SII-SWORD/CoKE huggingface dataset:
NWD1/2-like, winged helix-turn-helix domain (NWD1/2-like_wHTH)
Type: Domain

This domain is found in human NACHT domain- and WD repeat-containing protein 1/2 (NWD1/2), the orthologue Protein qui-1 from Caenorhabditis elegans and similar animal proteins. This domain is predicted to adopt a winged helix-turn-helix fold.

NWD1 may play a role in the control of androgen receptor protein steady-state levels . Qui-1 is involved in the avoidance response to the noxious chemicals and repellents, such as quinine, in ASH and ADL sensory neurons . In response to the noxious chemical quinine, it promotes dauer formation induced by pheromones .
PLOD1-3-like, GT domain (GT_PLOD)
Type: Domain

This entry represents the N-terminal glycosyltransferase (GT) domain found in collagen lysyl hydroxylases (LH or PLOD), mainly found in animals, including human procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1/2 and Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (PLOD1-3). The two N-terminal domains have a topology typical for glycosyltransferases, whereas the C-terminal has a DSBH fold. The domain represented by this entry is the only catalytically active domain and is solely responsible for the glycosyltransferase activity. This entry also represent an uncharacterised viral protein that displays a similar N-terminal fold.

Enzymes belonging to this family catalyse the lysine hydroxylation of collagens using Fe2+, 2-oxoglutarate, ascorbate and molecular oxygen . In humans, the three LH enzyme isoforms share significant sequence similarity. Mutations in PLOD genes that reduce or abolish their activity are associated with severe connective tissue diseases, including Ehlers-Danlos and Bruck syndromes . PLOD3 is considered the evolutionary ancestor of the family, as this isoform is the only one capable of further processing of hydroxylysines through glycosylation, whereas other isoforms might have lost such capability during evolution. These enzymes consist of three domains encompassing multiple active sites.
RDR2, plant PH-like domain (PH_RDR2)
Type: Domain

This domain is found in RNA-dependent RNA polymerase 2 (RDR2) from Arabidopsis thaliana and related plant proteins. It adopts a β-barrel structure with significant similarity to known PH domains .

RDR2 is involved in the production of small interfering RNAs (siRNAs). It binds to single-stranded RNA (ssRNA), engages ssRNAs longer than 7 nucleotides and initiates internal to their 3' ends . RDR2 is non-functional in the absence of associated Pol IV .
TMEM126-like (TMEM126-like)
Type: Family

This entry represents a family of proteins from nematodes that have sequence and structural similarity to the TMEM126 family of integral membrane proteins that are involved in the assembly of complex I. Therefore these proteins may have a similar function. However, it has also been suggested that this assembly function was only acquired by the TMEM126B proteins .
TMEM131 homolog, sixth Ig-like domain (Ig_TMEM131H_6)
Type: Domain

This entry represents the sixth Ig-like domain of TMEM131 from Drosophila and related sequences from flies. This protein is the orthologue of human TMEM131.

TMEM131 is a collagen binding transmembrane protein involved in collagen secretion by recruiting the ER-to-Golgi transport complex TRAPPIII . Human TMEM131 is predicted to contain eight Ig-like domains.
TMEM131 homolog, third Ig-like domain (TMEM131H_Ig_3)
Type: Domain

This entry represents the third Ig-like domain of TMEM131 from Drosophila and related sequences from flies. This protein is the orthologue of human TMEM131.

TMEM131 is a collagen binding transmembrane protein involved in collagen secretion by recruiting the ER-to-Golgi transport complex TRAPPIII . Human TMEM131 is predicted to contain eight Ig-like domains.
TgrO1-like, immunoglobulin-like domain (TgrO1-like_Ig)
Type: Domain

This immunoglobulin-like domain (Ig-like) is found twice in Tiger protein O1 from Dictyostelium discoideum (TgrO1) and similar sequences from lower eukaryotes. Its specific function is unknown.
TopBP1/SLF1, BRCT domain (TopB1_SLF1_BRCT)
Type: Domain

This entry represents a BRCT domain found in TopBP1 and SLF1. It corresponds to the eight BRCT domain of TopBP1 and the second one in SLF1.

TopBP1, also known as DNA topoisomerase II-beta-binding protein 1, or DNA topoisomerase II-binding protein 1, functions in DNA replication and damage response, acting as a scaffold protein . It binds double-stranded DNA breaks and nicks as well as single-stranded DNA . It has been shown to activate the ATR-ATRIP complex . TopBP1 contains eight copies of BRCT domain which specifically recognise and bind phosphorylated proteins, bringing proteins together into functional combinations .

SMC5-SMC6 complex localization factor protein 1 (SLF1) plays a role in the DNA damage response (DDR) pathway by regulating postreplication repair of UV-damaged DNA and genomic stability maintenance .
RNA dependent RNA polymerase core (RdRP)
Type: Domain

This domain is found mainly in eukaryotic RNA dependent RNA polymerases. It is composed of multiple domains representing the polymerase core.

This entry represents various eukaryotic RNA-dependent RNA polymerases (RDRP;

), such as RCRP-1, RDRP-2 and RDRP-6. These enzymes are involved in the amplification of regulatory microRNAs during post-transcriptional gene silencing ; they are also required for transcriptional gene silencing. Double-stranded RNA has been shown to induce gene silencing in diverse eukaryotes and by a variety of pathways . These enzymes also play a role in the RNA interference (RNAi) pathway, which is important for heterochromatin formation, accurate chromosome segregation, centromere cohesion and telomere function during mitosis and meiosis. RDRP enzymes are highly conserved in most eukaryotes, but are missing in archaea and bacteria. The core catalytic domain of RDRP enzymes is structurally similar to the beta' subunit of DNA-dependent RNA polymerases (DDRP), however the other domains of DDRP show no similarity to those of RDRP.

This entry also includes QDE-1 from the filamentous fungus Neurospora. QDE-1 is both an RdRP and a DNA-dependent RNA polymerase (DdRP). It is able to synthesize RNA from both ssRNA and single-stranded DNA (ssDNA) .
Receptor-like PK ALE2, N-terminal domain (ALE2_N)
Type: Domain

This entry represents the N-terminal in Receptor-like serine/threonine-protein kinase ALE2 and related proteins found mainly in plants. ALE2 is required during the differentiation of the protoderm into shoots, epidermis and cuticle . This domain is predicted to adopt a globular α/β structure that has some structural similarity to Notch domain.

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .
Receptor-type tyrosine-protein phosphatase U-like, Fn3 domain (Fn3_PTPRU)
Type: Domain

This entry represents the fourth divergent fibronectin type 3 domain found in a group of Receptor-type tyrosine-protein phosphatases (PTPR) including PTPR U, kappa, mu, T and related proteins. This domain is closest to the transmembrane α-helix.

PTPRU, also known as pancreatic carcinoma phosphatase 2 (PCP-2), belongs to the type IIb subfamily of receptor protein tyrosine phosphatases (RPTPs). It regulates CTNNB1 function both in cell adhesion and signalling. It may function in cell proliferation and migration and play a role in the maintenance of epithelial integrity. May play a role in megakaryocytopoiesis .

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.
TORTIFOLIA1/TORL1-2, C-terminal (TORTIFOLIA1/TORL1-2_C)
Type: Domain

This entry represents a domain found at the C-terminal of TORTIFOLIA1/SPIRAL2, TORTIFOLIA1-like protein 1/2 from Arabidopsis thaliana and related proteins. This domain may consist of TPRs.

TORTIFOLIA1/SPIRAL2 and SPIRAL2-like (SP2L) from Arabidopsis regulate the orientation of cortical microtubules and the direction of organ growth . TORTIFOLIA1-like protein 1 (also known as SPIRAL2) may regulate katanin-based microtubule (MT) severing . During virus infection, it may stabilise MT crossovers to support the formation and intercellular spread of the viral RNA complexes .
TORTIFOLIA1/SINE1-2, N-terminal (TORTIFOLIA1/SINE1-2_N)
Type: Domain

This entry represents a domain found at the N-terminal of TORTIFOLIA1/SPIRAL2, SPIRAL2-like (SP2L) and related sequences such as SINE1/2, which function during stomatal dynamics induced by light-dark transitions and abscisic acid (ABA), that requires F-actin reorganisation .

TORTIFOLIA1/SPIRAL2 and SPIRAL2-like (SP2L) from Arabidopsis regulate the orientation of cortical microtubules and the direction of organ growth . TORTIFOLIA1-like protein 1 (also known as SPIRAL2) may regulate katanin-based microtubule (MT) severing . During virus infection, it may stabilise MT crossovers to support the formation and intercellular spread of the viral RNA complexes .
TonB-dependent transporter Oar-like, beta-barrel domain (Oar-like_b-barrel)
Type: Domain

This entry represents the β-barrel domain of TonB-dependent transporter Oar from Myxococcus xanthus and similar bacterial outer membrane β-barrel proteins. Many of these proteins contain an N-terminal

domain.

TonB proteins are bacterial membrane proteins that play a crucial role in energy-dependent active transport systems. They have an N-terminal plug domain which acts as the channel gate, blocking the pore until the channel is bound by a ligand when it undergoes conformational changes and opens the channel and a C-terminal β-barrel domain. In Escherichia coli, the TonB protein interacts with outer membrane receptor proteins that carry out high-affinity binding and energy-dependent uptake of specific substrates into the periplasmic space . These substrates are either poorly permeable through the porin channels or are encountered at very low concentrations. In the absence of TonB, these receptors bind their substrates but do not carry out active transport. TonB-dependent regulatory systems consist of six components: a specialised outer membrane-localised TonB-dependent receptor (TonB-dependent transducer) that interacts with its energising TonB-ExbBD protein complex, a cytoplasmic membrane-localised anti-sigma factor and an extracytoplasmic function (ECF)-subfamily sigma factor . The TonB complex senses signals from outside the bacterial cell and transmits them via two membranes into the cytoplasm, leading to transcriptional activation of target genes. Energy for active transport is again obtained through physical interaction with TonB . The proteins that are currently known or presumed to interact with TonB include BtuB, CirA, FatA, FcuT, FecA , FhuA , FhuE, FepA which is important for iron uptake and allows the bacterium to extract iron from the environment , FptA, HemR, IrgA, IutA, PfeA, PupA and Tbp1. The TonB protein also interacts with some colicins.
PARP12-like, CCCH zinc finger tandem (Zfn-CCCH_PARP12)
Type: Domain

This domain containing tandem CCCH zinc fingers is found in human Protein mono-ADP-ribosyltransferase PARP12, and related proteins mainly found in vertebrates, including Zinc finger CCCH-type antiviral protein 1 (ZAP) and Zinc finger CCCH-type antiviral protein 1-like. PARP12 is a mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins . ZAP is an Antiviral protein which inhibits the replication of viruses by recruiting the cellular RNA degradation machineries to degrade the viral mRNAs .
Periphilin-1, C-terminal domain (Periphilin-1_C)
Type: Domain

This domain is found in human Periphilin-1 and related proteins. It folds into an α-helical hairpin and directs HUSH complex assembly by dimerising and binding a TASOR, another component of the HUSH complex .

Periphilin-1 is a component of the HUSH complex, a multiprotein complex that mediates epigenetic repression. The HUSH complex is recruited to genomic loci rich in H3K9me3 and is probably required to maintain transcriptional silencing . This protein acts as a transcriptional corepressor and regulates the cell cycle, probably via the HUSH complex . It is involved in epithelial differentiation and contributes to epidermal integrity and barrier formation . It is associated with gastric cancer .
Peroxisomal ATPase PEX6, double psi barrel domain (DPBB_PEX6)
Type: Domain

This domain is found in the human Peroxisomal ATPase PEX6 and related proteins from vertebrates. PEX6 is a component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling . PEX6 recognises PEX5 monoubiquitination at Cys 11, and enables its translocation out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel . In human PEX6, this domain is predicted to fold into a barrel-like structure with a double psi barrel topology. This domain precedes the AAA ATPase domains and shares detectable sequence and structural similarity with known double psi β-barrel domains such as the N-terminal domain of the N-ethylmaleimide-sensitive factor (NSF) (

).
Peroxisomal ATPase PEX6, N-terminal domain (PEX6_N)
Type: Domain

This domain is found N-terminal in human Peroxisomal ATPase PEX6 and related proteins from vertebrates. PEX6 is a component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling . PEX6 recognises PEX5 monoubiquitination at Cys 11, and enables its translocation out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel . In human PEX6, this domain predicted to fold into a barrel-like structure although with relatively low pLDDT score. It contains a number of conserved proline residues.
Ras/Rap GTPase-activating protein SynGAP-like, PH domain (SynGAP1-like_PH)
Type: Domain

This entry represents a pleckstrin homology (PH) domain found in animal RAS GTPase-activating proteins, including mouse RAS/RAP GTPase-activating protein SynGAP, RAS protein activator-like 3 (Rasal3), and disabled homolog 2-interacting protein (DAB2IP). This domain likely plays a role in membrane targeting and regulation of RAS-family GTPases.

SynGAP is a major constituent of the PSD essential for postsynaptic signalling, an inhibitory regulator of the Ras-cAMP pathway and a member of the NMDAR signalling complex in excitatory synapses .

Rasal3 functions as a Ras GTPase-activating protein. It. plays an important role in the expansion and functions of natural killer T (NKT) cells in the liver by negatively regulating RAS activity and the down-stream ERK signalling pathway .

Dab2ip functions as a scaffold protein implicated in the regulation of a large spectrum of both general and specialised signalling pathways. It is involved in several processes such as innate immune response, inflammation and cell growth inhibition, apoptosis, cell survival, angiogenesis, cell migration and maturation and also plays a role in cell cycle checkpoint control .
PH-like domain, kinetoplastids (PH_kinetoplastids)
Type: Domain

This entry represents PH-like domains found in a group of uncharacterised proteins from unicellular eukaryotes, primarily kinetoplastids. The domain is found in several different domain architectures with Pex24p-like domains

, or phosphatases.
PH-like domain 2, kinetoplastids (PH_2_kinetoplastids)
Type: Domain

This entry represents a domain found at the C-terminal of a group of uncharacterised kinetoplastid proteins. This domain adopts a PH-like domain fold.
PH-like domain, platyhelminthes (PH_platyhelminthes)
Type: Domain

This entry represents a PH-like domain found in uncharacterised platyhelminthes proteins that often have an N-terminal RasGAP domain (

).
Phage antiviral trigger protein Gp54-like (Gp54-like)
Type: Family

This entry represents a small phage family of proteins of approximately 66 amino acids that act as a trigger for bacterial antiviral defence systems . The protein adopts a rare six-stranded β-barrel fold in its unbound state. Upon binding to the bacterial CapRel defence protein, Gp54 undergoes a dramatic conformational change where the β-barrel unfolds and forms a hybrid eight-stranded β-sheet with CapRel. The interaction is entropically driven and activates CapRel's antiviral response. The β-barrel structure is unique, with the closest structural homologues being five-stranded SH3 domains. Gp54 represents one of two known protein triggers for the CapRel defence system, the other being phage major capsid proteins.
Piezo-type, mechanosensitive ion channel homolog domain (PIEZO_dom)
Type: Domain

This domain is found in Piezo-type mechanosensitive ion channel homolog from Arabidopsis thaliana (PIEZO) and related plant proteins. PIEZO is a pore-forming subunit of a mechanosensitive non-specific cation channel, that conducts both sodium and potassium ions. This domain is predicted to adopt an all-α structure.This entry is specific to plants.
PIFI-like, Ig-like domain (Ig_PIFI)
Type: Domain

PIFI is required during nonphotochemical quenching and is involved in NAD(P)H dehydrogenase complex-mediated chlororespiratory electron transport .

This predicted immunoglobulin-like (Ig-like) domain is found in Protein POST-ILLUMINATION CHLOROPHYLL FLUORESCENCE INCREASE, chloroplastic from Arabidopsis thaliana (PIFI) and similar plant proteins.
VWA7, beta-sandwich domain (VWA7_4)
Type: Domain

This domain is found in the human VWA7 and related proteins. The domain is predicted to fold into a β-sandwich.

VWA7 is found in the major histocompatibility complex class III region and it is likely implicated in lung cancers

The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders
. In von Willebrand factor, the type A domain (vWF) is the prototype for a protein superfamily. The vWF domain is found in various plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins . Although the majority of VWA-containing proteins are extracellular, the most ancient ones present in all eukaryotes are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport and the proteasome. A common feature appears to be involvement in multiprotein complexes. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands . A number of human diseases arise from mutations in VWA domains.
Serine/threonine-protein kinase PKH3, C-terminal PH domain (PH_PKH3_C)
Type: Domain

This entry represents a pleckstrin homology (PH) domain found at the C-terminal of PKH3 protein kinases. The domain is found C-terminal to a protein kinase catalytic domain (Pkinase,

). PKH3 kinases are involved in serine/threonine phosphorylation.

Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. In the central part of the catalytic domain there is a conserved aspartic acid residue which is important for the catalytic activity of the enzyme .
VWA7, Ig-like domain (Ig_VWA7)
Type: Domain

This domain id found in the human von Willebrand factor A domain-containing protein 7 (VWA7) and related proteins. It is predicted to fold into a β-sandwich with an Ig-like topology.

VWA7 is found in the major histocompatibility complex class III region and it is likely implicated in lung cancers

The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders
. In von Willebrand factor, the type A domain (vWF) is the prototype for a protein superfamily. The vWF domain is found in various plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins . Although the majority of VWA-containing proteins are extracellular, the most ancient ones present in all eukaryotes are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport and the proteasome. A common feature appears to be involvement in multiprotein complexes. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands . A number of human diseases arise from mutations in VWA domains.
PH-like domain 2, platyhelminthes (PH_2_platyhelminthes)
Type: Domain

This entry represents a PH domain found in a range of platyhelminthes proteins. This domain could be found adjacent to the C-terminal of DH domains

.