in a variety of functions such as cytoplasmic streaming, cell shape determination, tip growth, graviperception, cell wall deposition, etc.Recently some divergent actin-like proteins have been identified in several species. These proteins include centractin (actin-RPV) from mammals, fungi yeast ACT5, Neurospora crassa ro-4 and Pneumocystis carinii, which seems to be a component of a multi-subunit centrosomal complex involved in microtubule based vesicle motility (this subfamily is known as ARP1); ARP2 subfamily, which includes chicken ACTL, Saccharomyces cerevisiae ACT2, Drosophila melanogaster 14D and Caenorhabditis elegans actC; ARP3 subfamily, which includes actin 2 from mammals, Drosophila 66B, yeast ACT4 and Schizosaccharomyces pombe act2; and ARP4 subfamily, which includes yeast ACT3 and Drosophila 13E.This entry contains a signature that picks up both actins and the actin-like proteins and corresponds to positions 106 to 118 in actins.
Actin [
,
] is a ubiquitous protein involved in the formation of filamentsthat are major components of the cytoskeleton. These filaments interact
with myosin to produce a sliding effect, which is the basis of muscularcontraction and many aspects of cell motility, including cytokinesis. Each
actin protomer binds one molecule of ATP and has one high affinity site foreither calcium or magnesium ions, as well as several low affinity sites.
Actin exists as a monomer in low salt concentrations, but filaments formrapidly as salt concentration rises, with the consequent hydrolysis of ATP.
Actin from many sources forms a tight complex with deoxyribonuclease(DNase I) although the significance of this is still unknown. The formation
of this complex results in the inhibition of DNase I activity, and actinloses its ability to polymerise. It has been shown that an ATPase domain
of actin shares similarity with ATPase domains of hexokinase and hsp70proteins [
,
].In vertebrates there are three groups of actin isoforms: alpha, beta and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exists in most cell types as components of the cytoskeleton and as mediators of internal cell motility. In plants there are many isoforms which are probably involved in a variety of functions such as cytoplasmic streaming, cell shape determination, tip growth, graviperception, cell wall deposition, etc.
The QLQ domain is characterised by the conserved Gln-Leu-Gln residues. Another feature of this domain is the absolute conservation of bulky aromatic/hydrophobic and acidic amino acid residues such as Phe, Trp, Tyr, Leu, Glu, or their equivalents in terms of chemical and radial properties. The Pro residue is also absolutely conserved. These amino acid residues are critical for the function of the QLQ domain, probably for protein-protein interaction [
].Some proteins known to conatin a QLQ domain are listed below:Plant GROWTH-REGULATING FACTOR (GRF) proteins, putative transcription factors. Eukaryotic SWI2/SNF2, transcriptional coactivators.
This entry represents a domain found in a group of proteins of the PLP-dependent enzymes superfamily represented by the beta subunit of tryptophan synthase (TrpB) [
]. This group of diverse proteins also include threonine dehydratase, cysteine synthase, threonine synthase and pyridoxal phosphate-dependent deaminase.
Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site
Type:
Binding_site
Description:
Cysteine synthase () (CSase) is the enzyme responsible for the formation of cysteine from O-acetyl-serine and hydrogen sulphide with the concomitant release of acetic acid [
]. In bacteria such as Escherichia coli, two such forms of the enzyme are known (genes cysK and cysM). In plants there are also two forms, one located in the cytoplasm and the other in chloroplasts.Cystathionine beta-synthase (
) catalyses the first irreversible step in homocysteine transulphuration, the conjugation of homocysteine and serine forming cystathionine. Like Csase it is a pyridoxal-phosphate dependent enzyme [
].Both enzymes are evolutionary related. The pyridoxal-phosphate attaches to the lysine residue found in the N-terminal section of these enzymes; the sequence around the lysine residue is highly conserved.
Cysteine synthase (O-acetylserine (thiol)-lyase,
) is the enzyme responsible for the formation of cysteine from O-acetyl-serine and hydrogen sulphide with the concomitant release of acetic acid. In bacteria such two forms of the enzyme are known (genes cysK and cysM). CysK differs from CysM in that it can also use sulphide instead of thiosulphate, to produce cysteine instead of cysteine thiosulphonate.
This entry represents CysK-type cysteine synthases. It includes beta-cyanoalanine synthase, a mitochondrial cysteine synthase-like protein from plants [].
Cysteine synthase (also known as O-acetylserine (thiol)-lyase or O-acetyl-L-serine sulfhydrylase) is the enzyme responsible for the formation of cysteine from O-acetyl-serine and hydrogen sulphide with the concomitant release of acetic acid. In bacteria such two forms of the enzyme are known (genes cysK and cysM) [,
]. CysM differs from CysK in that it can also use thiosulphate instead of sulphide, to produce cysteine. Beta-cyanoalanine synthase is a mitochondrial cysteine synthase-like protein from plants [
]. It has cysteine synthase activity, but the cyanoalanine synthesis reaction is more efficient than the cysteine synthase activity.
This entry represents proteins found in the N-terminal region of the essential protein Yae1. Proteins containing this domain include ORAOV1 (Oral cancer-overexpressed protein 1) and YAE1 [
]. Their function is not clear. In Saccharomyces cerevisiae, Lto1 (ORAOV1 homologue) forms a complex with Rli1 and Yae1, which relieves the toxic effects of reactive oxygen species (ROS) on biogenesis and function of the ribosome [].
The ELM2 (Egl-27 and MTA1 homology 2) domain is a small domain of unknown function. It is found in the MTA1 protein that is part of the NuRD complex [
]. The domain is usually found to the N terminus of a myb-like DNA binding domain and a GATA binding domain. ELM2, in some instances, is also found associated with the ARID DNA binding domain . This suggests that ELM2 may also be involved in DNA binding, or perhaps is a protein-protein interaction domain.
Proteins in this family include PGAP6 (also known as TMEM8A), NGX6 (also known as TMEM8B) and myomaker (also known as TMEM8C). TMEM8C is embedded in the plasma membrane with seven membrane-spanning regions and a required intracellular C-terminal tail. It is essential for myoblast fusion and sufficient to promote fusion of fibroblasts with muscle cells [
]. TMEM8A and TMEM8B has no fusogenic activity. TMEM8A is a GPI-specific phospholipase A2 involved in Nodal signaling modulation through CRIPTO shedding []. TMEM8B plays a role in cell adhesion modulation in nasopharyngeal carcinoma cells [].
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].S14 is one of the proteins from the small ribosomal subunit.
In Escherichia coli, S14 is known to be required for the assembly of 30S particlesand may also be responsible for determining the conformation of 16S rRNA at the A site.
It belongs to a family of ribosomal proteins [] thatinclude bacterial, algal and plant chloroplast S14, yeast mitochondrial MRP2, cyanelle S14, archaebacteria Methanococcus vannielii S14, as well as yeast mitochondrial MRP2, yeast YS29A/B, and mammalian S29.
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].The proteins in this entry belong to the zinc-binding subfamily of ribosomal protein S14. They bind 1 zinc ion per subunit and bind to the 16S rRNA. S14 is required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site.
A number of eukaryotic proteins that seem to be involved with sterol synthesis and/or its regulation have been found [
] to be evolutionary related. These include mammalian oxysterol-binding protein (OSBP), a protein of about 800 amino-acid residues that binds a variety of oxysterols (oxygenated derivatives of cholesterol) [,
]; yeast Osh1, a protein of 859 residues that also plays a role in ergosterol synthesis []; yeast proteins Hes1 and Kes1, highly related proteins of 434 residues that seem to play a role in ergosterol synthesis [,
]; Probable transporter efuK from the fungi Hormonema carpetanum, which is involved in the biosynthesis of enfumafungin []; and OSBP-related proteins (ORP) from plants such as Arabidopsis thaliana [].This entry represents a sequence region in these proteins that contains a conserved pentapetide.
A number of eukaryotic proteins that seem to be involved with sterol synthesis and/or its regulation have been found [
] to be evolutionary related. These include mammalian oxysterol-binding protein (OSBP), a protein of about 800 amino-acid residues that binds a variety of oxysterols (oxygenated derivatives of cholesterol) [,
]; yeast Osh1, a protein of 859 residues that also plays a role in ergosterol synthesis []; yeast proteins Hes1 and Kes1, highly related proteins of 434 residues that seem to play a role in ergosterol synthesis [,
]; Probable transporter efuK from the fungi Hormonema carpetanum, which is involved in the biosynthesis of enfumafungin []; and OSBP-related proteins (ORP) from plants such as Arabidopsis thaliana [].
This entry represents a six transmembrane helix rhomboid domain.This domain is found in serine peptidases belonging to the MEROPS peptidase family S54 (Rhomboid, clan ST). They are integral membrane proteins related to the Drosophila melanogaster (Fruit fly) rhomboid protein
. Members of this family are found in archaea, bacteria and eukaryotes.
The rhomboid protease cleaves type-1 transmembrane domains using a catalytic dyad composed of serine and histidine. The active site is embedded within the membrane and the active site residues are on different transmembrane regions. From the tertiary structure of the Escherichia coli homologue GlpG [
] it was shown that hydrolysis occurs in a fluid filled cavity within the membrane. Initially, a catalytic triad including a highly conserved asparagine had been proposed, but this residue has been shown not to be essential []. Drosophila rhomboid cleaves the transmembrane proteins Spitz, Gurken and Keren within their transmembrane domains to release a soluble TGFalpha-like growth factor. Cleavage occurs in the Golgi, following translocation of the substrates from the endoplasmic reticulum membrane by Star, another transmembrane protein. The growth factors are then able to activate the epidermal growth factor receptor [,
].Few substrates of mammalian rhomboid homologues have been determined, but rhomboid-like protein 2 has been shown to cleave ephrin B3 [
]. Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite. Invasion of host cells first requires their recognition and this is achieved by parasite transmembrane adhesins interacting with host cell receptors. Before the parasite can enter a host cell the adhesins must be released by cleavage. In Toxoplasma rhomboid TgROM5 cleaves the adhesins, and in Plasmodium, which lacks a TgROM5 orthologue, PfROMs 1 and 4 cleave the diverse array of malaria parasite adhesins [].This entry also includes catalytically inactive rhomboid protease homologues, iRhom1/2, which are metazoan-specific and play crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling [
]. They regulate ADAM17 protease, acting as trafficking factors that escort ADAM17 from the ER to the later secretory pathway. They are required for the cleavage and release of a variety of membrane-associated proteins [,
]. iRhombs have been linked to the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy [] and also in neurological disorders such as Alzheimer's and Parkinson's diseases, inflammation, cancer and skin diseases [].
This group of proteins contain serine peptidases belonging to the MEROPS peptidase family S54 (Rhomboid, clan ST). They are integral membrane proteins related to the Drosophila melanogaster (Fruit fly) rhomboid protein
. Members of this family are found in archaea, bacteria and eukaryotes.The D. melanogaster rhomboid protease cleaves type-1 transmembrane domains using a catalytic triad composed of serine, histidine and asparagine contributed by different transmembrane domains. It cleaves the transmembrane proteins Spitz, Gurken and Keren within their transmembrane domains to release a soluble TGFalpha-like growth factor. Cleavage occurs in the Golgi, following translocation of the substrates from the endoplasmic reticulum membrane by Star, another transmembrane protein. The growth factors are then able to activate the epidermal growth factor receptor [
,
].Few substrates of mammalian rhomboid homologues have been determined, but rhomboid-like protein 2 (MEROPS S54.002) has been shown to cleave ephrin B3 [
]. Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite.
In budding yeast, TIP41 interacts with TAP42 to regulate protein phosphatase activity [
]. In mammalian cells, TIP41-like protein (TIPRL) does not directly bind TAP42, but rather primarily interacts with PP2A, PP4 or PP6 catalytic subunits. TIPRL inhibits PP4 activity to allow for H2AX phosphorylation and the subsequent DNA damage response [].
This entry represents RIC1 (Ribosomal control protein1) and has been identified in yeast as a Golgi protein involved in retrograde transport to the cis-Golgi network. It forms a heterodimer with Rgp1 and functions as a guanyl-nucleotide exchange factor [
] which activates YPT6 by exchanging bound GDP for free GTP. RIC1 is thereby required for efficient fusion of endosome-derived vesicles with the Golgi. The RIC1-RGP1 complex participates in the recycling of SNC1, presumably by mediating fusion of endosomal vesicles with the Golgi compartment and may also be indirectly involved in the transcription of both ribosomal protein genes and ribosomal RNA [,
,
].
A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF) has been shown [
,
,
,
] to be present, in a more or less conserved form, in a large number of other, mostly animal, proteins. EGF is a polypeptide of about 50 amino acids with three internal disulfide bridges. It first binds with high affinity to specific cell-surface receptors and then induces their dimerization, which is essential for activating the tyrosine kinase in the receptor cytoplasmic domain, initiating a signal transduction that results in DNA synthesis and cell proliferation.A common feature of all EGF-like domains is that they are found in the extracellular domain of membrane-bound proteins or in proteins known to be
secreted (exception: prostaglandin G/H synthase). The EGF-like domain includes six cysteine residues which have been shown to be involved in disulfide bonds. The structure of several EGF-like domains has been solved. The fold consists of two-stranded β-sheet followed by a loop to a C-terminal shorttwo-stranded sheet.
