This entry represents a PHP-like (Polymerase and Histidinol Phosphatase) domain, the catalytic site of which has four motifs with conserved histidine residues. This domain has a 7-stranded β/α barrel fold; this structure shows some similarity to the TIM-barrel fold metallohydrolases. PHP-like domains are found in alpha-subunit of bacterial DNA polymerase III (
) and family X DNA polymerases in addition to histidinol phosphatase (
) [
]. Proteins carrying a distorted (α/β)7 barrel PHP-like fold include the hypothetical protein YcdX from Escherichia coli (which contains a trinuclear metal-binding site on the C-terminal side of the barrel) [,
], as well as ribonuclease P protein component 3 (Rnp3) () from Pyrococcus horikoshii (no metal site on the C-terminal side of the barrel) [
].
Dirigent proteins impart stereoselectivity on the phenoxy radical-coupling reaction, yielding optically active lignans from two molecules of coniferyl alcohol in the biosynthesis of lignans, flavonolignans, and alkaloids and thus plays a central role in plant secondary metabolism [
,
]. This family also includes homologue DRR206 (disease resistance response protein 206). DRR206 is induced by the metabolite pinoresinol monoglucoside and is involved in phytoalexin (lignan) biosynthesis as a defense response [].
Cytochrome b-c1 complex subunit 7 (QCR7, also known as UQCRB) is a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. QCR7 is involved in redox-linked proton pumping [
,
,
].
Dimeric α-β barrel domains exhibit an α+β sandwich fold with an antiparallel β-sheet that forms a closed barrel. These domains dimerise through the β-sheet, and in some cases these dimers may assemble into higher oligomers. Domains with this structure are found in proteins from several different families, including bacterial actinorhodin biosynthesis monooxygenase (ActVa-Orf6), which catalyses the oxidation of an aromatic intermediate of the actinorhodin biosynthetic pathway [
]; bacterial muconalactone isomerase, a decamer composed of five dimers []; and the C-terminal domain of archaeal LprA, a member of the Lrp/AqsnC family of transcription regulators [].
The stress-response A/B barrel domain is found in a class of stress-response
proteins in plants. It is also found in some bacterial fructose-bisphosphate aldolase such as at the C terminus of a fructose 1,6-bisphosphate aldolase from Hydrogenophilus thermoluteolus () [
]. is found in the pA01 plasmid, which encodes genes for molybdopterin uptake and degradation of plant alkaloid nicotine.
The stress-response A/B barrel domain forms a very stable dimer. This dimer
belongs to the superfamily of dimeric alpha+beta barrels in which the twoβ-sheets form a β-barrel. The two molecules in the dimer are related by
a 2-fold axis parallel to helix H1 and β-strands B3 and B4. C-terminal residues extending from the beta4 strand of each monomer wrap around and connect with the beta2 strand and alpha1 helix of the opposing monomer to form the dimer interface [,
,
].The outer surface of the β-sheets of the two molecules forms a β-barrel-like structure defining a central pore.The function of the stress-response A/B barrel domain is unknown [
,
,
], but it is upregulated in response to salt stress in Populus balsamifera (balsam poplar) [].Some proteins known to contain a stress response A/B barrel domain are listedbelow:
- Arabidopsis thaliana At3g17210- Arabidopsis thaliana At5g22580-Populus tremula stable protein 1 (SP-1)(Populus species), a thermostable stress-responsive protein.- Pseudomonas hydrogenothermophila fructose 1,6-bisphosphate aldolase (cbbA).The structure of one of these proteins has been solved (
) and the domain forms an α-β barrel dimer [
].
This entry represents a group of plant-specific proteins, including protein SOSEKI 1-5 from Arabidopsis thaliana and Physcomitrium patens. SOSEKI proteins (SOK1-5) integrate apical-basal and radial organismal axes to localize to polar cell edges and contain a DIX oligomerization domain that resembles that in the animal Dishevelled polarity regulator [
,
].
The mammalian B-cell receptor-associated proteins of 29 and 31kDa (BAP29 and BAP31) are integral membrane proteins with a role in endoplasmic reticulum (ER) quality control and sorting [
,
,
]. BAP31 is also involved in apoptosis []. Saccharomyces cerevisiae possesses three homologues of BAP31 known as Yet1, Yet2, and Yet3 [].
Protein virilizer may be involved in mRNA splicing regulation. Most of the studies on virilizer were carried out in fruit fly. In Drosophila, protein virilizer is required for male and female viability, sex determination and dosage compensation. It is involved in the female-specific splicing of Sxl transcripts. It is required for proper inclusion of regulated exons in Ubx transcripts [
,
,
].
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].This entry describes domain 2 found in type IA topoisomerases, which may be an extension of the Toprim domain. The structures of bacterial topoisomerases I and III have been shown to consist of four domains that together form a toroidal structure with a central hole large enough to accommodate single- and double-stranded DNA. The N-terminal Toprim domain together with domain 3 forms the active site of the enzyme, while domains 2 and 4 form a single-strand DNA-binding groove [
,
]. The Toprim domain () forms a compact Rossmann fold that coordinates the Mg+2 ion [
].
DNA topoisomerase, type IA, central region, subdomain 1
Type:
Homologous_superfamily
Description:
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].Type IA topoisomerases are comprised of four domains that together form a toroidal structure with a central hole large enough to accommodate single- and double-stranded DNA: an N-terminal alpha/beta Toprim domain, domain 2 and the C-terminal domain 4 are winged-helix domains, and domain 3 is a β-barrel. Domains 1 (Toprim) and 3 form the active site of the enzyme, while the winged helix domains 2 and 4 form a single-strand DNA-binding groove [
,
]. This entry represents the α-bundle subdomain 1 of the central region of topoisomerase type IA enzymes, where the central region covers both domains 2 and 3.
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].This entry describes the DNA-binding domain (domain 3) found in type IA topoisomerases. The structures of bacterial topoisomerases I and III have been shown to consist of four domains that together form a toroidal structure with a central hole large enough to accommodate single- and double-stranded DNA. The N-terminal Toprim domain together with domain 3 (β-barrel) forms the active site of the enzyme, while domains 2 and 4 (both winged-helix-like) form a single-strand DNA-binding groove [
,
]. All topoisomerases cleave DNA by forming a transient phosphotyrosine bond; in type IA topoisomerases, the active site tyrosine is in domain 3 [
].
This entry describes the type IA topoisomerases, which are highly conserved enzymes that are structurally distinct from type IB enzymes. The structures of both topoisomerases I and III have been elucidated, and consist of four domains that together form a toroidal molecule with a central hole that is large enough to accommodate single- and double-stranded DNA [
]. It is believed that the domains transiently separate from one another to allow the entrance and exit of DNA strands.DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].DNA topoisomerase I (
) is one of the two types of enzyme that catalyze the interconversion of topological DNA isomers [
,
,
]. Type I topoisomerases act by catalyzing the transient breakage of DNA, one strand at a time, and the subsequent rejoining of the strands. When a prokaryotic type I topoisomerase breaks a DNA backbone bond, it simultaneously forms a protein-DNA link where the hydroxyl group of a tyrosine residue is joined to a 5'-phosphate on DNA, at one end of the enzyme-severed DNA strand. Prokaryotic organisms, such as Escherichia coli, have two type I topoisomerase isozymes: topoisomerase I (gene topA) and topoisomerase III (gene topB). Eukaroytes also contain homologues of prokaryotic topoisomerase III. The signature pattern of this entry contains a number of conserved residues and spans the active site tyrosine.
The Toprim (topoisomerase-primase) domain is a structurally conserved domain of ~100 amino acids that is found in bacterial DnaG-type primases, small primase-like proteins from bacteria and archaea, type IA and type II topoisomerases, bacterial and archaeal nucleases of the OLD family and bacterial DNA repair proteins of the RecR/M family. The Toprim domain can be found alone or in combination with several other domains, such as the ASM domain, the superfamily 2 helicase domain, the superfamily 3 helicase domain, the DnaB interaction domain, the C4 'little finger' domain, the CHC2 zinc finger, the ATPase domain of the HSP90-gyrase-histidine kinase superfamily, the S5 domain, the SET domain, the helix-hairpin-helix (HhH) DNA-binding domain, the mobilisation (MOB) domain or the ATPase domain of the ABC transporter/SMC superfamily. The Toprim domain is a catalytic domain involved in DNA strand breakage and rejoining [
].The Toprim domain has two conserved motifs, one of which centres at a conserved glutamate and the other one at two conserved aspartates (DxD). Both motifs are preceded by conserved hydrophobic regions predicted to form β-strands. The glutamate residue is probably involved in catalysis, whereas the DxD motif is involved in the co-ordination of Mg(2++) that is required for the activity of all Toprim-containing enzymes. The Toprim domain has a compact alpha/beta fold, with four conserved strands and three helices; with the exception of the second helix and the C-terminal strands, each of these elements contains positions that are highly conserved. The Toprim domain contains three regions that can accommodate variable sized inserts, which are particularly prominent in the topoisomerases [
,
,
].
DNA topoisomerase, type IA, central region, subdomain 2
Type:
Homologous_superfamily
Description:
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (
; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].Type IA topoisomerases are comprised of four domains that together form a toroidal structure with a central hole large enough to accommodate single- and double-stranded DNA: an N-terminal alpha/beta Toprim domain, domain 2 and the C-terminal domain 4 are winged-helix domains, and domain 3 is a β-barrel. Domains 1 (Toprim) and 3 form the active site of the enzyme, while the winged helix domains 2 and 4 form a single-strand DNA-binding groove [
,
]. This entry represents the β-sandwich subdomain 2 of the central region of topoisomerase type IA enzymes, where the central region covers both domains 2 and 3.
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].Type IA topoisomerases are comprised of four domains that together form a toroidal structure with a central hole large enough to accommodate single- and double-stranded DNA: an N-terminal alpha/beta Toprim domain, domain 2 and the C-terminal domain 4 are winged-helix domains, and domain 3 is a β-barrel. Domains 1 (Toprim) and 3 form the active site of the enzyme, while the winged helix domains 2 and 4 form a single-strand DNA-binding groove [
,
]. This entry represents the central portion of the enzyme, which covers domains 2 and 3 in topoisomerase type IA enzymes.
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].This entry describes the core region of type IA topoisomerases, which are highly conserved enzymes that are structurally distinct from type IB enzymes. The structures of both topoisomerases I and III have been elucidated, and consist of four domains that together form a toroidal molecule with a central hole that is large enough to accommodate single- and double-stranded DNA [
]. It is believed that the domains transiently separate from one another to allow the entrance and exit of DNA strands.
DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks [
]. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis [,
]. DNA topoisomerases are divided into two classes: type I enzymes (; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (
; topoisomerases II, IV and VI) break double-strand DNA [
].Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB [
]. They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases [,
]. The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases [,
].This entry describes topoisomerase I from bacteria, which is more closely related to archaeal than to eukaryotic topoisomerase I [
]. Topoisomerase I is the major enzyme for relaxing negatively supercoiled DNA, and its presence is balanced by reverse gyrase, which can introduce negative supercoils. Prokaryotic topoisomerase I folds in an unusual way to give 4 distinct domains, enclosing a hole large enough to accommodate a double-stranded DNA segment. A tyrosine at the active site, which lies at the interface of 2 domains, is involved in transient breakage of a DNA strand, and the formation of a covalent protein-DNA intermediate through a 5'-phosphotyrosine linkage. The structure reveals a plausible mechanism by which this and related enzymes could catalyse the passage of one DNA strand through a transient break in another strand []. Topoisomerase I require Mg2+ as a cofactor for catalysis to take place.
There are two types of fatty acid synthase systems. The type I system is found in metazoans and is carried out
by a multifunctional polypeptide with multiple active sites. In contrast, the type II system found in bacteria and plantsconsists of a set of discrete monofunctional proteins, each encoded by a separate gene. ACP1 is central to both of these
pathways because it functions to ferry the pathway intermediates between active site centres or enzymes. ACPs are alsocritical to the function of other metabolic pathways such as polyketide synthases. The type II fatty acid synthase ACPs are abundant, small, acidic proteins that carry the acyl intermediates attached as thioesters to the terminus of the 4'-phosphopantetheine prosthetic group. This prosthetic group is added post-translationally to apoACP by holo-(acyl carrier protein) synthase (AcpS), which transfers the 4'-phosphopantetheine moiety of CoA to a serine reidue of apoACP.The crystal structures of a number of the type II fatty acid synthase ACPs have been determined. The structures reveal a novel trimeric arrangement of molecules resulting in three active sites [
,
].
Acyl carrier protein (ACP) is an essential cofactor in the synthesis of fatty acids by the fatty acid synthetases systems in bacteria and plants. In addition to fatty acid synthesis, ACP is also involved in many other reactions that require acyl transfer steps, such as the synthesis of polyketide antibiotics, biotin precursor, membrane-derived oligosaccharides, and activation of toxins, and functions as an essential cofactor in lipoylation of pyruvate and alpha-ketoglutarate dehydrogenase complexes [
]. Phosphopantetheine (or pantetheine 4' phosphate) is the prosthetic group of acyl carrier proteins (ACP) in some multienzyme complexes where it serves as a 'swinging arm' for the attachment of activated fatty acid and amino-acid groups []. Phosphopantetheine is attached to a serine residue in these proteins. The core structure of ACP consists of a four-helical bundle, where helix three is shorter than the others.Several other proteins share structural homology with ACP, such as the bacterial apo-D-alanyl carrier protein, which facilitates the incorporation of D-alanine into lipoteichoic acid by a ligase, necessary for the growth and development of Gram-positive organisms [
]; and the thioester domain of the bacterial peptide carrier protein (PCP) found within large modular non-ribosomal peptide synthetases, which are responsible for the synthesis of a variety of microbial bioactive peptides [].
Cytochromes c (cytC) can be defined as electron-transfer proteins having one or several haem c groups, bound to the protein by one or, more
generally, two thioether bonds involving sulfhydryl groups of cysteine residues. The fifth haem iron ligand is always provided by a histidine residue. CytC possess a wide range of properties and function in a large number of different redox processes.Ambler [
] recognised four classes of cytC. Class I includes the low-spin soluble cytC of mitochondria and bacteria, with the haem-attachment site towards the N terminus, and the sixth ligand provided by a methionine residue about 40 residues further on towards the C terminus []. On the basis of sequence similarity, class I cytC were further subdivided into five classes, IA to IE. Class IB includes the eukaryotic mitochondrial cyt C and prokaryotic 'short' cyt C2 exemplified by Rhodopila globiformis cyt C2; Class IA includes 'long' cyt C2, such as Rhodospirillum rubrum cyt C2 and Aquaspirillum itersonii cyt C-550, which have several extra loops by comparison with Class IB cyt C.Class I cytC has a characterised fold which comprises 5 α-helices arranged in a unique tertiary structure and a conserved N-terminal sequence -Cys-Xxx-Xxx-Cys-His- where the cysteines mediate the covalent cross-linking of the heme to the protein and the His [
].The 3D structures of a considerable number of class IA and IB cytC have been determined. The proteins consist of 3-6 α-helices; the three most conserved 'core' helices form a 'basket' around the haem group, with one haem edge exposed to the solvent. Most class I cytC have conserved aromatic residues clustered around the haem and axial ligands.
It is thought that NAPs act as histone chaperones, shuttling both core and linker histones from their site of synthesis in the cytoplasm to the nucleus. The proteins may be involved in regulating gene expression and therefore cellular differentiation [
,
].The centrosomal protein c-Nap1, also known as Cep250, has been implicated in the cell-cycle-regulated cohesion of microtubule-organizing centres. This 281kDa protein consists mainly of domains predicted to form coiled coil structures. The C-terminal region defines a novel histone-binding domain that is responsible for targeting CNAP1, and possibly condensin, to mitotic chromosomes [
]. During interphase, C-Nap1 localizes to the proximal ends of both parental centrioles, but it dissociates from these structures at the onset of mitosis. Re-association with centrioles then occurs in late telophase or at the very beginning of G1 phase, when daughter cells are still connected by post-mitotic bridges. Electron microscopic studies performed on isolated centrosomes suggest that a proteinaceous linker connects parental centrioles and C-Nap1 may be part of a linker structure that assures the cohesion of duplicated centrosomes during interphase, but that is dismantled upon centrosome separation at the onset of mitosis [].
Orotate phosphoribosyltransferase (OPRTase) is involved in the biosynthesis of pyrimidine nucleotides. This entry represents the orotate phosphoribosyl transferase domain.
Orotidine 5'-phosphate decarboxylase (OMPdecase) [
,
] catalyses the last step in the de novobiosynthesis of pyrimidines, the decarboxylation of OMP into UMP. In higher eukaryotes OMPdecase is part, with orotate phosphoribosyltransferase, of a bifunctional enzyme, while the prokaryotic and fungal OMPdecases are monofunctional protein.
Some parts of the sequence of OMPdecase are well conserved across species. The best conserved region is located in the N-terminal half of OMPdecases and is centred around a lysine residue which is essential for the catalytic function of the enzyme.This entry also includes enzymes such as 3-hexulose-6-phosphate synthase
and 3-keto-L-gulonate-6-phosphate decarboxylase
.
Orotidine 5'-phosphate decarboxylase (OMPdecase) [
,
] catalyses the last step in the de novobiosynthesis of pyrimidines, the decarboxylation of OMP into UMP. In higher eukaryotes OMPdecase is part, with orotate phosphoribosyltransferase, of a bifunctional enzyme, while the prokaryotic and fungal OMPdecases are monofunctional protein.
Some parts of the sequence of OMPdecase are well conserved across species. The best conserved region is located in the N-terminal half of OMPdecases and is centred around a lysine residue which is essential for the catalytic function of the enzyme.
Orotidine 5'-phosphate decarboxylase (OMPdecase) (
) [
,
] catalyses the last step in the de novobiosynthesis of pyrimidines, the decarboxylation of OMP into UMP. In higher eukaryotes OMPdecase is part, with orotate phosphoribosyltransferase, of a bifunctional enzyme, while the prokaryotic and fungal OMPdecases are monofunctional proteins.Some parts of the sequence of OMPdecase are well conserved across species. The best conserved region is located in the N-terminal half of OMPdecases and is centred around a lysine residue which is essential for the catalytic function of the enzyme.
Orotate phosphoribosyltransferase (OPRTase) is involved in the biosynthesis of pyrimidine nucleotides. In the pyrimidine synthesis pathway, OPRT catalyses the reversible phosphoribosyl transfer from 5'-phospho-alpha-D-ribose 1'-diphosphate (PRPP) to orotic acid (OA), forming pyrophosphate and orotidine 5'-monophosphate (OMP) [
]. The structures and properties of the OPRTases from different species have been described in several publications [,
,
,
].
Proteins in this entry are E3 ubiquitin-protein ligases that mediate ubiquitination and subsequent proteasomal degradation of target proteins. Proteins in this entry include Sina and Sinah (Sina homologue) from flies and SIAH1/2 from humans.The seven in absentia (sina) gene was first identified in Drosophila. The Drosophila Sina protein is essential for the determination of the R7 pathway in photoreceptor cell development: the loss of functional Sina results in the transformation of the R7 precursor cell to a non-neuronal cell type. The Sina protein contains an N-terminal RING finger domain C3HC4-type. Through this domain, Sina binds E2 ubiquitin-conjugating enzymes (UbcD1). Sina also interacts with Tramtrack (TTK88) via PHYL. Tramtrack is a transcriptional repressor that blocks photoreceptor determination, while PHYL down-regulates the activity of TTK88. In turn, the activity of PHYL requires the activation of the Sevenless receptor tyrosine kinase, a process essential for R7 determination. It is thought that Sina targets TTK88 for degradation, therefore promoting the R7 pathway. Murine and human homologues of Sina have also been identified. The human homologue SIAH1 [
] also binds E2 enzymes (UbcH5) and through a series of physical interactions, targets beta-catenin for ubiquitin degradation. Siah-1 expression is enhanced by p53, itself promoted by DNA damage. Thus this pathway links DNA damage to beta-catenin degradation [,
].
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. SINA/Siah family proteins represent mammalian homologs of the Drosophila SINA (seven in absentia) protein. SINA is required for R7 photoreceptor cell differentiation within the sevenless pathway [
]. Members of this family are E3 ubiquitin ligases that regulate ubiquitination and protein degradation. Siahs are known to recognise several target proteins including Deleted in Colorectal Cancer (DCC), synaptophysin and Numb and promote their degradation [,
]. SINA/Siah sequences are highly conserved from plants to mammals. Whereas the N terminus and RING domain of Siah bind E2 proteins, the C terminus can be considered as a substrate- and cofactor-interaction domain (substrate-binding domain, SBD) that interacts with a number of proteins, some of which are degraded []. The SBD domain displays some sequence similarities with the C-terminal region of TRAF proteins. It contains a cysteine-rich region, the SIAH-type zinc finger, with eight totally conserved Cys and His residues that coordinate two zinc atoms []. The crystal structure of SIAH-type zinc finger has been solved []. It folds in two subdomains, each one binding one zinc atom and consisting of two β-strands and an α-helix.
The seven in absentia (sina) is a RING-type E3 ubiquitin ligase first identified in Drosophila. The Drosophila Sina protein is essential for the determination of the R7 pathway in photoreceptor cell development: the loss of functional Sina results in the transformation of the R7 precursor cell to a non-neuronal cell type. The Sina protein contains an N-terminal RING finger domain C3HC4-type, through which it binds E2 ubiquitin-conjugating enzymes (UbcD1). Sina also interacts with Tramtrack (TTK88) via PHYL. Tramtrack is a transcriptional repressor that blocks photoreceptor determination, while PHYL down-regulates the activity of TTK88. In turn, the activity of PHYL requires the activation of the Sevenless receptor tyrosine kinase, a process essential for R7 determination. It is thought that Sina targets TTK88 for degradation, therefore promoting the R7 pathway. The remainder C-terminal part is involved in interactions with other proteins, and consists of two zinc fingers and a TRAF-like domain.Murine and human homologues of Sina have also been identified, namely Siah1 and Siah2 [
,
]. The human homologue Siah-1 [] also binds E2 enzymes (UbcH5) and through a series of physical interactions, targets beta-catenin for ubiquitin degradation. Siah-1 expression is enhanced by p53, itself promoted by DNA damage. Thus, this pathway links DNA damage to beta-catenin degradation [,
].In addition to the Drosophila protein and mammalian homologues, whose similarity was noted previously, this family also includes putative homologues from Caenorhabditis elegans, Arabidopsis thaliana [
].
This domain has four conserved cysteine residues. It is found in proteins Tim8, Tim9, Tim10 and Tim13, which are involved in mitochondrial protein import [
] and seem to be localised to the mitochondrial intermembrane space. The Tim8-Tim13 complex has a complex architecture, similar to the Tim9-Tim10 complex, composed of a hexametric architecture with long helices which look like tentacles extend from a central loop []. In each subunit of the Tim9-Tim10 complex, a signature "twin CX3C"motif forms two intramolecular disulfides [
].Defects in the Tim8A gene (DDP1) have been shown to be the cause of 2 human syndromes: Mohr-Tranebjaerg syndrome (MTS); also known as dystonia-deafness syndrome (DDS) or X-linked progressive deafness type 1 (DFN-1); and Jensen syndrome (JENSS); also known as opticoacoustic nerve atrophy with dementia.
This entry represents a domain found in the N terminus of the pre-rRNA-processing protein Ipi1. This domain can also be found in testis-expressed sequence 10 protein (TEX10).In Saccharomyces cerevisiae, Ipi1 is a component of the RIX1 complex required for processing of ITS2 sequences from 35S pre-rRNA [
,
]. In humans, TEX10 is a component of some MLL1/MLL complex, a protein complex that can methylate lysine-4 of histone H3 [
].
This is the cytosolic domain of integral membrane proteins, such as plant OSCA1, yeast PHM7 and CSC1-like protein 1 (also known as TRANSMEMBRANE PROTEIN 63A),
[
,
]. Members of this entry are mechanosensitive calcium-permeable ion channels consisting of an N-terminal transmembrane domain (RSN1_TM), a cytosolic domain and a 7TM region at the C-terminal. Fold recognition programs consistently and with high significance predict this domain to be distantly homologous to RNA binding proteins from the RRM clan [,
]. Human CSC1-like protein 1 is involved myelin development [].
Sequences containing this domain belong to the terpene synthase family [
]. It has been suggested that this gene family be designated tps (for terpene synthase). Sequence comparisons reveal similarities between the monoterpene (C10) synthases, sesquiterpene (C
15) synthases and the diterpene (C
20) synthases. It has been split into six subgroups on the basis of phylogeny, called Tpsa-Tpsf [
].Tpsa includes vetispiradiene synthase
, 5-epi- aristolochene synthase,
and (+)-delta-cadinene synthase
.
Tpsb includes (-)-limonene synthase,
.
Tpsc includes copalyl diphosphate synthase (kaurene synthase A),
.
Tpsd includes taxadiene synthase,
, pinene synthase,
and myrcene synthase,
.
Tpse includes ent-kaurene synthase B
.
Tpsf includes linalool synthase
.
In the fungus Phaeosphaeria sp. (strain L487) the synthesis of ent-kaurene from geranylgeranyl diphosphate is promoted by a single bifunctional protein [
].This domain is involved in the cyclization of linear terpenes [
,
,
,
,
,
].
This entry contains proteins belonging to the UPF0496 family, found in plants. This family includes AT14A like proteins from Arabidopsis thaliana. At14a contains a small domain that has sequence similarities to integrins from fungi, insects and humans. Transcripts of At14a are found in all Arabidopsis tissues and the protein localises partly to the plasma membrane [
].
This family consists of sequences found in a number of hypothetical plant proteins of unknown function. The region of interest contains nine highly conserved cysteine residues and is approximately 160 amino acids in length, which probably represent a zinc-binding domain.
The 125-residue ALOG (Arabidopsis LSH1 and oryza G1) domain is rich in basic
amino acids, especially arginine, and is highly conserved among land plants.Members of the ALOG family of proteins function as key developmental
regulators. It has been proposed that the ALOG domain originated from the N-terminal DNA-binding domains of integrases belonging to the tyrosine
recombinase superfamily encoded by a distinct type of DIRS1-like LTRretrotransposon found in several eukaryotes. Secondary structure predictions
revealed an all-alpha helical domain with four conserved helices [,
].Some proteins known to contain an ALOG domain are listed below:Arabidopsis thaliana LIGHT_DEPENDENT SHORT HYPOCOTYLS1 (LSH1), involved in
phytochrome-dependent light signalling.Oryza G1, involved in the specification of sterile lemma identity.Plant defence proteins.
This family of proteins includes the SDT1/SSM1 gene from yeast, which has been shown to code for a pyrimidine (UMP/CMP) 5'nucleotidase [
,
]. The family spans plants, fungi and bacteria. These enzymes are members of the haloacid dehalogenase (HAD) superfamily of hydrolases, specifically the IA subfamily.
The Haloacid Dehalogenase (HAD) superfamily is defined by the presence of three short catalytic motifs [
]. The subfamilies are defined [] based on the location and the observed or predicted fold of a so-called capping domain [], or the absence of such a domain. Subfamily I consists of sequences in which the capping domain is found in between the first and second catalytic motifs. Subfamily II consists of sequences in which the capping domain is found between the second and third motifs. Subfamily III sequences have no capping domain in either of these positions.The Subfamily IA and IB capping domains are predicted by PSI-PRED to consist of an α-helical bundle. Subfamily IA and IB are separated based on an apparent phylogenetic bifurcation. Of the three motifs defining the HAD superfamily, the third has three variant forms: (1) hhhhsDxxx(x)D, (2) hhhhssxxx(x)D and (3) hhhhDDxxx(x)s where _s_ refers to a small amino acid and _h_ to a hydrophobic one. All three of these variants are found in subfamily IA.NOTE: Three variant models were created by TIGRFAMs with some overlap among them to cover subfamily IA. This serves the purpose of eliminating the overlap with models of more distantly related HAD subfamilies caused by an overly broad single model.
PsaD is a small, extrinsic polypeptide located on the stromal side (cytoplasmic side in cyanobacteria) of the photosystem I reaction centre complex. It is required for native assembly of PSI reaction clusters and is implicated in the electrostatic binding of ferredoxin within the reaction centre [
]. PsaD forms a dimer in solution which is bound by PsaE however PsaD is monomeric in its native complexed PSI environment [].
According to structural similarities and conserved sequence motifs, FAD-binding domains have been grouped in three main families: (i) the ferredoxin reductase (FR)-type FAD-binding domain, (ii) the FAD-binding domains that adopt a Rossmann fold and (iii) the p-cresol methylhydroxylase (PCMH)-type FAD-binding domain [
].The PCMH-type FAD-binding domain consists of two α-β subdomains: one is composed of three parallel β-strands (B1-B3) surrounded by α-helices, and is packed against the second subdomain containing five antiparallel β-strands (B4-B8) surrounded by α-helices [
]. The two subdomains accommodate the FAD cofactor between them []. This superfamily represents the first (N-terminal) subdomain, which is found in:FAD-linked oxidases (N-terminal domain), such as vanillyl-alochol oxidase (
) [
], flavoprotein subunit of p-cresol methylhydroxylase () [
], D-lactate dehydrogenases (,
-cytochrome) [
], Cholesterol oxidases () [
], Cytokinin dehydrogenase 1 () [
].Uridine diphospho-N-acetylenolpyruvylglucosamine reductase (MurB) (N-terminal domain) [
].CO dehydrogenase flavoprotein (N-terminal domain; [
]) family.
This domain is found in the berberine bridge and berberine bridge-like enzymes, flavoproteins which have an unusual bicovalent attachment of the FAD cofactor that are involved in the biosynthesis of numerous isoquinoline alkaloids. They catalyse the transformation of the N-methyl group of (S)-reticuline into the C-8 berberine bridge carbon of (S)-scoulerine [
,
]. This domain is found in many flavoproteins mainly from bacteria, fungi and plants.
Glutaredoxins [
,
,
], also known as thioltransferases (disulphide reductases), are small proteins of approximately one hundred amino-acid residues which utilise glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system [].Glutaredoxin functions as an electron carrier in the glutathione-dependent synthesis of deoxyribonucleotides by the enzyme ribonucleotide reductase. Like thioredoxin (TRX), which functions in a similar way, glutaredoxin possesses an active centre disulphide bond [
]. It exists in either a reduced or an oxidized form where the two cysteine residues are linked in an intramolecular disulphide bond. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH ->GSH reductase ->GSH ->GRX ->protein substrates [
,
,
,
]. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress.Glutaredoxin has been sequenced in a variety of species. On the basis of extensive sequence similarity, it has been proposed [
] that Vaccinia virus protein O2L is most probably a glutaredoxin. Finally, it must be noted that Bacteriophage T4 thioredoxin seems also to be evolutionary related. In position 5 of the pattern T4 thioredoxin has Val instead of Pro.This entry represents the Glutaredoxin active site.
This domain is found in mitochondrial proteins, including FAM210A (and its homologues) and B, which contain a transmembrane peptide [
,
,
]. Its function is not clear. FAM210A, a protein essential in maintaining skeletal muscle structure and strength [], interacts with mitochondrial translation elongation factor EF-Tu and promotes mitochondrial protein expression. In FAM210A, this domain is responsible for binding EF-Tu []. FAM210B plays a role in erythroid differentiation and is involved in cell proliferation and tumor cell growth suppression [,
]. This domain is also present in the uncharacterised protein C106.07c from fission yeast and putative N-terminal acetyltransferase 2 from Baker's yeast.
A large ribonuclear protein complex is required for the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [
,
]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble [
]. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. This entry contains Utp11, a large ribonuclear protein that associates with snoRNA U3 [
].
Trafficking protein particle complex subunit 2, also known as Sedlin, is a 140 amino-acid protein with a putative role in endoplasmic reticulum-to-Golgi transport [
]. Several missense mutations and deletion mutations in the SEDL gene, which result in protein truncation by frame shift, are responsible for spondyloepiphyseal dysplasia tarda, a progressive skeletal disorder (OMIM:313400) [].
Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP. There are several different types of transmembrane ATPases, which can differ in function (ATP hydrolysis and/or synthesis), structure (e.g., F-, V- and A-ATPases, which contain rotary motors) and in the type of ions they transport [
,
]. The different types include:F-ATPases (ATP synthases, F1F0-ATPases), which are found in mitochondria, chloroplasts and bacterial plasma membranes where they are the prime producers of ATP, using the proton gradient generated by oxidative phosphorylation (mitochondria) or photosynthesis (chloroplasts).V-ATPases (V1V0-ATPases), which are primarily found in eukaryotes and they function as proton pumps that acidify intracellular compartments and, in some cases, transport protons across the plasma membrane []. They are also found in bacteria [].A-ATPases (A1A0-ATPases), which are found in Archaea and function like F-ATPases, though with respect to their structure and some inhibitor responses, A-ATPases are more closely related to the V-ATPases [
,
].P-ATPases (E1E2-ATPases), which are found in bacteria and in eukaryotic plasma membranes and organelles, and function to transport a variety of different ions across membranes.E-ATPases, which are cell-surface enzymes that hydrolyse a range of NTPs, including extracellular ATP.V-ATPases (also known as V1V0-ATPase or vacuolar ATPase) are found in the eukaryotic endomembrane system, and in the plasma membrane of prokaryotes and certain specialised eukaryotic cells. V-ATPases hydrolyse ATP to drive a proton pump, and are involved in a variety of vital intra- and inter-cellular processes such as receptor mediated endocytosis, protein trafficking, active transport of metabolites, homeostasis and neurotransmitter release [
]. V-ATPases are composed of two linked complexes: the V1 complex (subunits A-H) contains the catalytic core that hydrolyses ATP, while the V0 complex (subunits a, c, c', c'', d) forms the membrane-spanning pore. V-ATPases may have an additional role in membrane fusion through binding to t-SNARE proteins [].This entry represents subunit B from the V1 complex of V-ATPases. There are three copies each of subunits A (
) and B, both of which participate in nucleotide binding. However, only subunit A is catalytic for ATP hydrolysis, subunit B being noncatalytic [
,
].
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.This entry represents the beta regulatory subunit of V-type ATP synthase, known as subunit B in eukaryota.
The MADF (myb/SANT-like domain in Adf-1) domain is an approximately 80-amino-acid module that directs sequence specific DNA binding to a site consisting of multiple tri-nucleotide repeats. The MADF domain is found in one or more copies in eukaryotic and viral proteins and is often associated with the BESS domain [
]. MADF is related to the Myb DNA-binding domain (). The retroviral oncogene v-myb, and its cellular counterpart c-myb, are nuclear DNA-binding proteins that specifically recognise the sequence YAAC(G/T)G. It is likely that the MADF domain is more closely related to the myb/SANT domain than it is to other HTH domains. Some proteins known to contain a MADF domain are listed below: Drosophila Adf-1, a transcription factor first identified on the basis of its interaction with the alcohol dehydrogenase promoter but that binds the promoters of a diverse group of genes [
]. Drosophila Dorsal-interacting protein 3 (Dip3), which functions both as an activator to bind DNA in a sequence specific manner and a coactivator to stimulate synergistic activation by Dorsal and Twist [
]. Drosophila Stonewall (Stwl), a putative transcription factor required for maintenance of female germline stem cells as well as oocyte differentiation.
In certain plant and yeast proteins, the DnaJ-1 proteins have a three-domain structure. The x-domain lies between the N-terminal DnaJ and the C-terminal Z domains [
]. This domain found in Plasmodium falciparum RESA (ring-infected erythrocyte surface antigen) has been shown to bind to spectrin and stablize the tetramer [].
Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles [
], and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus [
].This entry includes cyclin PHO80 and other cyclins that partner with the cyclin-dependent kinase (CDK) PHO85. The PHO80/PHO85 cyclin-cdk complex is used for a regulatory process other than cell-cycle control [
]. This entry also includes other PHO80-like cyclins that are involved in the cell-cycle control. They belong to the P/U family and interact preferentially with CDKA1 [].
S-adenosylmethionine decarboxylase (AdoMetDC) [
] catalyzes the removal of the carboxylate group of S-adenosylmethionine to form S-adenosyl-5'-3-methylpropylamine which then acts as the n-propylamine group donor in the synthesis of the polyamines spermidine and spermine from putrescine.The catalytic mechanism of AdoMetDC involves a covalently-bound pyruvoyl group. This group is post-translationally generated by a self-catalyzed intramolecular proteolytic cleavage reaction between a glutamate and a serine. This cleavage generates two chains, beta (N-terminal) and alpha (C-terminal). The N-terminal serine residue of the alpha chain is then converted by nonhydrolytic serinolysis into a pyruvyol group.
S-adenosylmethionine decarboxylase (AdoMetDC) [
] catalyzes the removal of the carboxylate group of S-adenosylmethionine to form S-adenosyl-5'-3-methylpropylamine which then acts as the n-propylamine group donor in the synthesis of the polyamines spermidine and spermine from putrescine.The catalytic mechanism of AdoMetDC involves a covalently-bound pyruvoyl group. This group is post-translationally generated by a self-catalyzed intramolecular proteolytic cleavage reaction between a glutamate and a serine. This cleavage generates two chains, beta (N-terminal) and alpha (C-terminal). The N-terminal serine residue of the alpha chain is then converted by nonhydrolytic serinolysis into a pyruvyol group.
The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner [
]. The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) []. Annexins are absent from yeasts and prokaryotes [].Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long [
]. Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.
Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication [
].This entry represents annexin D proteins found in plants. Plant annexins generally lack N-terminal domains and functional calcium-binding sites in their second and third repeats. There are eight and nine annexin genes in the complete genomes of Arabidopsis and rice, respectively. These are a result of gene or genome duplication events [
].
Annexins [
,
,
,
,
,
,
,
] are a group of calcium-binding proteins that associate reversibly with membranes. They bind to phospholipid bilayers in the presence of micromolar free calcium concentration. The binding is specific for calcium and for acidic phospholipids. Annexins have been claimed to be involved in cytoskeletal interactions, phospholipase inhibition, intracellular signaling, anticoagulation, and membrane fusion. Annexins are widely distributed among eukaryotes but largely absent in prokaryotes and yeast. They are classified according to the evolutionary divisions of the eukaryotes into five families: A (ANXA, vertebrates, including humans), B (ANXB, invertebrates), C (ANXC, fungi), D (ANXD, true plants), E (ANXE, protists).Each of these proteins consist of a unique N-terminal domain followed by four or eight copies (in annexin A6) of a conserved segment of approximately 70 residues. The tertiary structure of annexins is evolutionary conserved; a single molecule resembles a slightly curved disk with the calcium and phospholipid-binding sites located on the more convex surface and the more concave surface facing the cytoplasm. Each single annexin repeat (sometimes known as an 'endonexin fold') is comprised of five α-helices(A-E). Four of them (A, B, D and E) are arranged parallel and form a tightly packed helix-loop-helix bundle. In contrast, helix C is almost perpendicular and covers the remaining four on the surface. Each of the
repeats has the potential to have a type II Ca(2)-binding bipartite motif, located on two different α-helices (GxGT-(38-40 residues)-D/E), buttypically some of them are non-functional. The core of the helix bundle is composed largely of hydrophobic residues, while hydrophilic residues are
exposed on the surface of the protein and between the repeats. The N-terminal domain of variable length, amino acid composition, and determinants of hydrophobicity plays an important role in mediating the interaction of annexins with other intracellular protein partners, such as those of the S100family cytoplasmic proteins [
,
,
].This region spans positions 9 to 61 of the repeat and includes the only perfectly conserved residue (an arginine in position 22).
NdhS/CRR31 (chlororespiratory reduction 31) is a subunit of the chloroplast NADH dehydrogenase-like (NDH) complex [
]. It is also a subunit of the cyanobacterial NDH-1 complex [,
]. NAD(P)H-oxidizing subunits have not been found in chloroplasts or cyanobacteria, where ferredoxin is probably the electron donor. NdhS contributes to the formation of a ferredoxin binding site of NDH []and is necessary for high affinity binding of ferredoxin [
].The cyanobacterial NDH-1 complex, also known as NADPH:plastoquinone oxidoreductase or type I NAD(P)H dehydrogenase, is involved in plastoquinone reduction and cyclic electron transfer (CET) around photosystem I. The chloroplast NDH is more similar to cyanobacterial NDH-1, which is believed to be the origin of chloroplast NDH, than to mitochondrial NADH dehydrogenase present in the same species [
,
]. The NDH complexes of chloroplasts, however, contain many subunits that are absent from cyanobacterial NDH-1 complexes.
Aminotransferases share certain mechanistic features with other pyridoxal-phosphate dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue. On the basis of sequence similarity, these various enzymes can be grouped [
] into subfamilies.This entry represents a subfamily of aminotransferases, called class-IV, with currently consists of proteins of about 270 to 415 amino-acid residues that share a few regions of sequence similarity. Surprisingly, the best conserved region does not include the lysine residue to which the pyridoxal-phosphate group is known to be attached, in ilvE, but is located some 40 residues at the C terminus side of the pyridoxal-phosphate-lysine. The D-amino acid transferases (D-AAT), which are among the members of this entry, are required by bacteria to catalyse the synthesis of D-glutamic acid and D-alanine, which are essential constituents of bacterial cell wall and are the building block for other D-amino acids. Despite the difference in the structure of the substrates, D-AATs and L-ATTs have strong similarity [
,
].This group also includes transaminase htyB from
Aspergillus rugulosus, which is one of the enzymes required for the biosynthesis of the antifungal agent echinocandin B. HtyB catalyses the production of L-homotyrosine from the intermediate 2-oxo-4-(4-hydroxybenzyl)butanoic acid [
]. Also included in this group is branched-chain amino acid aminotransferase gloG from the yeast Glarea lozoyensis, which is required for biosynthesis of the mycotoxin pneumocandin, also a lipohexapeptide of the echinocandin family [
].
The metallo-beta-lactamase fold contains five sequence motifs. The first four motifs are found in
and are common to all metallo-beta-lactamases. The fifth motif appears to be specific to function. This entry represents the fifth motif from metallo-beta-lactamases involved in DNA repair [
].
TMEM70 is a family of proteins essential for assembly of the mitochondrial proton-transporting ATP synthase complex within the inner mitochondrial membrane [
,
,
].
This is a group of cysteine peptidases which constitute MEROPS peptidase family C54 (Aut2 peptidase family, clan CA).A cysteine peptidase is a proteolytic enzyme that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring. In only one family of cysteine peptidases, is the role of the general base assigned to a residue other than a histidine: in peptidases from family C89 (acid ceramidase) an arginine is the general base. Cysteine peptidases can be grouped into fourteen different clans, with members of each clan possessing a tertiary fold unique to the clan. Four clans of cysteine peptidases share structural similarities with serine and threonine peptidases and asparagine lyases. From sequence similarities, cysteine peptidases can be clustered into over 80 different families [
]. Clans CF, CM, CN, CO, CP and PD contain only one family.Cysteine peptidases are often active at acidic pH and are therefore confined to acidic environments, such as the animal lysosome or plant vacuole. Cysteine peptidases can be endopeptidases, aminopeptidases, carboxypeptidases, dipeptidyl-peptidases or omega-peptidases. They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid,
N-ethylmaleimide or
p-chloromercuribenzoate.
Clan CA includes proteins with a papain-like fold. There is a catalytic triad which occurs in the order: Cys/His/Asn (or Asp). A fourth residue, usually Gln, is important for stabilising the acyl intermediate that forms during catalysis, and this precedes the active site Cys. The fold consists of two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a β-barrel with the active site His and Asn (or Asp). There are over thirty families in the clan, and tertiary structures have been solved for members of most of these. Peptidases in clan CA are usually sensitive to the small molecule inhibitor E64, which is ineffective against peptidases from other clans of cysteine peptidases [].Clan CD includes proteins with a caspase-like fold. Proteins in the clan have an α/β/α sandwich structure. There is a catalytic dyad which occurs in the order His/Cys. The active site His occurs in a His-Gly motif and the active site Cys occurs in an Ala-Cys motif; both motifs are preceded by a block of hydrophobic residues [
]. Specificity is predominantly directed towards residues that occupy the S1 binding pocket, so that caspases cleave aspartyl bonds, legumains cleave asparaginyl bonds, and gingipains cleave lysyl or arginyl bonds.Clan CE includes proteins with an adenain-like fold. The fold consists of two subdomains with the active site between them. One domain is a bundle of helices, and the other a β-barrel. The subdomains are in the opposite order to those found in peptidases from clan CA, and this is reflected in the order of active site residues: His/Asn/Gln/Cys. This has prompted speculation that proteins in clans CA and CE are related, and that members of one clan are derived from a circular permutation of the structure of the other.Clan CL includes proteins with a sortase B-like fold. Peptidases in the clan hydrolyse and transfer bacterial cell wall peptides. The fold shows a closed β-barrel decorated with helices with the active site at one end of the barrel [
]. The active site consists of a His/Cys catalytic dyad.Cysteine peptidases with a chymotrypsin-like fold are included in clan PA, which also includes serine peptidases. Cysteine peptidases that are N-terminal nucleophile hydrolases are included in clan PB. Cysteine peptidases with a tertiary structure similar to that of the serine-type aspartyl dipeptidase are included in clan PC. Cysteine peptidases with an intein-like fold are included in clan PD, which also includes asparagine lyases.
These sequences describe 2-dehydro-3-deoxyphosphooctonate aldolase. Alternate names include 3-deoxy-d-manno-octulosonic acid 8-phosphate and KDO-8 phosphate synthetase. It catalyzes the aldol condensation of phosphoenolpyruvate with D-arabinose 5-phosphate.phosphoenolpyruvate + D-arabinose 5-phosphate + H
2O = 2-dehydro-3-deoxy-D-octonate 8-phosphate + phosphate
In Gram-negative bacteria, this is the first step in the biosynthesis of 3-deoxy-D-manno-octulosonate, part of the oligosaccharide core of lipopolysaccharide.
Members of the 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthetase family catalyse the first step in aromatic amino acid biosynthesis from chorismate. Class I includes bacterial and yeast enzymes; class II includes higher plants and various microorganisms (see
) [
]. The first step in the common pathway leading to the biosynthesis of aromatic compounds is the stereospecific condensation of phosphoenolpyruvate (PEP) and D-erythrose-4-phosphate (E4P) giving rise to 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP). This reaction is catalyzed by DAHP synthase, a metal-activated enzyme, which in microorganisms is the target for negative-feedback regulation by pathway intermediates or by end products. In Escherichia coli there are three DAHP synthetase isoforms, each specifically inhibited by one of the three aromatic amino acids. The crystal structure of the phenylalanine-regulated form of DAHP synthetase shows the fold as is a (beta/alpha)8 barrel with several additional beta strands and alpha helices [
].
The WPP domain is thought to be exclusively found in plants. The WPP stands for a tryptophan-proline-proline motif that is highly conserved in the domain [
]. The WPP domain is known to direct RanGAP (Ran GTPase-activating protein) to the nuclear envelope []. RanGAP is an accessory protein for the small signaling GTPase Ran, which is involved in nucleocytoplasmic transport. Non-RanGAP nuclear envelope proteins are also known to encode WPP domains, such as MFP1 attachment factor 1 (MAF1) [], WPP1 [] and WPP2 [].
Fructose bisphosphatase (FBPase)
is a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate [
,
]. It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg2+and Mn
2+being preferred) and the enzyme is potently inhibited by Li
+. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) [
]. Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism [].
Plant cell walls are crucial for development, signal transduction, and disease resistance in plants. Cell walls are made of cellulose,
hemicelluloses, and pectins. Xyloglucan (XG), the principal load-bearing hemicellulose of dicotyledonous plants, has a terminal fucosylresidue. This fucosyltransferase adds this residue [
].
This entry includes SURF1 and Shy1 proteins. The surfeit locus 1 gene (SURF1 or surf-1) encodes a conserved protein of about 300 amino-acid residues that seems to be involved in the biogenesis of
cytochrome c oxidase []. Vertebrate SURF1 is evolutionary related to yeastprotein Shy1, which is a mitochondrial inner membrane protein required for assembly of cytochrome c oxidase [
]. There seems to be two transmembrane regions in these proteins,one in the N-terminal, the other in the C-terminal.
Defects in SURF1 are a cause of Leigh syndrome (LS). LS is a severe neurological disorder characterised by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency [
,
,
].
Amidohydrolases are a diverse superfamily of enzymes which catalyse the hydrolysis of amide or amine bonds in a large number of different substrates including urea, cytosine, AMP, formylmethanofuran, etc [
,
]. Also included in this superfamily are the phopshotriesterase enzymes, which hydrolyse P-O bonds. Members participate in a large number of processes including nucleotide metabolism, detoxification and neuronal development. They use a variety of divalent metal cofactors for catalysis: for example adenosine deaminase binds a single zinc ion, phopsphotriesterase binds two, while urease binds nickel. It has been postulated that since some of these proteins, such as those some of those involved in neuronal devlopment, appear to have lost their metal-binding centres, their function may simply be to bind, but not hydrolyse, their target molecules.This entry represents a subset of amidohydrolase domains that participate in different functions including cytosine degradation, atrazine degradation and other metabolic processes. The structure of the domain from Escherichia coli has been studied, and like other amidohydrolases it forms a classical α-β TIM-barrel fold []. The active site is located in the mouth of the enzyme barrel and contains a bound iron ion that coordinates a hydroxyl nucleophile. Substrate binding involves a significant conformational change that sequesters the reaction complex from solvent.
Prenylated Rab acceptor protein 1 (PRA1) family includes PRAF1/2/3 from mammals, Yip3 from budding yeasts and several PRA proteins from plants.In budding yeast, Yip3 interacts with members of the Rab GTPase family and may be involved in transport between the ER and Golgi complex [
].In humans, PRAF1 is a general Rab protein regulator required for vesicle formation from the Golgi complex. It may control vesicle docking and fusion by mediating the action of Rab GTPases to the SNARE complexes [
]. It inhibits the removal of Rab GTPases from the membrane by GDI []. PRAF2 plays a pro-apoptotic role in cerulenin-induced neuroblastoma apoptosis []. PRAF3 negatively modulates SLC1A1/EAAC1 glutamate transport activity by decreasing its affinity for glutamate [].
Ribulose-phosphate 3-epimerase (
) (also known as RPE, pentose-5-phosphate 3-epimerase or PPE) is the enzyme that converts D-ribulose 5-phosphate (Ru5P) into D-xylulose 5-phosphate in Calvin's reductive pentose phosphate cycle. In Ralstonia eutropha (Alcaligenes eutrophus) two copies of the gene coding for PPE are known [
], one is chromosomally encoded , the other one is on a plasmid
. PPE has been found in a wide range of bacteria, archaebacteria, fungi and plants. All the proteins have from 209 to 241 amino acid residues. The enzyme has a TIM barrel structure.
This family also includes other enzymes from the ribulose-phosphate 3-epimerase family, like D-allulose-6-phosphate 3-epimerase and other putative pentose-5-phosphate 3-epimerases. D-allulose-6-phosphate 3-epimerase catalyses the reversible epimerization of D-allulose 6-phosphate to D-fructose 6-phosphate, but it can also catalyse with lower efficiency the reversible epimerization of D-ribulose 5-phosphate to D-xylulose 5-phosphate [
].
Members of this protein family are part of the ribonuclease P complex (
) that takes part in endonucleolytic cleavage of RNA, removing 5'-extra-nucleotide from tRNA precursor. This process is essential for tRNA processing.
RNA polymerases catalyse the DNA dependent polymerisation of RNA. Prokaryotes contain a single RNA polymerase compared to three in eukaryotes (not including mitochondrial and chloroplast polymerases). This domain, domain 5, represents the discontinuous cleft domain that is required to form the central cleft or channel where the DNA is bound [
,
].
The task of transcribing nuclear genes is shared between three RNA polymerases in eukaryotes: RNA polymerase (pol) I synthesizes
the large rRNA, pol II synthesizes mRNA and pol III synthesizes tRNA and 5S rRNA []. Pol I transcription is localised to discrete sites called nucleoli; these can be likened to ribosomefactories, in which rRNA is synthesised by pol I in the fibrillar centres and then processed and assembled into ribosomes in
the surrounding granular regions []. Prokaryotes, in contrast, posses a single RNA polymerase, with transcription being controlled by the particular signam factor interacting with the catalytic core.This entry describes an N-terminal conserved region which can be found in the largest subunits of prokaryoptic and eukaryotic RNA polymerases.
RNA polymerases catalyse the DNA dependent polymerisation of RNA from DNA, using the four ribonucleoside triphosphates as substrates. Prokaryotes contain a single RNA polymerase compared to three in eukaryotes (not including mitochondrial and chloroplast polymerases). Eukaryotic RNA polymerase I is essentially used to transcribe ribosomal RNA units, polymerase II is used for mRNA precursors, and III is used to transcribe 5S and tRNA genes. Each class of RNA polymerase is assembled from nine to fourteen different polypeptides. Members of the family include the largest subunit from eukaryotes; the gamma subunit from Cyanobacteria; the beta'
subunit from bacteria; the A' subunit from archaea; and the B'' subunit from chloroplast RNA polymerases.
RNA polymerases catalyse the DNA dependent polymerisation of RNA. Prokaryotes contain a single RNA polymerase compared to three in eukaryotes (not including mitochondrial and chloroplast polymerases). This domain, domain 3, represents the pore domain. The 3' end of RNA is positioned close to this domain. The pore delimited by this domain is thought to act as a channel through which nucleotides enter the active site and/or where the 3' end of the RNA may be extruded during back-tracking [
,
,
].
RNA polymerases catalyse the DNA-dependent polymerisation of RNA. Prokaryotes contain a single RNA polymerase compared to three in eukaryotes (not including mitochondrial and chloroplast polymerases). This domain, domain 1, represents the clamp domain, which is a mobile domain involved in positioning the DNA, maintenance of the transcription bubble and positioning of the nascent RNA strand [
,
,
].
This conserved region is found in four-carbon acid sugar kinases from a range of Proteobacteria as well as the Gram-positive Oceanobacillus iheyensis. These four-carbon acid sugar kinases are composed of two domains: an N-terminal domain and a C-terminal domain connected by a variable linker sequence. The N-terminal domain exhibits an α/β-fold composed of an eight-stranded parallel β-sheet. The C-terminal domain also exhibits an α/β-fold composed of a seven-stranded mixed β-sheet. The acid sugar is bound by the N-terminal domain, while nucleotide by the C-terminal domain [
].Proteins containing this domain include D-threonate kinase from Salmonella typhimurium (DtnK), 3-oxo-tetronate kinase from Methylobacterium radiotolerans, 3-oxo-isoapionate kinase from Paraburkholderia graminis and D-erythronate kinase from Heliobacterium modesticaldum. DtnK catalyzes the ATP-dependent phosphorylation of D-threonate to D-threonate 4-phosphate and is also able to phosphorylate 4-hydroxy-L-threonine, which may serve to deal with the toxicity of this compound [
,
].
6-Phosphogluconate dehydrogenase (
) (6PGD) is an oxidative carboxylase that catalyses the decarboxylating reduction of 6-phosphogluconate into ribulose 5-phosphate in the presence of NADP. This reaction is a component of the hexose mono-phosphate shunt and pentose phosphate pathways (PPP) [
,
]. Prokaryotic and eukaryotic 6PGD are proteins of about 470 amino acids whose sequence are highly conserved []. The protein is a homodimer in which the monomers act independently []: each contains a large, mainly α-helical domain and a smaller β-α-β domain, containing a mixed parallel and anti-parallel six-stranded β-sheet []. NADP is bound in a cleft in the small domain, the substrate binding in an adjacent pocket []. This family represents the NADP binding domain of 6-phosphogluconate dehydrogenase which adopts a Rossman fold. The C-terminal domain is described in
.
This domain can also be found in 3-hydroxyisobutyrate dehydrogenases (HIBADH) and related proteins [
].
3-hydroxyisobutyrate dehydrogenase-related, conserved site
Type:
Conserved_site
Description:
This entry identifies a conserved site in reductases/dehydrogenases.3-hydroxyisobutyrate dehydrogenase (
) catalyzes the NAD-dependent, reversible oxidation of 3-hydroxbutyrate to methylmalonate [
]. In eukaryotes, it is a homodimeric mitochondrial protein involved in valine catabolism. In Pseudomonas aeruginosa [] (gene mmsB), it is involved in the distal valine metabolic pathway.2-hydroxy-3-oxopropionate reductase (
) catalyses the NAP(P)H dependent reduction of 2-hydroxy-3-oxopropionate (tartronate semialdehyde) to D-glycerate.
6-phosphogluconate dehydrogenase (
) catalyzes the NADP-dependent decarboxylation of 6-phosphogluconate to D-ribulose 5-phosphate and CO
2.
This entry contains related reductases/dehydrogenases:3-hydroxyisobutyrate dehydrogenase (HIBADH) (
) catalyzes the NAD-dependent, reversible oxidation of 3-hydroxbutyrate to methylmalonate [
]. In eukaryotes, it is a homodimeric mitochondrial protein involved in valine catabolism. In Pseudomonas aeruginosa [] (gene mmsB), it is involved in the distal valine metabolic pathway.2-hydroxy-3-oxopropionate reductase (
) catalyses the NAP(P)H dependent reduction of 2-hydroxy-3-oxopropionate (tartronate semialdehyde) to D-glycerate.
2-(hydroxymethyl)glutarate dehydrogenase (
) catalyses the conversion of 2-formylglutarate to (S)-2-hydroxymethylglutarate [].L-threonate dehydrogenase catalyses oxidation of L-threonate to 2-oxo-tetronate [
].Putative oxidoreductase GLYR1, also known as 3-hydroxyisobutyrate dehydrogenase-like protein or nuclear protein NP60, which regulates p38 MAP kinase activity [
].
Class-II aldolases [
], mainly found in prokaryotes and fungi, are homodimeric enzymes, which require a divalent metal ion, generally zinc, for their activity. They include fructose-bisphosphate aldolase [,
], a glycolytic enzyme that catalyses the reversible aldol cleavage or condensation of fructose-1,6-bisphosphate into dihydroxyacetone-phosphate and glyceraldehyde 3-phosphate. The family also includes the Escherichia coli galactitol operon protein, gatY, which catalyses the transformation of tagatose 1,6-bisphosphate into glycerone phosphate and D-glyceraldehyde 3-phosphate; and E. coli N-acetyl galactosamine operon protein, agaY, which catalyses the same reaction. There are two histidine residues in the first half of the sequence of these enzymes that have been shown to be involved in binding a zinc ion [].
Glycoside hydrolase, family 2, immunoglobulin-like beta-sandwich
Type:
Domain
Description:
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 2
comprises enzymes with several known activities: beta-galactosidase (); beta-mannosidase (
); beta-glucuronidase (
).
These enzymes contain a conserved glutamic acid residue which has been shown [
], in Escherichia coli lacZ (), to be the general acid/base catalyst in the active site of the enzyme.
This entry describes the immunoglobulin-like β-sandwich domain [
].
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 2
comprises enzymes with several known activities; beta-galactosidase (); beta-mannosidase (
); beta-glucuronidase (
).
These enzymes contain a conserved glutamic acid residue which has been shown [
], in Escherichia coli lacZ (), to be the general acid/base catalyst in the active site of the enzyme.
Beta-galactosidase from E. coli has a TIM-barrel-like core surrounded by four other largely beta domains [
].
This domain comprises the small chain of dimeric beta-galactosidases
. This domain is also found in single chain beta-galactosidase, which is comprised of five domains, where it represents domain 5. It contains an N-terminal loop that swings towards the active site upon the deep binding of a ligand to produce a closed conformation [
].
Phosphoethanolamine N-methyltransferase catalyses N-methylation of phosphoethanolamine, phosphomonomethylethanolamine and phosphodimethylethanolamine, the three methylation steps required to convert phosphoethanolamine to phosphocholine.
This family represents a group of glycosyltransferases from plants and fungi, including Mnn10/Mnn11 from budding yeasts, Gma12/Gmh1-3 from fission yeasts and xyloglucan 6-xylosyltransferase 1/2 (XXT1/XXT2) from Arabidopsis.Mnn10 and Mnn11 are subunits of a Golgi mannosyltransferase complex, which mediates elongation of the polysaccharide mannan backbone [
]. Gma12 is involved in the O- and N-linked oligosaccharide modification of proteins transported through the Golgi stack, while Gmh3 is involved in the galactosylation of the N-linked core oligosaccharide Man9GlcNAc2 [
].XXT1 and XXT2 are xylosyltransferases specific to UDP-D-xylose that accepts both cellopentaose and cellohexaose as substrates, with a better use of cellohexaose, to produce xyloglucan [
].
This family consists of previously named Reversibly Glycosylated Proteins (RGPs), which are plant-specific cytosolic proteins that tend to associate with the Golgi membranes and have been implicated in polysaccharide biosynthesis [
,
,
,
]. In Arabidopsis thaliana the RGP protein family consists of five closely related members, three of which have been identified as UDP-arabinopyranose mutases that catalyze the formation of UDP-L-arabinofuranose (UDP-Araf) from UDP-Larabinopyranose (UDP-Arap). This interconversion is essential for cell wall establishment and plant development []..
Trm1 (
) dimethylates a single guanine residue at position 26 of a number of tRNAs using S-adenosyl-L-methionine as donor of the methyl groups [
,
]. In Saccharomyces cerevisiae, Trm1 is required for the modification of both mitochondrial and cytoplasmic tRNAs [].
This entry represents a group of plant-type phosphatidylinositol-4-phosphate 5-kinases (PIP5K;
), which play an essential role in coordinating plant growth, especially in response to environmental factors. This enzyme phosphorylates phosphatidylinositol-4-phosphate to produce phosphatidylinositol-4,5-bisphosphate as a precursor of two second messengers, inositol-1,4,5-triphosphate and diacylglycerol, and as a regulator of many cellular proteins involved in signal transduction and cytoskeletal organisation. This enzyme is involved in flowering, and may suppress floral initiation by modifying the expression of genes related to floral induction. It appears to be stress-induced [
,
].
Sigma-2 receptor, also known as TMEM97, is an intracellular orphan receptor highly expressed in various rapidly proliferating cancer cells and regarded as a cancer cell biomarker. It is a cytochrome-related protein that binds to various pharmacological compounds, and modulates the cytosolic Ca2+ concentration, dopaminergic transmission, and cocaine-induced addiction behavior [
,
,
]. It may have a role as regulator of cellular cholesterol homeostasis [] and function as a sterol isomerase [].
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 domain constitutes a conserved region found in proteins that participate in diverse functions relevant to chromosome metabolism and cell cycle control [
].The domain contains 8 cysteine/ histidine residues which are proposed to be the conserved residues involved in zinc binding.
This entry represents the C-terminal domain of Valyl-tRNA synthetase, which consists of two helices in a long alpha-hairpin [
].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [
,
]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [,
,
]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].
Class I and II aminoacyl-tRNA synthetase, tRNA-binding arm
Type:
Homologous_superfamily
Description:
This superfamily represents an α-helical tRNA-binding arm found in class I and II aminoacyl-tRNA synthetase enzymes, as well as in the methicillin resistance protein FemA.The tRNA-binding arm domain is conserved between class I and class II aminoacyl-tRNA synthetase enzymes (
), consisting of two alpha helices in an antiparallel hairpin with a left-handed twist. The appended tRNA-binding domains recognise a small number of nucleotides that are conserved specifically in each cognate tRNA species for the discrimination between the cognate and noncognate tRNAs [
]. These nucleotides are called identity elements, and constitute the identity set. The tRNA-binding arm occurs as the C-terminal domain in some class I enzymes, such as valyl-tRNA synthetase, and as the N-terminal domain in some class II enzymes, such as phenylalanyl-tRNA synthetase.The methicillin resistance protein, FemA (factors essential for methicillin resistance), contains a probable tRNA-binding arm that is similar in structure to those found in tRNA synthetases. In FemA, the tRNA-binding arm is inserted into the C-terminal NAT-like domain, and is thought to bind tRNA-glycine. FemA, along with FemB and FemX, plays a vital role in peptidoglycan biosynthesis specific to Staphylococci [].
