SII-SWORD/CoKE huggingface dataset:
Peptidase M20 (Peptidase_M20)
Type: Family

This group of proteins contains the metallopeptidases and non-peptidase homologues (amidohydrolases) that belong to the MEROPS peptidase family M20 (clan MH) . The peptidases of this clan have two catalytic zinc ions at the active site, bound by His/Asp, Asp, Glu, Asp/Glu and His. The catalysed reaction involves the release of an N-terminal amino acid, usually neutral or hydrophobic, from a polypeptide . The peptidase M20 family has four subfamilies:

M20A -type example, glutamate carboxypeptidase from Pseudomonas sp. RS16 (

)

M20B -type example, peptidase T from Escherichia coli (

)

M20C -type example, X-His dipeptidase from E. coli (

)

M20D -type example, carboxypeptidase Ss1 from Sulfolobus solfataricus (

)

Homologues from the family that are not peptidases include:

Acetylornithine deacetylase, which releases an acetyl group and L-ornithine from N(2)-acetyl-L-ornithine

N-acetyldiaminopimelate deacetylase, which catalyses the conversion of N-acetyl-diaminopimelate to diaminopimelate and acetate

N-carbamoyl-L-amino-acid hydrolase, which converts D,L-5-monosubstituted hydantoins into D-or L-amino acids

Aminoacylase-1, which hydrolyses N-acylated or N-acetylated amino acids

Succinyl-diaminopimelate desuccinylase (

), which catalyses the hydrolysis of N-succinyl-L,L-diaminopimelic acid, forming succinate and LL-2,6-diaminoheptanedioate (DAP, a component of bacterial cell walls)
Polymerase, nucleotidyl transferase domain (Polymerase_NTP_transf_dom)
Type: Domain

A small region that overlaps with a nuclear localization signal and binds to the RNA primer contains three aspartates that are essential for catalysis. Sequence and secondary structure comparisons of regions surrounding these aspartates with sequences of other polymerases revealed a significant homology to the palm structure of DNA polymerase beta, terminal deoxynucleotidyltransferase and DNA polymerase IV of Saccharomyces cerevisiae, all members of the family X of polymerases. This homology extends as far as cca: tRNA nucleotidyltransferase and streptomycin adenylyltransferase, an antibiotic resistance factor .

Proteins containing this domain include kanamycin nucleotidyltransferase (KNTase) which is a plasmid-coded enzyme responsible for some types of bacterial resistance to aminoglycosides. KNTase inactivates antibiotics by catalysing the addition of a nucleotidyl group onto the drug. In experiments, Mn2+ strongly stimulated this reaction due to a 50-fold lower Ki for 8-azido-ATP in the presence of Mn2+. Mutations of the highly conserved Asp residues 113, 115, and 167, critical for metal binding in the catalytic domain of bovine poly(A) polymerase, led to a strong reduction of cross-linking efficiency, and Mn2+ no longer stimulated the reaction. Mutations in the region of the "helical turn motif" (a domain binding the triphosphate moiety of the nucleotide) and in the suspected nucleotide-binding helix of bovine poly(A) polymerase impaired ATP binding and catalysis. The results indicate that ATP is bound in part by the helical turn motif and in part by a region that may be a structural analogue of the fingers domain found in many polymerases.
Class I-like SAM-dependent O-methyltransferase (SAM_O-MeTrfase)
Type: Family

Members of this family are O-methyltransferases, including catechol O-methyltransferase , caffeoyl-CoA O-methyltransferase and norbelladine 4'-O-methyltransferase . The family includes also bacterial O-methyltransferases that may be involved in antibiotic production .
Amine oxidase (Amino_oxidase)
Type: Domain

This entry consists of various amine oxidases, including maize polyamine oxidase (PAO) , L-amino acid oxidases (LAO) and various flavin containing monoamine oxidases (MAO). The aligned region includes the flavin binding site of these enzymes. In vertebrates, MAO plays an important role in regulating the intracellular levels of amines via their oxidation; these include various neurotransmitters, neurotoxins and trace amines . In lower eukaryotes such as aspergillus and in bacteria the main role of amine oxidases is to provide a source of ammonium . PAOs in plants, bacteria and protozoa oxidise spermidine and spermine to an aminobutyral, diaminopropane and hydrogen peroxide and are involved in the catabolism of polyamines . Other members of this group include tryptophan 2-monooxygenase, putrescine oxidase, corticosteroid binding proteins and antibacterial glycoproteins.
FAD-binding domain (FAD-bd)
Type: Domain

This domain is involved in FAD binding in a number of enzymes, including human Kynurenine 3-monooxygenase (KMO), which is related to neuroinflammatory conditions , archaeal Digeranylgeranylglycerophospholipid reductase (GGR), involved in the biosynthesis of archaeal membrane lipids and bacterial 3-(3-hydroxy-phenyl)propionate/3-hydroxycinnamic acid hydroxylase (MhpA).
Chaperone DnaJ, C-terminal (DnaJ_C)
Type: Domain

Molecular chaperones are a diverse family of proteins that function to protect proteins in the intracellular milieu from irreversible aggregation during synthesis and in times of cellular stress. The bacterial molecular chaperone DnaK is an enzyme that couples cycles of ATP binding, hydrolysis, and ADP release by an N-terminal ATP-hydrolizing domain to cycles of sequestration and release of unfolded proteins by a C-terminal substrate binding domain. Dimeric GrpE is the co-chaperone for DnaK, and acts as a nucleotide exchange factor, stimulating the rate of ADP release 5000-fold . DnaK is itself a weak ATPase; ATP hydrolysis by DnaK is stimulated by its interaction with another co-chaperone, DnaJ. Thus the co-chaperones DnaJ and GrpE are capable of tightly regulating the nucleotide-bound and substrate-bound state of DnaK in ways that are necessary for the normal housekeeping functions and stress-related functions of the DnaK molecular chaperone cycle.

Besides stimulating the ATPase activity of DnaK through its J-domain, DnaJ also associates with unfolded polypeptide chains and prevents their aggregation . Thus, DnaK and DnaJ may bind to one and the same polypeptide chain to form a ternary complex. The formation of a ternary complex may result in cis-interaction of the J-domain of DnaJ with the ATPase domain of DnaK. An unfolded polypeptide may enter the chaperone cycle by associating first either with ATP-liganded DnaK or with DnaJ. DnaK interacts with both the backbone and side chains of a peptide substrate; it thus shows binding polarity and admits only L-peptide segments. In contrast, DnaJ has been shown to bind both L-and D-peptides and is assumed to interact only with the side chains of the substrate.

This domain consists of the C-terminal region of the DnaJ protein. The function of this domain is unknown. It is found associated with

and

.
DnaJ is a chaperone associated with the Hsp70 heat-shock system involved in protein folding and renaturation after stress. The two C-terminal domains CTDI and this, CTDII, are necessary for maintaining the J-domains in their specific relative positions .
DNA methylase N-4/N-6 (DNA_methylase_N4/N6)
Type: Domain

This domain is found in DNA methylases. In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. This family contains both N-4 cytosine-specific DNA methylases and N-6 Adenine-specific DNA methylases. N-4 cytosine-specific DNA methylases (

) are enzymes that specifically methylate the amino group at the C-4 position of cytosines in DNA. Such enzymes are found as components of type II restriction-modification systems in prokaryotes. Such enzymes recognise a specific sequence in DNA and methylate a cytosine in that sequence. By this action they protect DNA from cleavage by type II restriction enzymes that recognise the same sequence. N-6 adenine-specific DNA methylases (

) (A-Mtase) are enzymes that specifically methylate the amino group at the C-6 position of adenines in DNA. Such enzymes are found in the three existing types of bacterial restriction-modification systems (in type I system the A-Mtase is the product of the hsdM gene, and in type III it is the product of the mod gene). All of these enzymes recognise a specific sequence in DNA and methylate an adenine in that sequence.
RNA-binding S4 domain (S4_RNA-bd)
Type: Domain

The S4 domain is a small domain consisting of 60-65 amino acid residues that was detected in the bacterial small ribosomal subunit protein uS4, eukaryotic ribosomal uS4 (also known as S9), two families of pseudouridine synthases, a novel family of predicted RNA methylases, a yeast protein containing a pseudouridine synthetase and a deaminase domain, bacterial tyrosyl-tRNA synthetases, and a number of uncharacterised, small proteins that may be involved in translation regulation . The S4 domain probably mediates binding to RNA .
Sodium:neurotransmitter symporter, inebriated (Na/ntran_symport_inebriated)
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 .

On the basis of behavioural interactions with mutations in the Shaker K
+
channel gene of Drosophila, mutations in a new gene, called inebriated (ine), were isolated. Considering the distinctive phenotype displayed by these flies, it was postulated that the ine mutation might increase neuronal excitability . Subsequently the ine mutation was mapped, and the gene was cloned. The ine gene encodes a protein of 658 amino acids with a high degree of sequence similarity to members of the Na
+
/Cl
-
-dependent neurotransmitter transporter superfamily. Therefore ine mutations may cause increased excitability of the drosophila motor neuron, as a result of defective re-uptake of its substrate neurotransmitter, the identity of which remains to be determined . This neurotransmitter is also important for perinerual gilial growth and has also been shown to act as an osmolyte transporter .
Intracellular chloride channel (CLIC)
Type: Family

The chloride intracellular channel (CLIC) family represent a subgroup of the glutathione-S-transferase (GSTs) superfamily. CLIC proteins can exist as both soluble globular proteins and integral membrane proteins with ion channel function . Membrane insertion seems to be redox-regulated and has a strong pH dependence . CLIC proteins are enigmatic as they do not fit the patterns of other, well-characterised ion channel proteins that show clear and often multiple TM domains . They share a conserved C-terminal CLIC module, with several members containing additional, unrelated N-terminal domains. CLIC proteins are highly conserved in vertebrates, which usually possess six distinct paralogues (CLIC1-CLIC6) . They are multifunctional proteins and participate in a wide variety of signaling activities.
Thiazide-sensitive Na-K-Cl co-transporter (SLC12A3)
Type: Family

Solute carrier family 12 member 3 (Slc12a3) is also known as Tsc (thiazide-sensitive Na-Cl co-transporter). Tsc is a large integral membrane protein (~1000 amino acids) that mediates the coupled transport of Na
+
and Cl
-
in an electrically silent manner. In the mammalian kidney, it is the dominant mechanism mediating Cl
-
absorption in the early distal tubule, and here it is the target of the widely-used thiazide class of diuretic drugs. It is also known to be present in the urinary bladder of the winter flounder (Pseudopleuronectes americanus), from where the gene encoding it was initially cloned .

Hydrophobicity analysis predicts the Na-Cl co-transporter to have 12 transmembrane (TM) domains and comparisons with other cloned ion co-transporters reveals that a superfamily of electroneutral cation-chloride co-transporters exists, which includes the K-Cl co-transporters (

) and the Na-K-Cl co-transporters (

). All share a similar predicted membrane topology in a central hydrophobic domain, together with hydrophilic N- and C-termini that are likely cytoplasmic .

Mutations in the thiazide-sensitive Na-Cl co-transporter have been found that give rise to Gitelman's variant of Bartter's syndrome, an inherited kidney disease characterised by hypokalaemic alkalosis .
Atrophin-like (Atrophin-like)
Type: Family

Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins . The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteristic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity .

This entry includes Atrophin-1 and related proteins.
Filoviridae VP35 protein (Filo_VP35)
Type: Family

The filoviridae are a group of viruses that cause haemorrhagic fevers with a high mortality rate. The family currently contains three viruses: Ebola virus sp., Lake Victoria marburgvirus and Reston ebolavirus, named after their corresponding outbreak regions. They possess negative-stranded RNA genomes, which encode at least 7 proteins. The VP35 protein is found in the genomes of all filoviruses. Its function is presently unknown, but it is thought to share the function of the phosphorylated proteins (polymerase subunits) of rhabdoviruses and paramyxoviruses due to its position in the genome. There is no evidence however, to suggest that VP35 is phosphorylated .
Salmonella surface presentation of antigen M protein (Salm_SPAgM)
Type: Family

The Salmonella typhimurium Surface Presentation of Antigens M gene (SpaM) is one of 12 that form a cluster responsible for invasion properties . The gene product is required for entry by the bacterium into epithelial cells, and is thus considered to be a virulence factor . Other Spa genes in the cluster are related to invasion (Inv) genes in similar Salmonella and Shigella species , and flagella biosynthesis genes in Helicobacter pylori .

A homologue of this protein has been found recently in Salmonella enterica . The protein, named InvI, is required by the organism to gain access to mammalian epithelial cells, and cellular mutants (InvI-) failed to successfully infect these cells. It has also been found that the inv-spa loci of this particular species encode for a type III protein secretion system, essential in the bacterium's host cell invasion process .
Microtubule-associated protein Tau (Tau)
Type: Family

Tau proteins are microtubule-associated proteins that are involved in microtubule assembly and stabilisation. They may also play a wider role in cellular shape, motility and signal transduction . Tau mRNA is expressed predominantly in neurones, and particularly in their axons. Quite a number of isoforms have been detected, which in human brain have been shown to arise from alternative splicing of an mRNA from a single gene located on chromosome 17. The isoforms contain 352-441 amino acid residues. A larger tau isoform has also been detected, which is expressed principally in the peripheral nervous system .

Each isoform contains a variable number of C-terminal repeat regions that are thought to be responsible for tubulin-binding. The acidic N-terminal region projects from the micro-tubule surface when Tau is bound and may interact with other cytoskeletal elements. The middle region is proline-rich and may be a further binding site. It contains the target sites of many kinases, phosphorylation of this region may result in a change in the conformational state of the protein, and affect its ability to bind microtubules .

Tau does not appear to be an essential protein, since transgenic mice lacking tau appear to develop a normal nervous system with only mild alterations in the structure of certain small-calibre axons . However, it has received much recent attention due to its possible role in the aetiogenesis of a number of human neurodegenerative diseases, filamentous inclusions containing tau having been found in the brains of patients diagnosed with Alzheimer's disease, Pick's disease and progressive supranuclear palsy. Furthermore, tau gene mutations have been found in patients suffering familial frontotemporal dementia, which result in abnormal tau protein aggregates forming in the brain tissue .
Bride of sevenless protein (Bride_of_7less)
Type: Family

During development of the Drosophila retina, the bride of sevenless (boss) gene is required in photoreceptor neuron R8 for the development of photoreceptor neuron R7, suggesting that boss encodes or regulates an R7-specific inductive cue . The induction of R8 photoreceptor neuron neighbouring cells to assume an R7 cell fate is believed to be mediated by a direct interaction of boss with sevenless . An alternative model has been proposed in which the boss protein functions as a receptor, based on a (superficial) similarity to the G-protein-coupled family of membrane receptors . The boss gene encodes a protein of 896 amino acids with a putative N-terminal signal sequence, a large N-terminal extra-cellular domain, seven transmembrane (TM) segments and a C-terminal cytoplasmic tail . The boss protein from Drosophila virilis (Fruit fly) shares a high level of amino acid identity with the Drosophila melanogaster (Fruit fly) homologue, with highest levels of similarity in the TM domains .
Keratin, type I (Keratin_I)
Type: Family

Keratins are a well known group of intermediate filament proteins. Like actin filaments, keratins are flexible but provide a firm cell skeleton . Unlike actin, however, no known keratins are associated with motor functions. Approximately 10 keratins form the basis of hair or claw, with a further 20 found in internal body cavity epithelia. They are also found at desmosomes and hemi-desmosomes (cell/cell and cell/matrix contacts respectively). Type I keratins are a group of acidic intermediate filament proteins that exist as chains of hetero-dimers with basic type II keratins. Each type I keratin consists of head-, rod- and tail-like structures, the rod being constructed from three linked coils: 1A, 1B and 2. Type I proteins are associated with a number of inherited developmental disorders, such as baldness, beading of hair, and skin blistering.
Occludin (Occludin)
Type: Family

Occludin was the first molecular component of the tight junction to be identified. These are specialised membrane domains that form intercellular contacts between epithelial cells and create a regulated barrier to the paracellular movement of water, solutes and immune cells. They also provide a second type of barrier that contributes to cell polarity by restricting the lateral diffusion of lipids and proteins within cell membranes . Occludin is an ~65kDa type II integral membrane protein, which has been shown to have four transmembrane (TM) domains, two extracellular loops and cytoplasmic N- and C-termini. The extracellular loops are chemically quite distinctive, particularly the first, which has an unusually high content of tyrosine and glycine residues (~65%) that alternate along the sequence . Gene knockout experiments have suggested occludin is an accessory, rather than principal, structural component of tight junctions, since occludin-deficient cells are still able to form tight junctions when cultured in vitro .
Tumour necrosis factor alpha (TNF_alpha)
Type: Family

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities . Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia . The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine . A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers . Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide .

There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.

The structure of human TNF has been determined to 2.9 A using X-ray crystallography. The protein is trimeric, each subunit consisting of an anti-parallel β-sandwich. The subunits trimerise via a novel edge-to-face packing of β-sheets . It is believed that each TNF molecule has three receptor-interaction sites (between the three subunits), thus allowing signal transmission by receptor clustering .
Lymphotoxin-alpha (TNF_beta)
Type: Family

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities . Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia . The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine . A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers . Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide .

There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.

Lymphotoxin-alpha (LT-alpha or TNF-beta) and lymphotoxin-beta (LT-beta) are related cytokines produced by lymphocytes. The proteins are cytotoxic for a wide range of tumour cells in vitro and in vivo.

The structure of TNF-beta has been determined to 1.9 A using X-ray crystallography and phase determination via molecular replacement using TNF-alpha. Like TNF-alpha, lymphotoxin folds to form a 'jellyroll' β-sheet sandwich. Three-fold related LT subunits form a trimer primarily stabilised by hydrophobic interactions. A cluster of 6 basic residues around the 3-fold axis is thought to account for the acid lability of the trimer. Although the structural cores of TNF-alpha and LT are similar, insertions and deletions relative to TNF-alpha occur in loops at the 'top' of the LT trimer, significantly altering the local structure. The sites of two mutations (Asp-50 and Tyr-108) that abolish the cytotoxicity of LT are contained within poorly-ordered loops that flank the cleft between neighbouring subunits at the base of the molecule, suggesting that the receptor recognises an intersubunit binding site .