SII-SWORD/CoKE huggingface dataset:
Nitrate reductase, beta subunit (NO3_Rdtase_bsu)
Type: Family

The nitrate reductase enzyme complex allows bacteria to use nitrate as an electron acceptor during anaerobic growth. The enzyme complex consists of a tetramer that has an alpha, beta and 2 gamma subunits. The alpha and beta subunits have catalytic activity and the gamma subunits attach the enzyme to the membrane and are b-type cytochromes that receive electrons from the quinone pool and transfers them to the beta subunit. The sequences in this family are the beta subunit for nitrate reductase I (narH) and nitrate reductase II (narY) for Gram-positive and Gram-negative bacteria. A few thermophiles and archaea also match the model. A number of the sequences in this set are experimentally characterised, these include: E.Coli NarH (

) and NarY (

) ,

from Bacillus subtilis, and related proteins from Pseudomonas fluorescens, Paracoccus denitrificans, and Paracoccus halodenitrificans (Halomonas halodenitrificans).
Splicing factor ELAV/Hu (ELAD_HU_SF)
Type: Family

These sequences represent the ELAV/Hu subfamily of splicing factors found in metazoa. ELAV stands for the Drosophila Embryonic lethal abnormalvisual protein . ELAV-like splicing factors are also known in human as HuB (ELAV-like protein 2), HuC (ELAV-like protein 3, HuD (LAV-like protein 4) and HuR (ELAV-like protein 1). HuR is ubiquitously expressed whereas HuB, HuC and HuD are neuron-specific . HuD stands for the human paraneoplastic encephalomyelitis antigen D of which there are 4 variants in human . These genes are most closely related to the sex-lethal subfamily of splicing factors found in Dipteran insects (

).
HAD-superfamily hydrolase,subfamily IIIA (HAD-SF_hydro_IIIA)
Type: Domain

This group of proteins is a part of the haloacid dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. The Class III subfamilies are characterised by the lack of any domains located either between the first and second conserved catalytic motifs (as in the Class I subfamilies) or between the second and third conserved catalytic motifs (as in the Class II subfamilies) of the superfamily domain . The IIIA subfamily contains five major clades: histidinol-phosphatase , histidinol-phosphatase-related protein, DNA 3-phosphatase and sequences related to YqeG and YrbI.

In the case of histidinol phosphatase and PNK-3'-phosphatase, this entry represents a domain of a bifunctional system. In the histidinol phosphatase HisB, a C-terminal domain is an imidazoleglycerol-phosphate dehydratase which catalyses a related step in histidine biosynthesis . In PNK-3'-phosphatase, N- and C-terminal domains constitute the polynucleotide kinase and DNA-binding components of the enzyme.
Bifunctional polynucleotide phosphatase/kinase PNKP (PNKP)
Type: Family

This entry includes bifunctional polynucleotide phosphatase/kinase PNKP from animals. PNKP plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways. It has been shown that the DNA 3'-phosphatase activity of PNKP takes precedence over its DNA 5'-kinase activity in vitro . It contains a forkhead-associated domain, which is a protein-protein interaction domain required for the association of PNKP with CK2-phosphorylated XRCC1 and XRCC4, and independent DNA 3'-phosphatase and 5'-kinase domains .
Polynucleotide 3'-phosphatase (Polynucleotide_phosphatase)
Type: Domain

These proteins catalyse the dephosphorylation of DNA 3'-phosphates. It is believed that this activity is important for the repair of single-strand breaks in DNA caused by radiation or oxidative damage. This region is often , but not always linked to a DNA 5'-kinase domain . As is common in this superfamily, DNA 3-phosphatase is magnesium dependent. A difference between this enzyme and other HAD-superfamily phosphatases is in the third conserved catalytic motif which usually contains two conserved aspartate residues believed to be involved in binding the magnesium ion. Here, the second aspartate is usually replaced by an arginine residue which may indicate an interaction with the phosphate backbone of the substrate. Alternatively, there is an additional conserved aspartate downstream of the usual site which may indicate a slightly different fold in this region.
Leucine-rich repeat, cysteine-containing subtype (Leu-rich_rpt_Cys-con_subtyp)
Type: Repeat

Leucine-rich repeats (LRR) consist of 2-45 motifs of 20-30 amino acids in length that generally folds into an arc or horseshoe shape . LRRs occur in proteins ranging from viruses to eukaryotes, and appear to provide a structural framework for the formation of protein-protein interactions .Proteins containing LRRs include tyrosine kinase receptors, cell-adhesion molecules, virulence factors, and extracellular matrix-binding glycoproteins, and are involved in a variety of biological processes, including signal transduction, cell adhesion, DNA repair, recombination, transcription, RNA processing, disease resistance, apoptosis, and the immune response .

Sequence analyses of LRR proteins suggested the existence of several different subfamilies of LRRs. The significance of this classification is that repeats from different subfamilies never occur simultaneously and have most probably evolved independently. It is, however, now clear that all major classes of LRR have curved horseshoe structures with a parallel β sheet on the concave side and mostly helical elements on the convex side. At least six families of LRR proteins, characterised by different lengths and consensus sequences of the repeats, have been identified. Eleven-residue segments of the LRRs (LxxLxLxxN/CxL), corresponding to the β-strand and adjacent loop regions, are conserved in LRR proteins, whereas the remaining parts of the repeats (herein termed variable) may be very different. Despite the differences, each of the variable parts contains two half-turns at both ends and a "linear" segment (as the chain follows a linear path overall), usually formed by a helix, in the middle. The concave face and the adjacent loops are the most common protein interaction surfaces on LRR proteins.
3D structure of some LRR proteins-ligand complexes show that the concave surface of LRR domain is ideal for interaction with α-helix, thus supporting earlier conclusions that the elongated and curved LRR structure provides an outstanding framework for achieving diverse protein-protein interactions . Molecular modeling suggests that the conserved pattern LxxLxL, which is shorter than the previously proposed LxxLxLxxN/CxL is sufficient to impart the characteristic horseshoe curvature to proteins with 20-to 30-residue repeats .

This is a cysteine-containing, leucine-rich repeat which is wide spread amongst eukaryotes proteins but does not appear to be found in archae, bacteria or viruses.
Helicase-like, DEXD box c2 type (Helicase-like_DEXD_c2)
Type: Domain

This domain of unknown function is found in the Xeroderma pigmentosum group D (XPD) proteins which belong to a family of ATP-dependent helicases characterised by a 'D-E-A-H' motif. This resembles the 'D-E-A-D-box' of other known helicases, which represents a special version of the B motif of ATP-binding proteins. In XPD, His replaces the second Asp. The DEAD box helicases are involved in various aspects of RNA metabolism, including nuclear transcription, pre-mRNA splicing, ribosome biogenesis, nucleocytoplasmic transport, translation, RNA decay and organellar gene expression.
ATP-dependent helicase, C-terminal (ATP-dep_Helicase_C)
Type: Domain

This domain of unknown function is found at the C terminus of some
ATP-dependent helicases characterised by a 'D-E-A-H' motif. This resembles the 'D-E-A-D-box' of other known helicases,
a special version of the B motif of ATP-binding proteins however His replaces the second Asp. The DEAD
box helicases are involved in various aspects of RNA metabolism, including nuclear transcription, pre-mRNA splicing,
ribosome biogenesis, nucleocytoplasmic transport, translation, RNA decay and organellar gene expression.
LamG-like jellyroll fold (LamG-like)
Type: Domain

This LamG-like jellyroll fold domain is found in the metalloproteinase Pappalysin-1 and Usherin . Its function is unknown.
AWS domain (AWS_dom)
Type: Domain

This domain, Associated With SET (AWS), whose specific function is still unknown, is found in a group of histone-lysine N-methyltransferases and similar eukaryotic proteins, including Histone-lysine N-methyltransferase, H3 lysine-36 specific from humans (H3-K36-HMTase or Nsd1). Nsd1 is a transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context. Mutations in this protein are associated with several human disorders such as Sotos syndrome . This cysteine-rich domain is often found in association with the SET domain (

).
DZF domain (DZF_dom)
Type: Domain

This entry represents the DZF domain, which is found exclusively in metazoa.

The DZF domain (domain associated with zinc fingers) is a dimerisation domain found in :

Interleukin enhancer-binding factor 3 (also known as Nuclear factor of activated T-cells 90 kDa, NF90, DRBP76 or NFAR), contains two double-stranded RNA-binding motifs (dsRBMs) and interacts with highly structured RNAs as well as the dsRNA-activated protein kinase (PKR).

Interleukin enhancer-binding factor 2 (also known as NF45), which appears to function predominantly as a heterodimeric complex with NF90.

Spermatid perinuclear RNA-binding protein (SPNR, also known as STRBP), a testes specific paralogue of NF90.

Zinc finger RNA-binding protein (Zfr).

Nuclear factors NF90 and NF45 form a protein complex involved in a variety of cellular processes and are thought to affect gene expression both at the transcriptional and translational level. In addition, this complex affects the replication of several viruses through direct interactions with viral RNA. NF90 and NF45 dimerise through their common DZF domain. The DZF domain shows structural similarity to the template-free nucleotidyltransferase family of RNA modifying enzymes. However, the lack of conserved catalytic residues suggests that the DZF domain encodes a 'pseudotransferase' that is no longer able to catalyse transfer of nucleotides.

The DZF dimerisation domain form an oblong structure with a flat face on one side and a curved face on the other. The DZF domain is bipartite and characterised by an N-terminal mixed α/β region that contains a central anti-parallel β-sheet and a C-terminal α-helical region. The overall structure has a pseudo two-fold rotational symmetry.

The central β-sheet forms the base of a cleft between the N- and C-terminal halves while dimerisation is mediated by the α-helices at the C terminus .
POX domain (POX_dom)
Type: Domain

This domain in found exclusively in plant proteins, associated with homeobox domain

which may suggest these proteins are homeodomain transcription factors. Proteins containing this domain include BEL1-like homeodomain protein 1 (BLH1) from Arabidopsis thaliana. BLH1 interacts with KNAT2 and KNAT5 and affects plant development .
Zinc finger, PMZ-type (Znf_PMZ)
Type: Domain

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 entry describes a plant mutator transposase zinc finger.
Bromodomain associated domain (BTP)
Type: Domain

This domain is found in eukaryotic bromodomain containing transcription factors and PHD domain containing proteins (

). This domain has a histone-like fold and is predicted to bind DNA .
FBD domain (FBD)
Type: Domain

This domain is found at the C-terminal of F-box domain containing proteins from plants. Its precise function is unknown, but it is thought to be associated with nuclear processes . Proteins in this entry are involved in the ubiquitin-proteasome pathway. They function as components of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes [2]. They have a F-box domain at the N-terminal (

). AtMIF1 (also known as F-box protein AT3G62230) from Arabidopsis, physically interacts with MYB domain protein 5 (MYB5), which results in MYB5 degradation representing a new regulatory pathway, 26S proteasome-AtMIF1-MYB5 that regulates oil content of seeds, increasing their oil content without affecting plant growth . This domain has a LRR-like fold.
PSP, proline-rich (PSP_pro-rich)
Type: Domain

PSP is a proline-rich domain of unknown function found in spliceosome associated proteins.
CID domain (CID_dom)
Type: Domain

The C-terminal domain (CTD) of the large subunit of RNA polymerase II is a platform for mRNA processing factors and links gene transcription to mRNA capping, splicing and polyadenylation. CTD recognition is dependent on the phosphorylation state of the CTD itself, which varies during the course of transcription but has also been linked to the isomerization state of the CTD's proline residues. Several RNA-processing factors recognise the CTD by means of a conserved CTD-interacting domain (CID). Factors with CID domains include the serine/arginine-rich-like factors SCAF4 and SCAF8, Nrd1 (which is implicated in polyadenylation-independent RNA 3'-end formation) and Pcf11. Pcf11 is a conserved and essential subunit of the yeast cleavage factor 1A, which is required for 3'-RNA processing and transcription termination .

The CID domain is a right-handed superhelix of eight α-helices forming a compact domain. The CID fold closely resembles that of VHS domains

and is related to armadillo-repeat proteins

, except for the two amino-terminal helices. Amino acid residues in the hydrophobic core of the domain are highly conserved across CID domains .
SPK domain (SPK_dom)
Type: Domain

SPK is a domain of unknown function that is found in some SET and PHD domain-containing proteins and protein kinases.
TLDc domain (TLDc_dom)
Type: Domain

The Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) domain is present in all eukaryotes, and its primary sequence is highly conserved among species. The TLDc domain is present in several proteins that share a protective function against oxidative stress (OS). The TLDc domain alone is able to confer oxidative resistance properties to all the TLDc members. The TLDc domain-containing proteins could influence the expression of key oxygen free-radical scavengers that, in turn, reduce the levels of ROS in the cell .
Zinc finger, DBF-type (Znf_DBF)
Type: Domain

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.

In eukaryotes, initiation of DNA replication requires the assembly of pre-replication complexes (pre-RCs) on chromatin during the G1 phase. In the S phase, pre-RCs are activated by two protein kinases, Cdk2 and Cdc7, which results in the loading of replication factors and the unwinding of replication origins by the MCM helicase complex . Cdc7 is a serine/threonine kinase that is conserved from yeast to human. It is regulated by its association with a regulatory subunit, the Dbf4 protein. This complex is often referred to as DDK (Dbf4-dependent kinase) .

DBF4 contains an N-terminal BRCT domain and a C-terminal conserved region that could potentially coordinate one zinc atom, the DBF4-type zinc finger. This entry represents the zinc finger, which is important for the interaction with Cdc7 .
Neuralized homology repeat (NHR) domain (NHR_dom)
Type: Domain

The neuralized homology repeat (NHR) domain is a module of ~160 amino acids, which has been identified as a tandem repeat in drosophila neuralized, a protein involved in development of the central and peripheral nervous system . Several other fly, worm, and mammalian neuralized-like proteins were found to contain between one and six NHR domains associated with other modules, such as RING, SOCS, or SPRY . It has been suggested that the NHR domain is required for the localization of neuralized to the plasma membrane . As it has been proposed that NHR domains do partly resemble SPRY domains, it is possible that NHR possess microtubule-binding functions, similar to those proposed for SPRY domains .
SPRY-associated (PRY)
Type: Domain

PRY is a 50-60 amino acids domain associated with SPRY domains, adjacent to its N-terminal. The SPRY domain (

) is a protein-protein interaction module involved in many important signaling pathways . Distant homologues are domains in butyrophilin/marenostrin/pyrin, evolutionarily more ancient than SPRY/B30.2 counterpart. PRY and SPRY domains are structurally very similar and consist of a β sandwich fold . Ca2+-release from the sarcoplasmic or endoplasmic reticulum, the intracellular Ca2+ store, is mediated by the ryanodine receptor (RyR) and/or the inositol trisphosphate receptor (IP3R).

The proteins identified by the PRY domain, clearly fall into 3 sets which can be defined by their combination of signatures:

This group contains an immunoglobulin domain N-terminal to the PRY and butyrophilin domains. Butyrophilins are glycoproteins that are expressed on the apical surfaces of secretory cells in lactating mammary tissue and which may function in the secretion of milk-fat droplets.

This group contain a RING-finger domain N-terminal to the PRY domain. The RING-finger is a specialised type of Zn-finger of 40 to 60 residues that binds two atoms of zinc, and is probably involved in mediating protein-protein interactions. There are two different variants, the C3HC4-type and a C3H2C3-type, which is clearly related despite the different cysteine/histidine pattern. The latter type is sometimes referred to as 'RING-H2 finger' is not found associated with this group of proteins. This set of proteins are described as TRIM (TRIpartite Motif) family members and are involved in cellular compartmentalisation . The TRIM family sequences are defined by a Ring finger domain, a B-box type1 (B1) and a B-box type 2 (B2) followed by a coiled-coil (CC) region . Genes belonging to this family are implicated in a variety of processes such as development and cell growth and are involved in human disease.

Many of these proteins, with the PRY domain have a number of C-terminal signatures, SPRY, RFP-like (also known as B30.2 domain or PRYSPRY) and butyrophilin domain .

The third set of proteins have the C-terminal signatures but have no N-terminal RING-finger or immunoglobulin domain signatures. These proteins have not been functionally described.
RWD domain (RWD_dom)
Type: Domain

The RWD domain is a conserved region of about 110 amino acid residues, which has been identified in the mouse GCN2 eIF2alpha kinase and histidyl-tRNA synthetase and in presumed orthologues in other eukaryotic species from yeast to vertebrates. Additionally, it is also found in WD repeat containing proteins, yeast DEAD (DEXD)-like helicases, many RING-finger containing proteins, the UPF0029 uncharacterised protein family and a range of hypothetical proteins. The RWD domain has been named after the better characterised RING finger and WD repeat containing proteins and DEAD-like helicases. It has been proposed that the RWD domain might have a function in protein interaction .
BRK domain (BRK_domain)
Type: Domain

The function of this domain is unknown . It is often found associated with helicases and transcription factors.
UAS (UAS)
Type: Domain

UAS is a domain of unknown function found in FAF1 proteins (FAS-associated factor 1) and in other proteins, many of which are described as having no known function.
MADF domain (MADF-dom)
Type: Domain

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.

Drosophila protein clifford, a chromatin-binding protein involved in the organisation of active promoters and insulators .
Pre-C2HC domain (Pre_C2HC_dom)
Type: Domain

This domain (PRE_C2HC) is present in proteins associated with nuclear functions and is found exclusively in the arthropods, including a number of Drosophila species, the silk moth and the gypsy moth. These proteins are possibly involved in RNA binding or single strand DNA binding.