SII-SWORD/CoKE huggingface dataset:
H/ACA ribonucleoprotein complex, subunit Nhp2-like (H/ACA_rnp_Nhp2-like)
Type: Family

This entry represents H/ACA ribonucleoprotein complex subunit NHP2 and similar proteins from eukaryotes, including NHP2-like protein 1 from mammals (SNU13 homologue) and 13 kDa ribonucleoprotein-associated protein (SNU13) from yeast.

Nhp2 is part of a complex which catalyses pseudouridylation of rRNA and is required for rRNA biogenesis. This involves the isomerisation of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Pseudouridine ("psi") residues may serve to stabilise the conformation of rRNAs. Nph2 associates non-specifically with RNA secondary structures instead of directly binding to an specific RNA motif. This protein seem to have evolved from the archaeal ribosomal L7Ae protein family .

H/ACA ribonucleoprotein particles (RNPs) are a family of RNA pseudouridine synthases that specify modification sites through guide RNAs. The function of these H/ACA RNPs is essential for biogenesis of the ribosome, splicing of precursor mRNAs (pre-mRNAs), maintenance of telomeres and probably for additional cellular processes . All H/ACA RNPs contain a specific RNA component (snoRNA or scaRNA) and at least four proteins common to all such particles: Cbf5, Gar1, Nhp2 and Nop10. These proteins are highly conserved from yeast to mammals and homologues are also present in archaea . The H/ACA protein complex contains a stable core composed of Cbf5 and Nop10, to which Gar1 and Nhp2 subsequently bind .
Type II secretion system protein GspH-like (T2SS_protein-GspH)
Type: Family

This entry includes type II secretion system protein H and closely related proteins. The proteins of the type II secretion system (T2SS) are named Gsp in general and Eps in V. cholerae. EpsH is a GspH homologue and one of the minor pseudopilin components of the T2SS. This protein has been structurally characterised . It adopts an α/β structure, in which a hydrophobic helix is cradled by a pair of four-stranded antiparallel β-sheets.

The type II secretion system (T2SS) is one of several extracellular secretion systems in gram-negative bacteria. It delivers toxins and a range of hydrolytic enzymes including proteases, lipases and carbohydrate-active enzymes to the cell surface or extracellular space . T2SS systems are composed of 11 to 15 different proteins, which are generally called GspA to GspO and GspS. The T2SS spans the two bacterial membranes and ensures secretion of folded proteins across the outer membrane pore formed by GspD. The inner membrane complex contains GspC, GspL, GspM, and GspF. The cytoplasmic domains of GspL and GspF interact with an ATPase, GspE. GspE is thought to energize the formation of a short pseudopilus by several pilin-like proteins, GspG to GspK . GspD has been shown to interact with the inner membrane component GspC .
Viral spike glycoprotein (Spike_prot)
Type: Family

The glycoproteins of viral haemorrhagic scepticaemia virus and of infectious hematopoietic necrosis virus are similar, and are responsible for forming spikes on the surface of the virion. The glycoprotein mediates binding of the virus to susceptible host cells and induces uptake of the virus by the cell. The interaction between the internal components of the virion and the portion of the glycoprotein exposed on the cytoplasmic face of the plasma membrane probably directs envelopment and virus budding.
Transcription regulator Myc (Tscrpt_reg_Myc)
Type: Family

The class III basic helix-turn-helix (bHLH) transcription factors have proliferative and apoptotic roles and are characterised by the presence of a leucine zipper adjacent to the bHLH domain. The myc oncogene was first discovered in small-cell lung cancer cell lines where it is found to be deregulated . The Myc protein contains an N-terminal transcriptional regulatory domain followed by a nuclear localization signal and a C-terminal basic DNA binding domain tethered to a helix-loop-helix-leucine zipper (HLH-Zip) dimerization motif. Myc forms a heterodimer with Max, and this complex regulates cell growth through direct activation of genes involved in cell replication .

The `leucine zipper' is a structure that is believed to mediate the function of several eukaryotic gene regulatory proteins. The zipper consists of a periodic repetition of leucine residues at every seventh position, and regions containing them appear to span eight turns of α-helix. The leucine side chains that extend from one helix interact with those from a similar helix, hence facilitating dimerisation in the form of a coiled-coil. Leucine zippers are present in many gene regulatory proteins, including the CREB proteins, Jun/AP1 transcription factors, fos oncogene and fos-related proteins, C-myc, L-myc and N-myc oncogenes, and so on.
C2 phosphatidylinositol 3-kinase-type domain (PI3K-type_C2_dom)
Type: Domain

Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate 4,5-bisphonate (PI(4,5) P2 or PIP2) at the 3-position of the inositol ring, and thus generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which, in turns, initiates a vast array of signaling events. PI3Ks can be grouped into
three classes based on their domain organisation. Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a regulatory subunit of either the p85 type (associated with the class IA p110 isoforms p110alpha, p110beta or p110delta) or the p101 type (associated with the class IB p110
isoform p110gamma). Common to all catalytic subunits are an N-terminal adaptor-binding domain (ABD) that binds to p85/p101, a Ras- binding domain (RBD), a putative membrane-binding domain (C2), a helical domain of unknown function, and a kinase catalytic domain. Class II PI3Ks lack the ABD domain and are distinguished by a carboxy terminal C2 domain. Class III enzymes lack the ABD and RBD domains .

The PI3K-type C2 domain is an eight-stranded antiparallel β-sandwich consisting of two four-stranded β-sheets .
5'-3' exonuclease (5-3_exonuclease)
Type: Domain

This entry represents flap endonucleases from eukaryotes, bacteria, viruses and archaea. Flap endonucleases (FENs) catalyse the exonucleolytic hydrolysis of blunt-ended duplex DNA substrates and the endonucleolytic cleavage of 5'-bifurcated nucleic acids at the junction formed between single and double-stranded DNA .

In prokaryotes, the essential FEN reaction can be performed by the N-terminal 5'-3' exonuclease domain present on DNA polymerase I. Some eubacteria, however, possess a second gene encoding a 5'-3' exonuclease domain . Two distinct classes of these independent bacterial FENs exist: Xni (ExoIXI) from Escherichia coli and SaFEN (Staphylococcus aureus FEN). SaFEN has both FEN and 5'-3' exonuclease activities. Xni (ExoIX) was previously identified as a 3'-5' exonuclease and named exonuclease IX (exonuclease 9) but subsequently found to possess flap endonuclease activity, but not exonuclease activity .

Archaea, eukaryotes, bacteriophages and some viruses encode a separate FEN enzyme but lack FEN domains on their DNA polymerases . Escherichia phage T5 encodes the flap endonuclease D15, which catalyzes both the 5'-exonucleolytic and structure-specific endonucleolytic hydrolysis of DNA branched nucleic acid molecules . In bacteriophage T4, disruption of the rnh gene (which encodes a FEN, known historically as T4 RNase H) results in slower, less accurate DNA replication. Bacteriophage T4 has both 5' nuclease and flap endonuclease activities .
Chaperonin Cpn60/GroEL/TCP-1 family (Cpn60/GroEL/TCP-1)
Type: Family

The assembly of proteins has been thought to be the sole result of properties inherent in the primary sequence of polypeptides themselves. In some cases, however, structural information from other protein molecules is required for correct folding and subsequent assembly into oligomers . These 'helper' molecules are referred to as molecular chaperones, a subfamily of which are the chaperonins , which include 10kDa and 60kDa proteins. These are found in abundance in prokaryotes, chloroplasts and mitochondria. They are required for normal cell growth (as demonstrated by the fact that no temperature sensitive mutants for the chaperonin genes can be found in the temperature range 20 to 43 degrees centigrade ), and are stress-induced, acting to stabilise or protect disassembled polypeptides under heat-shock conditions .

The 10kDa chaperonin (Cpn10) and its bacterial homologue groES, exist as a ring-shaped oligomer of between 6 to 8 identical subunits, whereas the 60kDa chaperonin (Cpn60) and its bacterial homologue groEL, form a structure comprising 2 stacked rings, each ring containing 7 identical subunits . These ring structures assemble by self-stimulation in the presence of Mg2+-ATP. The Cpn10 and Cpn60 oligomers also require Mg2+-ATP in order to interact to form a functional complex, although the mechanism of this interaction is as yet unknown . This chaperonin complex is essential for the correct folding and assembly of polypeptides into oligomeric structures, of which the chaperonins themselves are not a part . The binding of Cpn10 to Cpn60 inhibits the weak ATPase activity of Cpn60.

TCP-1 (t-complex polypeptide 1) is a subunit of the hetero-oligomeric complex CCT (chaperonin containing TCP- 1) present in the eukaryotic cytosol. It is a member of the chaperonin family which includes GroEL, 60kDa heat shock protein (Hsp60), Rubisco subunit binding protein (RBP) and thermophilic factor 55 (TF55) .

BBS10 and BBS10 chaperonins play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia .
Alcohol dehydrogenase, Ceratitis-type (ADH_Ceratitis-type)
Type: Family

The short-chain dehydrogenases/reductases family (SDR) is a very large family of enzymes, most of which are known to be NAD- or NADP-dependent oxidoreductases. As the first member of this family to be characterised was Drosophila alcohol dehydrogenase, this family used to be called 'insect-type', or 'short-chain' alcohol dehydrogenases. Most members of this family are proteins of about 250 to 300 amino acid residues. Most dehydrogenases possess at least two domains , the first binding the coenzyme, often NAD, and the second binding the substrate. This latter domain determines the substrate specificity and contains amino acids involved in catalysis. Little sequence similarity has been found in the coenzyme binding domain although there is a large degree of structural similarity, and it has therefore been suggested that the structure of dehydrogenases has arisen through gene fusion of a common ancestral coenzyme nucleotide sequence with various substrate specific domains .

Insect ADH is very different from yeast and mammalian ADHs. The enzyme from Drosophila lebanonensis (Fruit fly) has been characterised by protein analysis and was found to have a 254-residue protein chain with an acetyl-blocked N-terminal Met . Comparisons with the enzyme from other species reveals that they have diverged considerably. The structural variation within Drosophila is about as large as that for mammalian zinc-containing alcohol dehydrogenase. The crystal structure of the apo form of D. lebanonensis ADH has been solved to 1.9A resolution. Three structural features characterise the active site architecture: (i) a deep cavity, covered by a flexible 33-residue loop and an 11-residue C-terminal tail of the neighbouring subunit, whose hydrophobic surface is likely to increase the specificity of the enzyme for secondary aliphatic alcohols; (ii) the Ser-Tyr-Lys residues of the catalytic triad are known to be involved in enzymatic catalysis; and (iii) three well-ordered water molecules in hydrogen bonding distance of side-chains of the catalytic triad may be significant for the proton release steps in the catalysis.

A number of proteins within the SDR family share a strong phylogenetic relationship with insect ADH. Amongst these are Drosophila ADH-related protein (duplicate of Adh or Adh-dup) ; Drosophila fat body protein; and development-specific 25Kd protein from Sarcophaga peregrina (Flesh fly). This group specifically identifies proteins related to Ceratitis capitata (Mediterranean fruit fly).
Alcohol dehydrogenase-related (ADH-rel)
Type: Family

The short-chain dehydrogenases/reductases family (SDR) is a very large family of enzymes, most of which are known to be NAD- or NADP-dependent oxidoreductases. As the first member of this family to be characterised was Drosophila alcohol dehydrogenase, this family used to be called 'insect-type', or 'short-chain' alcohol dehydrogenases. Most members of this family are proteins of about 250 to 300 amino acid residues. Most dehydrogenases possess at least two domains , the first binding the coenzyme, often NAD, and the second binding the substrate. This latter domain determines the substrate specificity and contains amino acids involved in catalysis. Little sequence similarity has been found in the coenzyme binding domain although there is a large degree of structural similarity, and it has therefore been suggested that the structure of dehydrogenases has arisen through gene fusion of a common ancestral coenzyme nucleotide sequence with various substrate specific domains .

Insect ADH is very different from yeast and mammalian ADHs. The enzyme from Drosophila lebanonensis (Fruit fly) has been characterised by protein analysis and was found to have a 254-residue protein chain with an acetyl-blocked N-terminal Met . Comparisons with the enzyme from other species reveals that they have diverged considerably. The structural variation within Drosophila is about as large as that for mammalian zinc-containing alcohol dehydrogenase. The crystal structure of the apo form of D. lebanonensis ADH has been solved to 1.9A resolution . Three structural features characterise the active site architecture: (i) a deep cavity, covered by a flexible 33-residue loop and an 11-residue C-terminal tail of the neighbouring subunit, whose hydrophobic surface is likely to increase the specificity of the enzyme for secondary aliphatic alcohols; (ii) the Ser-Tyr-Lys residues of the catalytic triad are known to be involved in enzymatic catalysis; and (iii) three well-ordered water molecules in hydrogen bonding distance of side-chains of the catalytic triad may be significant for the proton release steps in the catalysis.

A number of proteins within the SDR family share a strong phylogenetic relationship with insect ADH. Amongst these are Drosophila ADH-related protein (duplicate of Adh or Adh-dup) ; drosophila fat body protein; and development-specific 25Kd protein from Sarcophaga peregrina (Flesh fly).
Cytochrome c oxidase subunit II-like C-terminal (CcO_II-like_C)
Type: Domain

Cytochrome c oxidase (

) is an oligomeric enzymatic complex which is a component of the respiratory chain and is involved in the transfer of electrons from cytochrome c to oxygen. In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane. The number of polypeptides in the complex ranges from 3-4 (prokaryotes), up to 13(mammals). In Archaea, a cytochrome-c-type oxidase from Natronobacterium (cytochrome ba3) has been shown to consists of four subunits .

Subunit 2 (CO II) transfers the electrons from cytochrome c to the catalytic subunit 1. It contains two adjacent transmembrane regions in its N terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrial intermembrane space, respectively. CO II provides the substrate-binding site and contains a copper centre called Cu(A), probably the primary acceptor in cytochrome c oxidase. An exception is the corresponding subunit of the cbb3-type oxidase which lacks the copper A redox-centre. Several bacterial CO II have a C-terminal extension that contains a covalently bound haem c.

It has been shown that nitrous oxide reductase (gene nosZ) of Pseudomonas has sequence similarity in its C terminus to CO II. This enzyme is part of the bacterial respiratory system which is activated under anaerobic conditions in the presence of nitrate or nitrous oxide. NosZ is a periplasmic homodimer that contains a dinuclear copper centre, probably located in a 3-dimensional fold similar to the cupredoxin-like fold that has been suggested for the copper-binding site of CO II .
Sodium:neurotransmitter symporter, taurine (Na/ntran_symport_taurine)
Type: Family

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .

Cells regulate their volume and adapt to alterations in the tonicity of their local environment by adjusting their solute content accordingly. Resultant water movements rapidly establish osmotic balance. Solutes utilised in this manner are referred to as osmolytes and include: glycerophosphorylcholine, betaine, myo-inositol, sorbitol and taurine . Cell membrane transporters for betaine and taurine have been cloned, and by sequence similarity they have been shown to belong to the Na
+
and Cl
-
-coupled neurotransmitter transporter superfamily. The taurine transporter has a predicted length of ~620 amino acids and can also transport beta-alanine. It has been found to be widely distributed in the body, with transcripts being detected in the kidney (high abundance), ileal mucosa, liver, heart and in several regions of the brain including: the corpus callosum, striatum and anterior commisure. Functional studies have revealed that taurine transporter activity is regulated by hypertonicity, and this regulation appears to occur at the level of mRNA accumulation .
Sodium:neurotransmitter symporter, noradrenaline (Na/ntran_symport_noradrenaline)
Type: Family

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .

The human noradrenaline transporter is the primary target for
widely-used tricyclic antidepressant drugs, such as desipramine. Cloning studies
have revealed a single noradrenaline transporter isoform. The cDNA sequence
predicts a protein of ~617 amino acids, with 12-13 highly hydrophobic
regions, as would be expected for a member of the Na
+
and Cl
-
-coupled
neurotransmitter superfamily . In humans, this protein has been related to generalized anxiety disorder, bipolar disorder and schizophrenia . Related noradrenaline transporter species
have been identified in both Drosophila and Rana catesbeiana (Bull frog). In mammalian species,
mRNA for the transporter is localised to the brainstem and the adrenal
glands. Chromosome mapping has placed the encoding gene to chromosome
16q12.2 in humans . Recently, a bovine noradrenaline transporter variant
has been identified that shows altered targeting to the plasma membrane.
This has implicated the cytoplasmic facing C terminus in the intracellular
trafficking of this protein .
Sodium:neurotransmitter symporter, dopamine (Na/ntran_symport_dopamine)
Type: Family

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .

In the mammalian brain, the dopamine system is thought to be involved in the control of locomotion, cognition and endocrine function. The dopamine transporter is critical for the removal of dopamine from the extracellular space, following its release, and is the principal site of action for psycho-stimulant drugs, such as cocaine and amphetamines, which inhibit the transporter's activity. A single form of dopamine transporter (containing ~620 amino acids) has been isolated from humans and other mammals. Studies of its brain distribution show transcripts to be present in areas previously established to possess dopaminergic systems, such as the substantia nigra and ventral tegmental area, which regions are known to contain dopaminergic cell bodies . Targeted gene disruption of the dopamine transporter has confirmed its importance in maintaining low extracellular dopamine levels. Mice lacking the transporter show profound alterations in the homeostasis of the nigrostriatal dopamine system of the brain. Extracellular levels of dopamine are elevated and removal of released dopamine is ~300 times slower then in control mice. Additionally, the rather stereotyped behavioural responses observed in response to administration of cocaine or amphetamine are greatly attenuated .