This family is found in diverse acyltransferases involved in phospholipid biosynthesis [
]. This domain is found in tafazzins, phospholipid transacylases involved in the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation and whose defects cause of Barth syndrome; a severe inherited disorder which is often fatal in childhood and is characterised by cardiac and skeletal abnormalities []. Phospholipid/glycerol acyltransferase is not found in the viruses or the archaea and is under represented in the bacteria. Bacterial glycerol-phosphate acyltransferases are involved in membrane biogenesis since they use fatty acid chains to form the first membrane phospholipids [].
Several enzymes catalyse mechanistically related reactions which involve
the highly complex cyclic rearrangement of squalene or its 2,3 oxide.Lanosterol synthase (
) (oxidosqualene--lanosterol cyclase) catalyzes the cyclization of (S)-2,3-epoxysqualene to lanosterol, the
initial precursor of cholesterol, steroid hormones and vitamin D invertebrates and of ergosterol in fungi (gene ERG7).
Cycloartenol synthase () (2,3-epoxysqualene--cycloartenol
cyclase), is a plant enzyme that catalyzes the cyclization of (S)-2,3-epoxysqualene to cycloartenol, and hopene synthase () (squalene--hopene cyclase), is a bacterial
enzyme that catalyzes the cyclization of squalene into hopene, a key stepin hopanoid (triterpenoid) metabolism.
These enzymes are evolutionary related [] proteins of about 70 to 85 kD. This highly conserved region is rich in aromatic residues and is located in the C-terminal section.
Protein prenyltransferases catalyse the transfer of the carbon moiety of C15 farnesyl pyrophosphate or geranylgeranyl pyrophosphate synthase to a conserved cysteine residue in a CaaX motif of protein and peptide substrates. The addition of a farnesyl group is required to anchor proteins to the cell membrane. In the 3D structure of a mammalian Ras farnesyltransferases (Ftase), both subunits are largely composed of α-helices. The α-2 to α-15 helices in the alpha subunit fold into a novel helical hairpin structure, resulting in a crescent-shape domain that envelopes part of the subunit. The 12 helices of the beta-subunit form an α-α barrel. Six additional helices connect the inner core of helices and form the outside of the helical barrel. A deep cleft surrounded by hydrophobic amino acids in the centre of the barrel is proposed as the FPP-binding pocket. A single Zn2+ ion is located at the junction between the hydrophilic surface groove near the subunit interface [
,
,
,
].Terpenoid cyclases such as squalene cyclase, pentalenene synthase, 5-epi-aristolochene synthase, and trichodiene synthase are responsible for the synthesis of cholesterol, a hydrocarbon precursor of the pentalenolactone family of antibiotics, a precursor of the antifungal phytoalexin capsidiol, and the precursor of antibiotics and mycotoxins, respectively. In the structures of these three enzymes, the similar structural feature referred to as 'terpenoid synthase fold' with 10-12 mostly antiparallel α-helices is found, as also observed in protein prenyltransferases. The high structural similarity provides support for the hypothesis that the three families of prenyltransferases have related evolution despite their low sequence similarity [
].Alpha-2-macroglobulin inhibit all four classes of proteinases by a unique 'trapping' mechanism in which the inhibitor undergoes global structural transformation to lead active proteases into its molecular cage. It also shows other functions related with the immune-cell function such as the binding of cytokines or the facilitation of cell migration [
,
].
WD-40 repeats (also known as WD or beta-transducin repeats) are short ~40 amino acid motifs, often terminating in a Trp-Asp (W-D) dipeptide. WD40 repeats usually assume a 7-8 bladed β-propeller fold, but proteins have been found with 4 to 16 repeated units, which also form a circularised β-propeller structure. WD-repeat proteins are a large family found in all eukaryotes and are implicated in a variety of functions ranging from signal transduction and transcription regulation to cell cycle control and apoptosis. Repeated WD40 motifs act as a site for protein-protein or protein-DNA interaction, and proteins containing WD40 repeats are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins [
]. The specificity of the proteins is determined by the sequences outside the repeats themselves. Examples of such complexes are G proteins (beta subunit is a β-propeller), TAFII transcription factor, and E3 ubiquitin ligase [,
]. In Arabidopsis spp., several WD40-containing proteins act as key regulators of plant-specific developmental events.This entry represents a region that spans the WD-40 repeats in members of the WD repeat G protein beta family.
This entry rerpesnts the N-terminal domain of the histone-binding protein RBBP4. Proteins containing this domain include members from the WD repeat RBAP46 (RBBP7)/RBAP48(RBBP4)/MSI1 family.RBBP4 is a subunit of the chromatin assembly factor 1 (CAF-1) complex. The CAF-1 complex is a conserved heterotrimeric protein complex that promotes histone H3 and H4 deposition onto newly synthesized DNA during replication or DNA repair; specifically it facilitates replication-dependent nucleosome assembly with the major histone H3 (H3.1). This domain is an alpha helix which sits just upstream of the WD40 seven-bladed β-propeller in the human RBBP7 protein. RBBP7 folds into the β-propeller and binds histone H4 in a groove formed between this N-terminal helix and an extended loop inserted into blade six [
].
This superfamily represents a WD40/YVTN repeat-like domain. Both the WD40 and the YVTN repeated motifs consist of about 40 residues, and although they consist of distinct sequences, they do share a similar structure. Structurally, both the WD40 and the YVTN repeated motifs form seven-bladed propellers (although some members can contain eight blades), which consist of seven 4-stranded β-sheets. The WD40-type repeat domain is found in the beta-1 subunit of the signal-transducing G protein [
], in yeast Tup1 protein [], in Groucho [], in the yeast cell cycle protein Cdc4 [] and in actin-interacting protein 1 [].The YVTN-type repeat domain is found in archaeal surface layer proteins (SLPs) that protect cells from extreme environments [], in quinohemoprotein amine dehydrogenase (QHNDH) [], and in methylamine dehydrogenase [].
WD-40 repeats (also known as WD or beta-transducin repeats) are short ~40 amino acid motifs, often terminating in a Trp-Asp (W-D) dipeptide. WD40 repeats usually assume a 7-8 bladed β-propeller fold, but proteins have been found with 4 to 16 repeated units, which also form a circularised β-propeller structure. WD-repeat proteins are a large family found in all eukaryotes and are implicated in a variety of functions ranging from signal transduction and transcription regulation to cell cycle control and apoptosis. Repeated WD40 motifs act as a site for protein-protein or protein-DNA interaction, and proteins containing WD40 repeats are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins [
]. The specificity of the proteins is determined by the sequences outside the repeats themselves. Examples of such complexes are G proteins (beta subunit is a β-propeller), TAFII transcription factor, and E3 ubiquitin ligase [,
]. In Arabidopsis spp., several WD40-containing proteins act as key regulators of plant-specific developmental events.
WD-40 repeats (also known as WD or beta-transducin repeats) are short ~40 amino acid motifs, often terminating in a Trp-Asp (W-D) dipeptide. WD40 repeats usually assume a 7-8 bladed β-propeller fold, but proteins have been found with 4 to 16 repeated units, which also form a circularised β-propeller structure. WD-repeat proteins are a large family found in all eukaryotes and are implicated in a variety of functions ranging from signal transduction and transcription regulation to cell cycle control and apoptosis. Repeated WD40 motifs act as a site for protein-protein or protein-DNA interaction, and proteins containing WD40 repeats are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins [
]. The specificity of the proteins is determined by the sequences outside the repeats themselves. Examples of such complexes are G proteins (beta subunit is a β-propeller), TAFII transcription factor, and E3 ubiquitin ligase [,
]. In Arabidopsis spp., several WD40-containing proteins act as key regulators of plant-specific developmental events.This entry represents a conserved site found in the WD40 repeat.
This superfamily represents a domain consisting of a multi-helical fold comprising two curved layers of α-helices arranged in a regular right-handed superhelix, where the repeats that make up this structure are arranged about a common axis [
]. These superhelical structures present an extensive solvent-accessible surface that is well suited to binding large substrates such as proteins and nucleic acids. This topology has been found with a number of repeats and domains, including the armadillo repeat (found in beta-catenins and importins), the HEAT repeat (found in protein phosphatase 2a and initiation factor eIF4G), the PHAT domain (found in Smaug RNA-binding protein), the leucine-rich repeat variant, the Pumilo repeat, and in the H regulatory subunit of V-type ATPases. The sequence similarity among these different repeats or domains is low, however they exhibit considerable structural similarity. Furthermore, the number of repeats present in the superhelical structure can vary between orthologues, indicating that rapid loss/gain of repeats has occurred frequently in evolution. A common phylogenetic origin has been proposed for the armadillo and HEAT repeats [].
This entry represents a group of uncharacterised plant proteins, including B3 domain-containing protein At2g31720 (also known as Protein AUXIN RESPONSE FACTOR 70) from Arabidopsis. These are DNA-binding proteins likely to be involved in stress response [
].
The S1 domain was originally identified in ribosomal protein S1 but is found in a large number of RNA-associated proteins. The structure of the S1 RNA-binding domain from the Escherichia coli polynucleotide phosphorylase has been determined using NMR methods and consists of a five-stranded antiparallel beta barrel. Conserved residues on one face of the barrel and adjacent loops form the putative RNA-binding site [
]. The structure of the S1 domain is very similar to that of cold shock proteins. This suggests that they may both be derived from an ancient nucleic acid-binding protein [
].
6,7-dimethyl-8-ribityllumazine synthase (lumazine synthase, LS), catalyzes the formation of 6,7-dimethyl-8-ribityllumazine by condensation of 5-amino-6-(D-ribitylamino)uracil with 3,4-dihydroxy-2-butanone 4-phosphate, the penultimate step in the biosynthesis of riboflavin. The biosynthesis of one riboflavin molecule requires one molecule of GTP and two molecules of ribulose 5-phosphate as substrates. The final step in the biosynthesis of the vitamin involves the dismutation of 6,7-dimethyl-8-ribityllumazine catalyzed by riboflavin synthase (RS). The second product, 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione, is recycled in the biosynthetic pathway by 6,7-dimethyl-8-ribityllumazine synthase [
]. N-[2,4-dioxo-6-d-ribitylamino-1,2,3,4-tetrahydropyrimidin-5-yl]oxalamic acid derivatives inhibit riboflavin synthase [
].This family includes both lumazine synthase and riboflavin synthase. Both share sequence similarity, they appear to have diverged early in the evolution of archaea from a common ancestor.
UBA domains are a commonly occurring sequence motif of approximately 45 amino acid residues that are found in diverse proteins involved in the ubiquitin/proteasome pathway, DNA excision-repair, and cell signalling via protein kinases [
]. The human homologue of yeast Rad23A is one example of a nucleotide excision-repair protein that contains both an internal and a C-terminal UBA domain. The solution structure of human Rad23A UBA(2) showed that the domain forms a compact three-helix bundle []. Comparison of the structures of UBA(1) and UBA(2) reveals that both form very similar folds and have a conserved large hydrophobic surface patch which may be a common protein-interacting surface present in diverse UBA domains. Evidence that ubiquitin binds to UBA domains leads to the prediction that the hydrophobic surface patch of UBA domains interacts with the hydrophobic surface on the five-stranded β-sheet of ubiquitin [].This domain is similar in sequence to the N-terminal domain of translation elongation factor EF1B (or EF-Ts) from bacteria, mitochondria and chloroplasts [
].
The HECT (Homologous to the E6-AP Carboxyl Terminus) domain is an around 350 amino acids motif that has been identified in proteins that all belong to a particular E3 ubiquitin-protein ligase family [
]. HECT domain containing proteins accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then transfer it to lysine side chains of target proteins, and transfers additional ubiquitin molecules to the end of growing ubiquitin chains. The site of ubiquitin thioester formation is a conserved cysteine residue located in the last 32-36 aa of the HECT domain []. The amino-terminal part of the HECT domain has been involved in E2 binding [,
]. Once linked to ubiquitin, the target proteins are degraded in the 26 S proteasome.
E3 ubiquitin ligase, domain of unknown function DUF913
Type:
Domain
Description:
This is a domain of unknown function found towards the N terminus of a family of E3 ubiquitin protein ligases, including yeast TOM1, many of which appear to play a role in mRNA transcription and processing. This domain is found in association with and immediately C-terminal to another domain of unknown function: .
E3 ubiquitin ligase, domain of unknown function DUF908
Type:
Domain
Description:
This is a domain of unknown function found at the N terminus of a family of E3 ubiquitin protein ligases, including yeast TOM1, many of which appear to play a role in mRNA transcription and processing. This domain is found in association with and immediately N-terminal to another domain of unknown function: .
This domain contains repetitive element (RE) from a subgroup of HECT E3 ubiquitin ligases and the Y-family translesion polymerases, including human HUWE1 and REV1. Each of these repetitive elements are approximately 20 amino acids in length and contain two predicted helical segments separated by a Leu-Pro motif. The REs from the Y-family polymerases were shown to bind ubiquitin and were the basis for a novel ubiquitin-binding domain called the ubiquitin-binding motif (UBM) [
].
This entry represents a structural domain with an armadillo (ARM)-like fold, consisting of a multi-helical fold comprised of two curved layers of α-helices arranged in a regular right-handed superhelix, where the repeats that make up this structure are arranged about a common axis [
]. These superhelical structures present an extensive solvent-accessible surface that is well suited to binding large substrates such as proteins and nucleic acids.The sequence similarity among these different repeats or domains is low, however they exhibit considerable structural similarity. Furthermore, the number of repeats present in the superhelical structure can vary between orthologues, indicating that rapid loss/gain of repeats has occurred frequently in evolution. A common phylogenetic origin has been proposed for the armadillo and HEAT repeats [
].
UBA domains are a commonly occurring sequence motif of approximately 45 amino acid residues that are found in diverse proteins involved in the ubiquitin/proteasome pathway, DNA excision-repair, and cell signalling via protein kinases [
]. HHR23A, the human homologue of yeast Rad23A is a nucleotide excision-repair protein that contains both an internal and a C-terminal UBA domain. The fold of the UBA domain consists of a compact three-helical bundle with a right-handed twist, and have a conserved hydrophobic surface patch for protein-protein interactions. UBA-like domains can be found in other proteins as well, such as the TS-N domain in the elongation factor Ts (EF-Ts), which catalyses the recycling of the GTPase EF-Tu required for the binding of aminoacyl-tRNA top the ribosomal A site []; and the C-terminal domain of TAP/NXF1, which functions in nuclear export through the interaction of its UBA-like domain with FG nucleoporins [].
This family includes ribosomal RNA large subunit methyltransferase F (RlmF), and related proteins, including methyltransferase-like protein 16 (METTL16). METTL16 is a conserved RNA methyltransferase which interacts specifically with the MALAT1 triple helix. METTL16 shows nuclear localisation [
]. Another functional study indicates that METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Furthermore, results indicate that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal small nuclear RNA (snRNA) and it has evolved an additional function in vertebrates to control SAM homeostasis by post-transcriptionally regulating SAM synthetase gene expression [].RlmF methylates the adenine in position 1618 of 23S rRNA [
]. This family also includes psilocybin synthase (PsiM), which is a methyltransferase involved in the biosynthesis of the psychotropic agent psilocybin from the mushroom Psilocybe cubensis [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].
The Eyes absent proteins are members of a conserved regulatory network implicated in the development of the eye, muscle, kidney and ear. Eyes absent is a nuclear transcription factor, acting through interaction with
homeodomain-containing Sine oculis (also known as Six) proteins. Eyes absent is also a protein tyrosine phosphatase [,
], It does not resemble theclassical tyrosine phosphatases that use cysteine as a nucleophile and proceed by means of a thiol-phosphate intermediate. Rather, Eyes absent is the prototype for
a class of protein tyrosine phosphatases that use a nucleophilic aspartic acid in a metal-dependent reaction. Furthermore, the phosphatase activity of Eyes absentcontributes to its ability to induce eye formation in drosophila. Thus, Eyes absent belongs to the
phosphatase subgroup of the haloacid dehalogenase (HAD) superfamily and appears to act as a nuclear transcriptional coactivator with intrinsic phosphatase activity.The Eyes absent proteins contain a divergent 200-300 residue long N-terminal region and a conserved C-terminal domain of approximately 270 residues, the EYA domain, which is critical for activity and believed to participate in protein-protein interactions [
].
The haloacid dehydrogenase (HAD) superfamily includes phosphatases, phosphonatases, P-type ATPases, beta-phosphoglucomutases, phosphomannomutases, and dehalogenases, which are involved in a variety of cellular processes ranging from amino acid biosynthesis to detoxification[
].Crystal structures of proteins from the HAD superfamily show that these proteins all share a conserved alpha/beta-domain classified as a hydrolase fold, which is similar to the Rossmann fold [
]. This conserved domain usually contains an insertion (sub)domain. For example, the crystal structure of a phosphoglycolate phosphatase from Thermoplasma acidophilum [] revealed two distinct domains, a larger core domain and a smaller cap domain. The large domain is composed of a centrally located five-stranded parallel β-sheet with strand order S10, S9, S8, S1, S2 and a small β-hairpin, strands S3 and S4. This central sheet is flanked by a set of three α-helices on one side and two helices on the other. The topology of the large domain is conserved; however, structural variation is observed in the smaller domain among the different functional classes of the haloacid dehalogenase superfamily.
Members of the eye absent (EYA) family were originally characterised in fly eye development. EYA proteins are both transcriptional activators and tyrosine phosphatases [
,
], and have been shown to dephosphorylate H2AX, promoting repair and cell survival in the response to DNA damage []. EYA proteins (EYA1-4) are normally expressed early in development [
,
]. Their phosphatase activity regulates Six1-Dach-Eya transcriptional effects in precursor cell proliferation and survival in mammalian organogenesis [].
This entry represents an malate transporter which has been is identified as being critical for aluminium tolerance in Arabidopsis thaliana [
,
,
,
]. Some family members have been reported to permeable to chloride, nitrate, sulphate and malate [,
,
,
].
In budding yeast (Saccharomyces cerevisiae), SUI1 is a translation initiation
factor that functions in concert with eIF-2 and the initiator tRNA-Met indirecting the ribosome to the proper start site of translation [
]. SUI1 is a protein of 108 residues. Close homologues of SUI1 have been found [] in mammals, insects and plants. SUI1 is also evolutionary related to:Hypothetical proteins from bacteria such as Escherichia coli (yciH) or
Haemophilus influenzae (HI1225).Hypothetical proteins from archaea such as Methanococcus jannaschii
(MJ0463).Two eukaryotic proteins also seem to contain a C-terminal SUI1-like domain.
These are:Density-regulated protein (gene: DENR). This protein is found in mammals,
insects, nematodes, plants and fungi.Ligatin (gene: LGTN). This protein is found in mammals and insects.
eIF1/SUI1 (eukaryotic initiation factor 1) plays an important role in accurate initiator codon recognition during translation initiation. eIF1 interacts with 18S rRNA in the 40S ribosomal subunit during eukaryotic translation initiation. Point mutations in the yeast eIF1 implicate the protein in maintaining accurate start-site selection but its mechanism of action is unknown [
].Cells have evolved elaborate mechanisms to rid themselves of aberrant proteins and transcripts. The nonsense-mediated mRNA decay pathway (NMD) is an example of a pathway that eliminates aberrant mRNAs. In addition to its role in recognition of the AUG codon during translation initiation and maintenance of the appropriate reading frame during translation elongation by directing the ribosome to the proper start site of translation by functioning in concert with eIF-2 and the initiator tRNA-Met, the SUI1 protein plays a role in the NMD pathway [].
This domain is found in the N-terminal of various SNARE proteins, adopt a structure consisting of an antiparallel three-helix bundle. Its exact function has not been determined, though it is known that it regulates the SNARE motif, as well as mediate various protein-protein interactions involved in membrane-transport [].
The process of vesicular fusion with target membranes depends on a set of SNAREs (SNAP-Receptors), which are associated with the fusing membranes [
,
]. These proteins are classified as v-SNAREs and t-SNAREs based on their localisation on vesicle or target membrane while another classification scheme defines R-SNAREs and Q-SNAREs, as based on the conserved arginine or glutamine residue in the centre of the SNARE motif []. Target SNAREs (t-SNAREs) are localised on the target membrane and belong to two different families, the syntaxin-like family and the SNAP-25 like family. One member of each family, together with a v-SNARE localised on the vesicular membrane, are required for fusion.The N- and C-terminal coiled-coil domains of members of the SNAP-25 family and the most C-terminal coiled-coil domain of the syntaxin family are related to each other and form a new homology domain of approximately 60 amino acids. This domain is also found in other known proteins involved in vesicular membrane traffic, some of which belong to different protein families [
].
Soluble N-ethylmaleimide attachment protein receptor (SNARE) proteins are a family of membrane-associated proteins characterised by an α-helical coiled-coil domain called the SNARE motif [
]. These proteins are classified as v-SNAREs and t-SNAREs based on their localisation on vesicle or target membrane; another classification scheme defines R-SNAREs and Q-SNAREs, as based on the conserved arginine or glutamine residue in the centre of the SNARE motif. SNAREs are localised to distinct membrane compartments of the secretory and endocytic trafficking pathways, and contribute to the specificity of intracellular membrane fusion processes.The t-SNARE domain consists of a 4-helical bundle with a coiled-coil twist. The SNARE motif contributes to the fusion of two membranes. SNARE motifs fall into four classes: homologues of syntaxin 1a (t-SNARE), VAMP-2 (v-SNARE), and the N- and C-terminal SNARE motifs of SNAP-25. It is thought that one member from each class interacts to form a SNARE complex.The SNARE motif represented in this entry is found in the N-terminal domains of certain syntaxin family members: syntaxin 1a, which is required for neurotransmitter release[
], syntaxin 6, which is found in endosomal transport vesicles [], yeast Sso1p [], and Vam3p, a yeast syntaxin essential for vacuolar fusion []. The SNARE motifs in these proteins share structural similarity, despite having a low level of sequence similarity.
NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [].This entry includes the NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 (NDUFA12) and the NADH dehydrogenase [ubiquinone]1 alpha subcomplex assembly factor 2 (NDUFAF2). NDUFA12 is an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) [
,
]. NDUFA12 is believed not to be involved in catalysis []. NDUFAF2 is a paralogue of the structural subunit NDUFA12 and functions as an assembly factor [].
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.F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (
) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis [
]. These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.The ATPase F1 complex gamma subunit forms the central shaft that connects the F0 rotary motor to the F1 catalytic core. The gamma subunit functions as a rotary motor inside the cylinder formed by the alpha(3)beta(3) subunits in the F1 complex [
]. The best-conserved region of the gamma subunit is its C terminus, which seems to be essential for assembly and catalysis.
ATP synthase, F1 complex, gamma subunit conserved site
Type:
Conserved_site
Description:
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.F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (
) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis [
]. These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.The ATPase F1 complex gamma subunit forms the central shaft that connects the F0 rotary motor to the F1 catalytic core. The gamma subunit functions as a rotary motor inside the cylinder formed by the alpha(3)beta(3) subunits in the F1 complex [
]. The best-conserved region of the gamma subunit is its C terminus, which seems to be essential for assembly and catalysis.
Proteins in this family include AtS40-3 (At4g18980) from Arabidopsis thaliana and HvS40 from barley. HvS40 plays a role in regulation of leaf senescence [
,
]. AtS40-3 is induced during senescence and is also regulated in response to dark treatment, ABA, salicylicacid and pathogen attack [
].
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [
,
,
,
,
]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. This model describes a putative zinc finger domain found in three closely spaced copies in Arabidopsis protein LSD1 and in two copies in other proteins from the same species. The motif resembles CxxCRxxLMYxxGASxVxCxxC [
]. This domain may play a role in the regulation of transcription, via either repression of a prodeath pathway or activation of an antideath pathway, in response to signals emanating from cells undergoingpathogen-induced hypersensitive cell death.
Microbial pectin and pectate lyases are virulence factors that degrade the pectic components of the plant cell wall [
]. When the backbone of pectin is methylated it is known as pectin and is cleaved by pectin lyase, and when it is demethylated it is known as pectate and is cleaved by pectate lyase. Pectin lyase from Aspergillus niger displays a single-stranded, right-handed parallel β-helix topology (), where each coil contains three β-strands and three turn regions. Several other virulence factors share this β-helix topology, although they vary in the number of coils, including bacterial pectate lyases, fungal and bacterial galacturonases (such as rhamnogalacturonase and polygalacturonase), chrondroitinase B from Flavobacterium sp., iota-carrageenase from Alteromonas sp., pectin methylesterase (PemA), P22 tailspike protein from Enterobacteria phage P22, and the virulence factor P.69 pertactin from Bordetella pertussis that mediates adhesion to target mammalian cells [
].
This entry covers proteins that are closely related to the pectolytic enzyme, pectin lyase, which act as virulence factors. These proteins include pectate lyase, iota-carrageenase, and glycoside hydrolases from family 28 (such as galacturonases). Pectin lyases, pectate lyases and galacturonases all act on forms of pectin, one of the main components of the cell wall. When the backbone of pectin is methylated it is known as pectin, and can be cleaved by pectin lyase, a microbial virulence factor [
]. When the backbone of pectin is demethylated it is known as pectate, and can be cleaved by pectate lyase virulence factors, or hydrolysed by polygalacturonases [,
]. Iota-carrageenase is an enzyme that degrades carrageenan, a main component of the cell walls of various marine red algae. Unlike other carrageenase enzymes, iota-carrageenase belongs to the glycoside hydrolase structural family []. All these enzymes display a β-helical structure.
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 28
comprises enzymes with several known activities; polygalacturonase (
); exo-polygalacturonase (
); exo-polygalacturonase (); rhamnogalacturonase (EC not defined).
Polygalacturonase (PG) (pectinase) [
,
] catalyses the random hydrolysis of 1,4-alpha-D-galactosiduronic linkages in pectate and other galacturonans. In fruit, polygalacturonase plays an important role in cell wall metabolism during ripening. In plant bacterial pathogens such as Erwinia carotovora or Ralstonia solanacearum (Pseudomonas solanacearum) and fungal pathogens such as Aspergillus niger, polygalacturonase is involved in maceration and soft-rotting of plant tissue. Exo-poly-alpha-D-galacturonosidase () (exoPG) [
] hydrolyses peptic acid from the non-reducing end, releasing digalacturonate. PG and exoPG share a few regions of sequence similarity, and belong to family 28 of the glycosyl hydrolases.
The tertiary structures of pectate lyases and
rhamnogalacturonase A show a stack of parallel β-strands that are coiled into a large helix. Each coil of the helix representsa structural repeat that, in
some homologues, can be recognised from sequence information alone.Conservation of
asparagines might be connected with asparagine-ladders that contribute to thestability of the fold.
Proteins containing these repeats most often are enzymes with polysaccharidesubstrates [
].
This entry represents the C-terminal domain of 1-Cys peroxiredoxin, a member of the peroxiredoxin superfamily which protect cells against membrane oxidation through glutathione (GSH)-dependent reduction of phospholipid hydroperoxides to corresponding alcohols [
]. The C-terminal domain is crucial for providing the extra cysteine necessary for dimerisation of the whole molecule. Loss of the enzyme's peroxidase activity is associated with oxidation of the catalytic cysteine found upstream of this domain. Glutathionylation, presumably through its disruption of protein structure, facilitates access for GSH, resulting in spontaneous reduction of the mixed disulphide to the sulphydryl and consequent activation of the enzyme []. The domain is associated with , which carries the catalytic cysteine.
Alkyl hydroperoxide reductase subunit C/ Thiol specific antioxidant
Type:
Domain
Description:
Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels which mediate signal transduction in mammalian cells. Prxs can be regulated by changes to phosphorylation, redox and possibly oligomerisation states. Prxs are divided into three classes: typical 2-Cys Prxs; atypical 2-Cys Prxs; and 1-Cys Prxs. All Prxs share the same basic catalytic mechanism, in which an active-site cysteine (the peroxidatic cysteine) is oxidised to a sulphenic acid by the peroxide substrate. The recycling of the sulphenic acid back to a thiol is what distinguishes the three enzyme classes. Using crystal structures, a detailed catalytic cycle has been derived for typical 2-Cys Prxs, including a model for the redox-regulated oligomeric state proposed to control enzyme activity [
].Alkyl hydroperoxide reductase (Ahp) has two subunits, the small AhpC subunit and the large AhpF subunit [
]. AhpC is responsible for directly reducing organic hydroperoxides in its reduced dithiol form. Thiol specific antioxidant (TSA) is a physiologically important antioxidant which constitutes an enzymatic defence against sulphur-containing radicals and protects the cell against the oxidative stress caused by protein misfolding and aggregation []. This entry contains AhpC and TSA, as well as related proteins.
Peroxiredoxins are a family of ubiquitous proteins found in all kingdoms of life. They
are important for antioxidant defence and, in eukaryotes, participate in redox signalling [].This family includes alkyl hydroperoxide reductase subunit C (AphC) from bacteria [
], and peroxiredoxins 1 (PRDX1), 2 (PRDX2), 4 (PRDX4) and 6 (PRDX6).
The LysM (lysin motif) domain is a small globular domain, approximately 40 amino acids long. It is a widespread protein module involved in binding peptidoglycan in bacteria and chitin in eukaryotes. The domain was originally identified in enzymes that degrade bacterial cell walls [
], but proteins involved in many other biological functions also contain this domain. It has been reported that the LysM domain functions as a signal for specific plant-bacteria recognition in bacterial pathogenesis []. Many of these enzymes are modular and are composed of catalytic units linked to one or several repeats of LysM domains. LysM domains are found in bacteria and eukaryotes [].
This domain is found in diverse proteins homologous to inositol monophosphatase [
]. These proteins are Mg
2+-dependent/Li
+-sensitive phosphatases that catalyse a variety of reactions.
The major intrinsic protein (MIP) family is large and diverse, possessing over 100 members that form transmembrane channels. These channel proteins function in water, small carbohydrate (e.g., glycerol), urea, NH3, CO2 and possibly ion transport, by an energy independent mechanism. They are found ubiquitously in bacteria, archaea and eukaryotes.The MIP family contains two major groups of channels: aquaporins and glycerol facilitators. The known aquaporins cluster loosely together as do the known glycerol facilitators. MIP family proteins are believed to form aqueous pores that selectively allow passive transport of their solute(s) across the membrane with minimal apparent recognition. Aquaporins selectively transport water (but not glycerol) while glycerol facilitators selectively transport glycerol but not water. Some aquaporins can transport NH3 and CO2. Glycerol facilitators function as solute nonspecific channels, and may transport glycerol, dihydroxyacetone, propanediol, urea and other small neutral molecules in physiologically important processes. Some members of the family, including the yeast FPS protein and tobacco NtTIPA may transport both water and small solutes. The structures of various members of the MIP family have been determined by means of X-ray diffraction [
,
,
], revealing the fold to comprise a right-handed bundle of 6 transmembrane (TM) α-helices [,
,
]. Similarities in the N-and C-terminal halves of the molecule suggest that the proteins may have arisen through tandem, intragenic duplication of an ancestral protein that contained 3 TM domains [].
The major intrinsic protein (MIP) family is large and diverse, possessing over 100 members that form transmembrane channels. These channel proteins function in water, small carbohydrate (e.g., glycerol), urea, NH3, CO2 and possibly ion transport, by an energy independent mechanism. They are found ubiquitously in bacteria, archaea and eukaryotes.The MIP family contains two major groups of channels: aquaporins and glycerol facilitators. The known aquaporins cluster loosely together as do the known glycerol facilitators. MIP family proteins are believed to form aqueous pores that selectively allow passive transport of their solute(s) across the membrane with minimal apparent recognition. Aquaporins selectively transport water (but not glycerol) while glycerol facilitators selectively transport glycerol but not water. Some aquaporins can transport NH3 and CO2. Glycerol facilitators function as solute nonspecific channels, and may transport glycerol, dihydroxyacetone, propanediol, urea and other small neutral molecules in physiologically important processes. Some members of the family, including the yeast FPS protein and tobacco NtTIPA may transport both water and small solutes. The structures of various members of the MIP family have been determined by means of X-ray diffraction [
,
,
], revealing the fold to comprise a right-handed bundle of 6 transmembrane (TM) α-helices [,
,
]. Similarities in the N-and C-terminal halves of the molecule suggest that the proteins may have arisen through tandem, intragenic duplication of an ancestral protein that contained 3 TM domains []. This superfamily represents the aquaporin-like structural domain.
The major intrinsic protein (MIP) family is large and diverse, possessing over 100 members that form transmembrane channels. These channel proteins function in water, small carbohydrate (e.g., glycerol), urea, NH3, CO2 and possibly ion transport, by an energy independent mechanism. They are found ubiquitously in bacteria, archaea and eukaryotes.The MIP family contains two major groups of channels: aquaporins and glycerol facilitators. The known aquaporins cluster loosely together as do the known glycerol facilitators. MIP family proteins are believed to form aqueous pores that selectively allow passive transport of their solute(s) across the membrane with minimal apparent recognition. Aquaporins selectively transport water (but not glycerol) while glycerol facilitators selectively transport glycerol but not water. Some aquaporins can transport NH3 and CO2. Glycerol facilitators function as solute nonspecific channels, and may transport glycerol, dihydroxyacetone, propanediol, urea and other small neutral molecules in physiologically important processes. Some members of the family, including the yeast FPS protein and tobacco NtTIPA may transport both water and small solutes. The structures of various members of the MIP family have been determined by means of X-ray diffraction [
,
,
], revealing the fold to comprise a right-handed bundle of 6 transmembrane (TM) α-helices [,
,
]. Similarities in the N-and C-terminal halves of the molecule suggest that the proteins may have arisen through tandem, intragenic duplication of an ancestral protein that contained 3 TM domains []. This entry represents a conserved region which is located in the cytoplasmic loop between the second and third transmembrane regions of MIP family members.
A variety of substrate carrier proteins that are involved in energy transfer are found in the inner mitochondrial membrane [
,
,
,
,
]. Such proteins include: ADP/ATP carrier protein (ADP/ATP translocase); 2-oxoglutarate/malate carrier protein; phosphate carrier protein; tricarboxylate transport protein (or citrate transport protein); Solute carrier family 25 member 16 (also known as Graves disease carrier protein); yeast mitochondrial proteins MRS3 and MRS4; yeast mitochondrial FAD carrier protein; and many others. This family also includes peroxisomal proteins like PMP34 [].Sequence analysis of selected members of the carrier protein family has suggested the presence of six transmembrane (TM) domains, with varying
degrees of sequence conservation and hydrophilicity []. The TM regions, and adjacent hydrophilic loops, are more highly conserved than other regions of the proteins []. All members of the family appear to consist of a tripartite structure, each of the repeated segments being about 100 residues in length []. Each repeat contains two TM domains, the first being more hydrophobic, with conserved glycyl and prolyl residues. Five of the six TM domains are followed by the conserved sequence (D/E)-Hy(K/R), where - denotes any residue and Hy is a hydrophobic position [].
This superfamily represents a structural domain found in mitochondrial carrier proteins. Six α-helices form a compact transmembrane domain, which, at the surface towards the space between inner and outer mitochondrial membranes, reveals a deep depression. The structure suggests that transport substrates bind to the bottom of the cavity and that translocation results from a transition from a 'pit' to a 'channel' conformation [
].
A variety of substrate carrier proteins that are involved in energy transfer are found in the inner mitochondrial membrane or integral to the membrane of other eukaryotic organelles such as the peroxisome [
,
,
,
,
]. Such proteins include: ADP, ATP carrier protein (ADP/ATP translocase); 2-oxoglutarate/malate carrier protein; phosphate carrier protein; tricarboxylate transport protein (or citrate transport protein); Graves disease carrier protein; yeast mitochondrial proteins MRS3 and MRS4; yeast mitochondrial FAD carrier protein; and many others. Structurally, these proteins can consist of up to three tandem repeats of a domain of approximately 100 residues, each domain containing two transmembrane regions.
Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are [
,
]:Pseudouridine synthase I, TruA.Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.This superfamily represents the Pseudouridine synthase I (TruA) N-terminal domain.TruA from Escherichia coli modifies positions uracil-38, U-39 and/or U-40 in tRNA [
,
]. TruA contains one atom of zinc essential for its native conformation and tRNA recognition and has a strictly conserved aspartic acid that is likely to be involved in catalysis []. These enzymes are dimeric proteins that contain two positively charged, RNA-binding clefts along their surface. Each cleft contains a highly conserved aspartic acid located at its centre. The structural domains have a topological similarity to those of other RNA-binding proteins, though the mode of interaction with tRNA appears to be unique. This entry also includes the N-terminal domain of several different pseudouridine synthases from family 3, including: RsuA (acts on small ribosomal subunit), RluB, RluE and RluF (act on large ribosomal subunit).RsuA from Escherichia coli catalyses formation of pseudouridine at position 516 in 16S rRNA during assembly of the 30S ribosomal subunit [
,
]. RsuA consists of an N-terminal domain connected by an extended linker to the central and C-terminal domains. Uracil and UMP bind in a cleft between the central and C-terminal domains near the catalytic residue Asp 102. The N-terminal domain shows structural similarity to the ribosomal protein S4. Despite only 15% amino acid identity, the other two domains are structurally similar to those of the tRNA-specific psi-synthase TruA, including the position of the catalytic Asp. All four families of pseudouridine synthases share the same fold of their catalytic domain(s) and uracil-binding site.RluB, RluE and RluF are homologous enzymes which each convert specific uridine bases in E. coli ribosomal 23S RNA to pseudouridine:RluB modifies uracil-2605.RluE modifies uracil-3457.RluF modifies uracil-2604 and to a lesser extent U-2605.
Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are [
,
]:Pseudouridine synthase I, TruA.Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.This entry represents pseudouridine synthase I (TruA) from prokaryotes and tRNA pseudouridine synthase 1 (Pus1) from eukaryotes, which belongs to the TruA family. TruA from Escherichia coli modifies positions uracil-38, U-39 and/or U-40 in tRNA [
,
]. TruA contains one atom of zinc essential for its native conformation and tRNA recognition and has a strictly conserved aspartic acid that is likely to be involved in catalysis []. This protein adopts a dimeric assembly and shows two positively charged, RNA-binding clefts along their surface. Each cleft contains a highly conserved aspartic acid located at its centre. The structural domains have a topological similarity to those of other RNA-binding proteins, though the mode of interaction with tRNA appears to be unique. Pus1 from Saccharomyces cerevisiae acts at positions 27 and 28 of tRNAs, at positions 34 and 36 of intron-containing precursor tRNA(Ile), at position 35 in the intron-containing tRNA(Tyr) and at position 44 in U2 snRNA [,
,
]. This enzyme also catalyses pseudouridylation of mRNAs [].
Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are [
,
]:Pseudouridine synthase I, TruA.Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.This superfamily represents the Pseudouridine synthase I (TruA) C-terminal domain.TruA from Escherichia coli modifies positions uracil-38, U-39 and/or U-40 in tRNA [
,
]. TruA contains one atom of zinc essential for its native conformation and tRNA recognition and has a strictly conserved aspartic acid that is likely to be involved in catalysis []. These enzymes are dimeric proteins that contain two positively charged, RNA-binding clefts along their surface. Each cleft contains a highly conserved aspartic acid located at its centre. The structural domains have a topological similarity to those of other RNA-binding proteins, though the mode of interaction with tRNA appears to be unique.
Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are [
,
]:Pseudouridine synthase I, TruA.Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.This entry represents pseudouridine synthase I (TruA) α/β domain.TruA from Escherichia coli modifies positions uracil-38, U-39 and/or U-40 in tRNA [
,
]. TruA contains one atom of zinc essential for its native conformation and tRNA recognition and has a strictly conserved aspartic acid that is likely to be involved in catalysis []. These enzymes are dimeric proteins that contain two positively charged, RNA-binding clefts along their surface. Each cleft contains a highly conserved aspartic acid located at its centre. The structural domains have a topological similarity to those of other RNA-binding proteins, though the mode of interaction with tRNA appears to be unique.
Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are [
,
]:Pseudouridine synthase I, TruA.Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.TruA from Escherichia coli modifies positions U-38, U-39 and/or U-40 in tRNA [
,
]. TruA contains one atom of zinc essential for its native conformation and tRNA recognition and has a strictly conserved aspartic acid that is likely to be involved in catalysis []. These enzymes are dimeric proteins that contain two positively charged, RNA-binding clefts along their surface. Each cleft contains a highly conserved aspartic acid located at its centre. The structural domains have a topological similarity to those of other RNA-binding proteins, though the mode of interaction with tRNA appears to be unique.
TruB is responsible for the pseudouridine residue present in the T loops of virtually all tRNAs. TruB recognises the preformed 3-D structure of the T loop primarily through shape complementarity. It accesses its substrate uridyl residue by flipping out the nucleotide and disrupts the tertiary structure of tRNA [
].RsuA from E. coli catalyses formation of pseudouridine at position U-516 in 16S rRNA during assembly of the 30S ribosomal subunit [
]. RsuA consists of an N-terminal domain connected by an extended linker to the central and C-terminal domains. Uracil and UMP bind in a cleft between the central and C-terminal domains near the catalytic residue Asp 102. The N-terminal domain shows structural similarity to the ribosomal protein S4. Despite only 15% amino acid identity, the other two domains are structurally similar to those of the tRNA-specific psi-synthase TruA, including the position of the catalytic Asp. Our results suggest that all four families of pseudouridine synthases share the same fold of their catalytic domain(s) and uracil-binding site.RluC and RluD are homologous enzymes which each convert three specific uridine bases in E. coli ribosomal 23S RNA to pseudouridine: bases U-955, U-2504, and U-2580 in the case of RluC and U-1911, U-1915, and U-1917 in the case of RluD [
]. RluD also possesses a second function related to proper assembly of the 50S ribosomal subunit that is independent of Psi-synthesis []. Both RluC and RluD have an N-terminal S4 RNA binding domain. Despite the conserved topology shared by RluC and RluD, the surface shape and charge distribution are very different. TruD modifies uracil-13 in tRNA, and belongs to a recently identified and large family of pseudouridine synthases present in all kingdoms of life [
]. TruD is an overall V-shaped molecule with an RNA-binding cleft formed between two domains: a catalytic domain and an insertion domain. The catalytic domain has a fold similar to that of the catalytic domains of previously characterised pseudouridine synthases, whereas the insertion domain displays a novel fold.
AAA ATPases (ATPases Associated with diverse cellular Activities) form a large protein family and play a number of roles in the cell including cell-cycle regulation, protein proteolysis and disaggregation, organelle biogenesis and intracellular transport. Some of them function as molecular chaperones, subunits of proteolytic complexes or independent proteases (FtsH, Lon). They also act as DNA helicases and transcription factors [
].AAA ATPases belong to the AAA+ superfamily of ringshaped P-loop NTPases, which act via the energy-dependent unfolding of macromolecules [
,
]. There are six major clades of AAA domains (proteasome subunits, metalloproteases, domains D1 and D2 of ATPases with two AAA domains, the MSP1/katanin/spastin group and BCS1 and it homologues), as well as a number of deeply branching minor clades [].They assemble into oligomeric assemblies (often hexamers) that form a ring-shaped structure with a central pore. These proteins produce a molecular motor that couples ATP binding and hydrolysis to changes in conformational states that act upon a target substrate, either translocating or remodelling it [
].They are found in all living organisms and share the common feature of the presence of a highly conserved AAA domain called the AAA module. This domain is responsible for ATP binding and hydrolysis. It contains 200-250 residues, among them there are two classical motifs, Walker A (GX4GKT) and Walker B (HyDE) [
].The functional variety seen between AAA ATPases is in part due to their extensive number of accessory domains and factors, and to their variable organisation within oligomeric assemblies, in addition to changes in key functional residues within the ATPase domain itself.This entry covers a highly conserved region in the central part of the ATPase domain that is distinct from motifs A and B.
AAA proteases are ATP-dependent metallopeptidases present in eubacteria as well as in organelles of bacterial origin, i.e., mitochondria and chloroplasts. The AAA proteases are also known as FtsH, referring to the Escherichia coli enzyme (Filamentous temperature sensitive H). Most bacteria have a single gene encoding FtsH, three genes are present in yeast and humans, while 12 orthologs have been found in the genome of plants [].E. coil FtsH is a membrane-anchored ATP-dependent protease that degrades misfolded or misassembled membrane proteins as well as a subset of cytoplasmic regulatory proteins. FtsH is a 647-residue protein of 70kDa, with two putative transmembrane segments towards its N terminus which anchor the protein to the membrane, giving rise to a periplasmic domain of 70 residues and a cytoplasmic segment of 520 residues containing the ATPase and protease domains [
].The main function of organellar AAA/FtsH proteases is selective degradation of non-assembled, incompletely assembled and/or damaged membrane-anchored proteins. Additional functions of the AAA/FtsH proteases that are not directly connected with protein quality control are processing of pre-proteins, dislocation of membrane proteins or degradation of regulatory proteins [
,
,
].
Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role.
Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site []. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [].This domain is found in the FtsH family of proteins that include FtsH a membrane-bound ATP-dependent protease universally conserved in prokaryotes [
]. The FtsH peptidases, which belong to MEROPS peptidase family M41 (clan MA(E)), efficiently degrade proteins that have a low thermodynamic stability - e.g. they lack robust unfoldase activity. This feature may be key and implies that this could be a criterion for degrading a protein. In Oenococcus oeni (Leuconostoc oenos) FtsH is involved in protection against environmental stress [], and shows increased expression under heat or osmotic stress. These two lines of evidence suggest that it is a fundamental prokaryotic self-protection mechanism that checks if proteins are correctly folded. The precise function of this N-terminal region is unclear.
Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role.
Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site []. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [
].This group of metallopeptidases belong to MEROPS peptidase family M41 (FtsH endopeptidase family, clan MA(E)). The predicted active site residues for members of this family and thermolysin, the type example for clan MA, occur in the motif HEXXH.The peptidase M41 family belong to a larger family of zinc metalloproteases. This family
includes the cell division protein FtsH, and the yeast mitochondrial respiratory chain complexesassembly protein, which is a putative ATP-dependent protease required for assembly of the
mitochondrial respiratory chain and ATPase complexes. FtsH is an integral membrane protein,which seems to act as an ATP-dependent zinc metallopeptidase that binds one zinc ion.
This family contains UTP--glucose-1-phosphate uridylyltransferases (), UDP-sugar pyrophosphorylases (
), UDP-N-acetylglucosamine pyrophosphorylases (
) and UDP-N-acetylhexosamine pyrophosphorylases, all of which catalyse the transfer of an uridylyl group.
It has been shown that several proteins share two sequence motifs [
]. Two of these proteins, vertebrate and plant inositol monophosphatase (), and vertebrate inositol polyphosphate 1-phosphatase (
), are enzymes of the inositol phosphate second messenger signalling pathway, and share similar enzyme activity. Both enzymes exhibit an absolute requirement for metal ions (Mg2 is preferred), and their amino acid sequences contain a number of conserved motifs, which are also shared by several other proteins related to MPTASE (including products of fungal QaX and qutG, bacterial suhB and cysQ, and yeast hal2) [
]. The function of the other proteins is not yet clear, but it is suggested that they may act by enhancing the synthesis or degradation of phosphorylated messenger molecules []. Structural analysis of these proteins has revealed a common core of 155 residues, which includes residues essential for metal binding and catalysis. An interesting property of the enzymes of this family is their sensitivity to Li+. The targets and mechanism of action of Li+ are unknown, but overactive inositol phosphate signalling may account for symptoms of manic depression [].This entry represents a conserved signature pattern found within the inositol monophosphatase family of proteins. It is suggested [
] that these proteins may act by enhancing the synthesis or degradation of phosphorylated messenger molecules.
Sulphate is incorporated into 3-phosphoadenylylsulphate, PAPS, for utilization in pathways such as methionine biosynthesis. Transfer of sulphate from PAPS to an acceptor leaves adenosine 3'-5'-bisphosphate, APS. In plants these sequences represent a form of the enzyme, 3'(2'),5'-bisphosphate nucleotidase, which removes the 3'-phosphate from APS to regenerate AMP and help drive the cycle. Sensitivity of this essential enzyme to sodium and other metal ions results is responsible for characterisation of this enzyme as a salt tolerance protein [
]. Some members of this family are active also as inositol 1-monophosphatase.
It has been shown that several proteins share two sequence motifs [
]. Two of these proteins, vertebrate and plant inositol monophosphatase (), and vertebrate inositol polyphosphate 1-phosphatase (
), are enzymes of the inositol phosphate second messenger signalling pathway, and share similar enzyme activity. Both enzymes exhibit an absolute requirement for metal ions (Mg2 is preferred), and their amino acid sequences contain a number of conserved motifs, which are also shared by several other proteins related to MPTASE (including products of fungal QaX and qutG, bacterial suhB and cysQ, and yeast hal2) [
]. The function of the other proteins is not yet clear, but it is suggested that they may act by enhancing the synthesis or degradation of phosphorylated messenger molecules []. Structural analysis of these proteins has revealed a common core of 155 residues, which includes residues essential for metal binding and catalysis. An interesting property of the enzymes of this family is their sensitivity to Li+. The targets and mechanism of action of Li+ are unknown, but overactive inositol phosphate signalling may account for symptoms of manic depression [].This entry represents the metal-binding site found within the inositol monophosphatase family of proteins. It is suggested [
] that these proteins may act by enhancing the synthesis or degradation of phosphorylated messenger molecules. The signature pattern of this entry contains the aspartic and threonine residues involved in binding a metal ion [].
It has been shown that several proteins share two sequence motifs [
]. Two of these proteins, vertebrate and plant inositol monophosphatase (), and vertebrate inositol polyphosphate 1-phosphatase (
), are enzymes of the inositol phosphate second messenger signalling pathway, and share similar enzyme activity. Both enzymes exhibit an absolute requirement for metal ions (Mg2 is preferred), and their amino acid sequences contain a number of conserved motifs, which are also shared by several other proteins related to MPTASE (including products of fungal QaX and qutG, bacterial suhB and cysQ, and yeast hal2) [
]. The function of the other proteins is not yet clear, but it is suggested that they may act by enhancing the synthesis or degradation of phosphorylated messenger molecules []. Structural analysis of these proteins has revealed a common core of 155 residues, which includes residues essential for metal binding and catalysis. An interesting property of the enzymes of this family is their sensitivity to Li+. The targets and mechanism of action of Li+ are unknown, but overactive inositol phosphate signalling may account for symptoms of manic depression [].
The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) and thereby restricts its growth. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha and beta. Neither of the subunits shows sequence similarity to other filament-capping proteins [
].This entry represents the beta subunit (CAPZB), which is a protein of about 280 amino acid residues whose sequence is well conserved in eukaryotic species [
]. In Drosophila mutations in the alpha and beta subunits cause actin accumulation and subsequent retinal degeneration []. In humans CAPZB is part of the WASH complex that controls the fission of endosomes [].
F-actin capping protein, beta subunit, conserved site
Type:
Conserved_site
Description:
The actin filament system, a prominent part of the cytoskeleton in eukaryotic cells, is both a static structure and a dynamic network that can undergo rearrangements: it is thought to be involved in processes such as cell movement and phagocytosis [
], as well as muscle contraction.The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike gelsolin (see
) and severin this protein does not sever actin filaments. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha and beta. Neither of the subunits shows sequence similarity to other filament-capping proteins [
].The beta-subunit is a protein of about 280 amino acid residues whose sequence is well conserved in eukaryotic species [
]. The signature pattern in this entry is a conserved hexapeptide in the N-terminal region of the beta-subunit.
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 [
].Ubiquitin is a globular protein, the last four C-terminal residues (Leu-Arg-Gly-Gly) extending from the compact structure to form a 'tail', important for its function. The latter is mediated by the covalent conjugation of ubiquitin to target proteins, by an isopeptide linkage between the C-terminal glycine and the epsilon amino group of lysine residues in the target proteins.Ubiquitin is expressed as three different precursors: a polymeric head-to-tail concatemer of identical units (polyubiquitin), and two N-terminal ubiquitin moieties, UbL40 and UbS27, that are fused to the ribosomal polypeptides L40 and S27, respectively. Specific endopeptidases cleave these precursor molecules [
] to release ubiquitin moieties that are identical in sequence and contribute to the ubiquitin pool []. Some organisms express additional ubiquitin fusion proteins []. Furthermore, there are several ubiquitin-like proteins derived from ubiquitin [].This entry represents a domain characteristic of ubiquitin (Ub) and ubiquitin-like (Ubl) proteins such as SUMO [
,
] and Nedd8 [].
This domain of approximately 75 residues contains a highly conserved SATSv/iFN motif. The function is unknown but the domain is conserved from plants to humans.
Bromodomains are found in a variety of mammalian, invertebrate and yeast DNA-binding proteins [
]. Bromodomains are highly conserved α-helical motifs that can specifically interact with acetylated lysine residues on histone tails [,
]. In some proteins, the classical bromodomain has diverged to such an extent that parts of the region are either missing or contain an insertion (e.g., mammalian protein HRX, Caenorhabditis elegans hypothetical protein ZK783.4, yeast protein YTA7). The bromodomain may occur as a single copy, or in duplicate.This domain is present in proteins involved in a wide range of functions such as acetylating histones, remodeling chromatin, and recruiting other factors necessary for transcription, thus playing a critical role in the regulation of transcription [
].
Bromodomains are found in a variety of mammalian, invertebrate and yeast DNA-binding proteins [
]. Bromodomains are highly conserved α-helical motifs that can specifically interact with acetylated lysine residues on histone tails [,
]. In some proteins, the classical bromodomain has diverged to such an extent that parts of the region are either missing or contain an insertion (e.g., mammalian protein HRX, Caenorhabditis elegans hypothetical protein ZK783.4, yeast protein YTA7). The bromodomain may occur as a single copy, or in duplicate.This domain is present in proteins involved in a wide range of functions such as acetylating histones, remodeling chromatin, and recruiting other factors necessary for transcription, thus playing a critical role in the regulation of transcription [
].
The proton-dependent oligopeptide transporter (POT) family (also known as the peptide transport (PTR) family) is made up of a group of energy-dependent transporters found in organisms as diverse as bacteria and humans. The POT family of proteins is distinct from the ABC-type peptide transporters and was uncovered by sequence analyses of peptide transport proteins [
]. They seem to be mainly involved in the intake of small peptides []. However, some family members are nitrate permeases and others are involved in histidine transport [].
Phosphoribosyl pyrophosphate synthetase, conserved site
Type:
Conserved_site
Description:
Phosphoribosyl pyrophosphate synthetase (
) (PRib-PP synthetase) catalyses the formation of PRib-PP from ATP and ribose 5-phosphate. PRib-PP is then used in various biosynthetic pathways, for example
in the formation of purines, pyrimidines, histidine and tryptophan. PRib-PP synthetase requires inorganic phosphate and magnesium ions for its stability and activity. In mammals, three isozymes of PRib-PP synthetase are found, while in yeast there are at least four isozymes. A very conserved region containing two conserved aspartic acid residues as well as a histidine has been suggested to be involved in binding divalent cations [
]. These residues are all potential ligands for a cation such as magnesium.
Ribose-phosphate diphosphokinase, also known as ribose-phosphate pyrophosphokinase (RPPK), or phosphoribosyldiphosphate synthetase (
), catalyses the transfer of an intact diphosphate (PP) group from ATP to ribose-5-phosphate (R-5-P), which results in the formation of AMP and 5-phospho-D-ribosyl--1-diphosphate (PRPP).
PRPP is an essential precursor for purine and pyrimidine nucleotides, both in the de novo synthesis and in the salvage pathway, as well as in the synthesis of pyridine nucleotide coenzymes. The activity of PPPK is highly regulated. Besides competitive inhibition at the substrate binding sites, most RPPKs are regulated in an allosteric manner, in which ADP generally acts as the most potent inhibitor. In some systems, close homologues lacking enzymatic activity exist and perform regulatory functions.
Tetraacyldisaccharide 4'-kinase (LpxK) phosphorylates the 4'-position of a tetraacyldisaccharide 1-phosphate precursor (DS-1-P) of lipid [
]. This enzyme is involved in the synthesis of lipid A portion of the bacterial lipopolysaccharide layer (LPS). It is organised into two α/β/α sandwich domains linked by a two-stranded β-sheet [].
GDSL esterases and lipases are hydrolytic enzymes with multifunctional properties [
]. This new subclass of lipolytic enzymes possesses a distinct GDSL sequence motif different from the GxSxG motif found in many lipases []. Members include; Aeromonas hydrophila lipase, Vibrio mimicus lecithinase, Vibrio parahaemolyticus thermolabile haemolysin, rabbit phospholipase (AdRab-B), and Arabidopsis thaliana anter-specific proline-rich protein. 3D structures of several enzymes of this family revealed several β-strands and α-helices arranged in alternating order and the substrate-binding pocket between the central β-strand and long α-helix appears to be highly flexible [].
This domain is found towards the C terminus of the DEAD-box helicases (
). In these helicases it is apparently always found in association with
. There do seem to be a couple of instances where it occurs by itself - e.g.
. This C-terminal domain of the yeast helicase contains an oligonucleotide/oligosaccharide-binding (OB)-fold which seems to be placed at the entrance of the putative nucleic acid cavity. It also constitutes the binding site for the G-patch-containing domain of Pfa1p. When found on DEAH/RHA helicases, this domain is central to the regulation of the helicase activity through its binding of both RNA and G-patch domain proteins [
,
].
The Smr domain is an around 90-residue domain found in:The C-terminal region of the mutS2 proteins from bacteria and plants.The small mutS related (smr) proteins from bacteria and eukaryotes.These proteins could be involved in mismatch repair (MMR) or/and chromosome
crossing-over and segregation. It has been proposed that the Smr domain actsas a nicking endonuclease [
,
].
Protein phosphatase 2C (PP2C) is one of the four major classes of mammalian serine/threonine specific protein phosphatases (
). PP2C [
] is a monomeric enzyme of about 42kDa, that shows broad substrate specificity and is dependent on divalent cations (mainly manganese and magnesium) for its activity. The exact physiological role is still unclear. Three isozymes are currently known in mammals: PP2C-alpha, -beta and -gamma. In yeast, there are at least four PP2C homologues: phosphatase PTC1 [
] that have weak tyrosine phosphatase activity in addition to its activity on serines, phosphatases PTC2 and PTC3, and hypothetical protein YBR125c. Isozymes of PP2C are also known from Arabidopsis thaliana (Mouse-ear cress) (ABI1, PPH1), Caenorhabditis elegans (FEM-2, F42G9.1, T23F11.1), Leishmania chagasi and
Paramecium tetraurelia. In A. thaliana, the kinase associated protein phosphatase (KAPP)
[] is an enzyme that dephosphorylates the Ser/Thr receptor-like kinase RLK5 and contains a C-terminal PP2C domain.PP2C does not seem to be evolutionary related to the main family of serine/ threonine phosphatases: PP1, PP2A and PP2B. However, it is significantly similar to the catalytic subunit of pyruvate dehydrogenase phosphatase
() (PDPC) [
], which catalyzes dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex. PDPC is a mitochondrial enzyme and, like PP2C, is magnesium-dependent.
Protein phosphatases remove phosphate groups from various proteins that are the key components of a number of signalling pathways in eukaryotes and prokaryotes. Protein phosphatases that dephosphorylate Ser and Thr residues are classified into the phosphoprotein (PPP) and the protein phosphatase Mg2- or Mn2-dependent (PPM) families. The core structure of PPMs is the 300-residue PPM-type phosphatase domain that catalyses the dephosphorylation of phosphoserine- and phosphothreonine-containing protein. The PPM-type phosphatase domain is found as a module in diverse structural contexts and is modulated by targeting and regulatory subunits [
,
,
,
].Some proteins known to contain a PPM-type phosphatase domain are listed below:Bacillus subtilis stage II sporulation protein E (SpoIIE), controls the sporulation by dephosphorylating an anti-transcription factor SpoIIAA, reversing the actions of the SpoIIAB protein kinase in a process that is governed by the ADP/ATP ratio [levdikov].Mycobacterium tuberculosis PP2C-family Ser/Thr phosphatase (PstP).Eucaryotic PP2C, a negative regulator of protein kinase cascades that are activated as a result of stress.Yeast adenylyl cyclase, plays essential roles in regulation of cellular metabolism by catalysing the synthesis of a second messenger, cAMP [
].Mammalian mitochondrial pyruvate dehydrogenase phosphatase 1 (PDP1).Plant kinase-associated protein phosphatase (KAPP), regulates receptor-like kinase (RLK) signalling pathways.Plant absissic acid-insenstive 1 and 2 (ABI1 and ABI2), play a key absissic acid (ABA) signal transduction.The PP2C-type phosphatase domain consists of 10 segments of β-strands and 5 segments of α-helix and comprises a pair of detached subdomains. The first is a small β-sandwich with strand β1 packed against strands β2 and β3; the second is a larger β-sandwich in which a four-stranded β-sheet packs against a three-stranded β-sheet with flanking α-helices [
,
].
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 ribosomal L35A eukaryotic and archaebacterial ribosomal proteins can be grouped on the basis of sequence similarities. One of these families consists of:
Vertebrate L35A.Caenorhabditis elegans L35A (F10E7.7).Saccharomyces cerevisiae L37A/L37B (Rp47).Plant L35A.Pyrococcus woesei L35A homologue [
].These proteins have 87 to 110 amino-acid residues.
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 ribosomal L35A eukaryotic and archaebacterial ribosomal proteins can be grouped on the basis of sequence similarities. One of these families consists of:
Vertebrate L35A.Caenorhabditis elegans L35A (F10E7.7).Saccharomyces cerevisiae L37A/L37B (Rp47).Plant L35A.Pyrococcus woesei L35A homologue [
].These proteins have 87 to 110 amino-acid residues.
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 [
,
].Ribosomal protein, L27 is found in fungi, plants, algae and vertebrates
[,
].The family has a specific signature at the C terminus.
The KOW (Kyprides, Ouzounis, Woese) motif is found in a variety of ribosomal proteins and the bacterial transcription antitermination proteins NusG [
].
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 [,
].Ribosomal protein, L27 is found in fungi, plants, algae and vertebrates
[,
].The family has a specific signature at the C terminus.
This domain superfamily can be found in ribosomal protein L2, where it represents domain 2 and it is also found in other ribosomal proteins and in elongation factor P and translation initiation factor 5A , where it constitutes the N-terminal domain [
].
The fundamental activity of the ribosome is two-fold: to decode the message of the mRNA in the small subunit, and to form a peptide bond between peptidyl-tRNA and aminoacyl-tRNA by a peptidyl transferase activity in the large subunit. Several prokaryotic and eukaryotic proteins that are involved in the translation process contain an SH3-like domain. The structure of the translation protein SH3-like domain is a partly opened beta barrel, where the last strand is interrupted by a 3-10 helical turn. The structure of the RNA-binding C-terminal domain of the Bacillus stearothermophilus (Geobacillus stearothermophilus) ribosomal protein L2 has been shown to adopt the SH3-like barrel topology [
]. The L2 protein is located near the peptidyl transferase centre in the large ribosomal subunit where it may contribute to peptidyl transferase activity, and is involved in the assembly of the 23SrRNA. Likewise, the N-terminal domain of the ubiquitous eukaryotic translation elongation factor 5a (IF5A) protein adopts the SH3-like barrel topology [,
]. IF5A, previously thought to be an initiation factor, is now considered to be involved in translation elongation [] and in cell-cycle regulation. IF5A acts as a cofactor of the Rev protein in HIV-1-infected cells and of the Rex protein in T-cell leukaemia virus 1-infected cells.
Proteins that transport heavy metals in micro-organisms and eukaryotes share similarities in their sequences and structures.These proteins provide an important focus for research, some being involved in bacterial resistance to toxic metals, such as lead and cadmium, while others are involved in inherited human syndromes, such as Wilson's and Menke's diseases [
]. A conserved 30-residue domain has been found in a number of these heavy metal transport or detoxification proteins [
]. The domain, which has been termed Heavy-Metal-Associated (HMA), contains two conserved cysteines that are probably involved in metal binding. This sub-domain is found in copper-binding proteins.
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.P-ATPases (also known as E1-E2 ATPases) ([intenz:3.6.3.-]) are found in bacteria and in a number of eukaryotic plasma membranes and organelles []. P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H+, Na
+, K
+, Mg
2+, Ca
2+, Ag
+and Ag
2+, Zn
2+, Co
2+, Pb
2+, Ni
2+, Cd
2+, Cu
+and Cu
2+. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.
This superfamily represents the actuator (A) domain, and some transmembrane helices found in P-type ATPases [
]. It contains the TGES-loop which is essential for the metal ion binding which results in tight association between the A and P (phosphorylation) domains []. It does not contain the phosphorylation site. It is thought that the large movement of the actuator domain, which is transmitted to the transmembrane helices, is essential to the long distance coupling between formation/decomposition of the acyl phosphate in the cytoplasmic P-domain and the changes in the ion-binding sites buried deep in the membranous region []. This domain has a modulatory effect on the phosphoenzyme processing steps through its nucleotide binding [,
].
Proteins that transport heavy metals in micro-organisms and mammals share similarities in their sequences and structures.These proteins provide an important focus for research, some being involved in bacterial resistance to toxic metals, such as lead and cadmium, while others are involved in inherited human syndromes, such as Wilson's and Menke's diseases [
]. A conserved domain has been found in a number of these heavy metal transport or detoxification proteins [
]. The domain, which has been termed Heavy-Metal-Associated (HMA), contains two conserved cysteines that are probably involved in metal binding.Structure solution of the fourth HMA domain of the Menke's copper transporting ATPase shows a well-defined structure comprising a four-stranded antiparallel β-sheet and two α-helices packed in an α-β sandwich fold [
]. This fold is common to other domains and is classified as "ferredoxin-like".
P-ATPases (also known as E1-E2 ATPases) ([intenz:3.6.3.-]) are found in bacteria and in a number of eukaryotic plasma membranes and organelles []. P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H+, Na
+, K
+, Mg
2+, Ca
2+, Ag
+and Ag
2+, Zn
2+, Co
2+, Pb
2+, Ni
2+, Cd
2+, Cu
+and Cu
2+. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.
This entry represents the copper and cadmium-type heavy metal transporting P-type ATPases, and other related sequences that belong to the IB subfamily of P-type ATPases. Type IB ATPases are involved in transport of the soft Lewis acids: Cu
+, Ag
+, Cu
2+, Zn
2+, Cd
2+, Pb
2+and Co
2+. These proteins are involved in a variety of processes in both prokaryotes and eukaryotes.
In Arabidopsis, the copper-ATPase RAN1 delivers copper to create functional hormone receptors involved in ethylene signalling []. In humans, ATP7A supplies copper to copper-dependent enzymes in the secretory pathway, while ATP7B exports copper out of the cells. Defects in ATP7B are the cause of Wilson disease (WD), an autosomal recessive disorder in which copper cannot be incorporated into ceruloplasmin in liver and cannot be excreted from the liver into the bile []. Defects in ATP7A are the cause of Menkes disease (MNKD), also known as kinky hair disease. MNKD is an X-linked recessive disorder of copper metabolism characterised by generalised copper deficiency [].
This entry represents the several classes of P-type ATPases, including those that transport K
+(
), Mg
2+(
), Cd
2+(
), Cu
2+(
),
Zn2+(
), Na
+(
), Ca
2+(
), Na
+/K
+(
), and H
+/K
+(
). These P-ATPases are found in both prokaryotes and eukaryotes [
]. They are cation transport ATPases which form an aspartyl phosphate intermediate in the course of ATP hydrolysis. The region around the phosphorylated aspartate residue is perfectly conserved in all these ATPases and it is represented by this entry.
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.P-ATPases (also known as E1-E2 ATPases) ([intenz:3.6.3.-]) are found in bacteria and in a number of eukaryotic plasma membranes and organelles []. P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H+, Na
+, K
+, Mg
2+, Ca
2+, Ag
+and Ag
2+, Zn
2+, Co
2+, Pb
2+, Ni
2+, Cd
2+, Cu
+and Cu
2+. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.
This entry represents the P-type ATPases. These P-ATPases are found in both prokaryotes and eukaryotes.
P-ATPases (also known as E1-E2 ATPases) ([intenz:3.6.3.-]) are found in bacteria and in a number of eukaryotic plasma membranes and organelles []. P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H+, Na
+, K
+, Mg
2+, Ca
2+, Ag
+and Ag
2+, Zn
2+, Co
2+, Pb
2+, Ni
2+, Cd
2+, Cu
+and Cu
2+. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.
This superfamily represents the cytoplasmic domain N found in P-type ATPases. The cytoplasmic loops of the P-type ATPases form three separate modules, commonly named the A, P and N-domains [
,
. The N-domain comprises the nucleotide binding site [
]. This domain forms a seven-stranded antiparallel β-sheet with two additional β-strands forming a hairpin and five α-helices [].
