SII-SWORD/CoKE huggingface dataset:
HINT family (HINT)
Type: Family

HINT (histidine triad nucleotide-binding protein) are related to the HIT family members that carry a motif HxHxH/Qxx (x, is a hydrophobic amino acid) . On the basis of sequence, substrate specificity, structure, evolution and mechanism, HIT proteins are classified into three branches: the Hint branch, which consists of adenosine 5' -monophosphoramide hydrolases, the FHIT branch, that consists of diadenosine polyphosphate hydrolases, and the GalT branch consisting of specific nucloside monophosphate transferases .

HINT family includes members from all three forms of cellular life. In budding yeast Hnt1 has been shown to have adenosine monophosphoramidase activity . It is involved in secretion, peroxisome formation and gene expression . The bacterial and archaeal members of this family are mostly uncharacterised.
NGN domain, eukaryotic (NGN_Euk)
Type: Domain

The N-Utilization Substance G (NusG) protein and its eukaryotic homologue, Spt5, are involved in transcription elongation and termination. NusG contains an NGN domain at its N terminus and Kyrpides Ouzounis and Woese (KOW) repeats at its C terminus. Spt5 forms an Spt4-Spt5 complex that is an essential RNA polymerase II elongation factor. NusG was originally discovered as an N-dependent antitermination enhancing activity in Escherichia coli, and has a variety of functions such as its involvement in RNA polymerase elongation and Rho-termination in bacteria. Orthologues of the NusG gene exist in all bacteria, but their functions and requirements are different. Spt5-like is homologous to the Spt5 proteins present in all eukaryotes, which is unique as it encodes a protein with an additional long carboxy-terminal extension that contains WG/GW motifs. Spt5-like, or KTF1 (KOW domain-containing Transcription Factor 1), is a RNA-directed DNA methylation (RdDM) pathway effector in plants .
Homoaconitase, swivel domain (Homoaconitase_swivel)
Type: Domain

This entry represents the swivel domain found in homoaconitase and other uncharacterised proteins of the aconitase family . Homoaconitase is part of an unusual lysine biosynthesis pathway found only in filamentous fungi, in which lysine is synthesized via the alpha-aminoadipate pathway. In this pathway, homoaconitase catalyses the conversion of cis-homoaconitic acid into homoisocitric acid. The reaction mechanism is believed to be similar to that of other aconitases. The swivel domain is believed to undergo swivelling conformational change in the enzyme mechanism .
Protocatechuate 3,4-dioxygenase (3_4-PCD)
Type: Family

Protocatechuate 3,4-dioxygenase (3,4-PCD) catalyzes the oxidative ring cleavage of 3,4-dihydroxybenzoate to produce beta-carboxy-cis,cis-muconate. 3,4-PCDs are large aggregates of 12 protomers, each composed of an alpha- and beta-subunit and an Fe3+ ion bound in the beta-subunit at the α-β-subunit interface. 3,4-PCD is a member of the aromatic dioxygenases which are non-heme iron intradiol-cleaving enzymes that break the C1-C2 bond and utilize Fe3+ .
Hydroxyquinol/catechol 1,2-dioxygenase (1_2-HQD/HQD)
Type: Family

Hydroxyquinol 1,2-dioxygenase (1,2-HQD) catalyzes the ring cleavage of hydroxyquinol (1,2,4-trihydroxybenzene), an intermediate in the degradation of a large variety of aromatic compounds including some polychloro- and nitroaromatic pollutants, to form 3-hydroxy-cis,cis-muconates. 1,2-HQD belongs to the aromatic dioxygenase family, a family of mononuclear non-heme intradiol-cleaving enzymes. It can act on catechol, but its activity for hydroxyquinol is 6.8-fold higher .

This family also includes fungal catechol 1,2-dioxygenase and intradiol ring-cleavage dioxygenase hqdA.
Phytocyanin-like (Phytocyanin-like)
Type: Family

Phytocyanins are blue copper proteins found in chloropasts of higher plants. They can be further subdivided into uclacyanins, stellacyanins, plantacyanins, and early nodulins. Stellacyanins have a blue copper coordinated by two His, one Cys and one Gln. In plantacyanins and uclacyanins, the ligands of the type-I Cu sites are two His, one Cys and one Met . Early nodulins (also known as phytocyanin-like proteins) lack amino acid residues that coordinate Cu, so they are involved in other processes without binding Cu . They may act as a carbohydrate transporters .
Gingipain, N-terminal (Gingipain_N)
Type: Domain

Gingipain, produced by Porphyromonas gingivalis , exemplifies the peptidase family C25. P. gingivalis is one of the primary Gram-negative pathogens that causes periodontitis, a disease also associated with other diseases such as diabetes and cardiovascular disease. The gingipain subgroup contains extracellular Arg- and Lys-specific proteinases called Arg-gingipain (Rgp) and Lys-gingipain (Kgp) ; RgpA and RgpB are Arg-specific gingipains encoded by two closely related genes, rgpA and rgpB , while Lys-specific gingipain is encoded by the single kgp gene . Mutant studies have shown that, among the large quantities of proteolytic enzymes produced by P. gingivalis, these three proteases are major virulence factors of this bacterium .

All three genes encode an N-terminal pre-pro fragment, followed by the protease domain; however, rgpA and kgp also encode additional C-terminal HA (hemaglutinin/adhesion) subunits which consist of several sequence-related adhesion domains . Although unique, their cysteine protease active site residues (His and Cys) forming the catalytic dyad, are well-conserved, cleaving the C-terminal peptide bond with Arg or Lys residues. Gingipains are evolutionarily related to other highly specific proteases including caspases, clostripain, legumains, and separase . Gingipains function by dysregulating host defense and inflammatory responses, and degrading host proteins, e.g. tissue, cells, matrix, plasma and immunological proteins. It has been suggested that they enhance gingival crevicular fluid (GCF) production through activation of the kallikrein/kinin pathways, thus increasing vascular permeability and causing gingival inflammation, a distinctive feature of periodontitis. RgpA and RgpB are also able to cleave and activate coagulation factors IX and X in order to activate prothrombin to produce thrombin, which in turn increases production of GCF . The gingipains also play a pivotal role in the survival of P. gingivalis in the host by attacking the host defense system through cleavage of several immunological molecules, while at the same time evading the host-immune response by dysregulating the cytokine network .
Rhizopine-oxygenase-like (Rhizopine-oxygenase-like)
Type: Family

This entry includes the putative hydrocarbon oxygenase, MocD, a bacterial rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) oxygenase, and other related proteins. It has been proposed that MocD, MocE (Rieske-like ferredoxin), and MocF (ferredoxin reductase) under the regulation of MocR, act in concert to form a ferredoxin oxygenase system that demethylates 3-O-MSI to form scyllo-inosamine. This domain family appears to be structurally related to the membrane fatty acid desaturases and the alkane hydroxylases. They all share in common extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within homologs, stearoyl CoA desaturase and alkane hydroxylase .
Creatinase, C-terminal (Creatinase_C)
Type: Domain

This entry represents the C-terminal domain of creatine amidinohydrolase, which hydrolyzes creatine to sarcosine and urea .
Peptidase C39-like A (Peptidase_C39-like_A)
Type: Domain

This entry represents a sub-group of peptidase C39 homologues in which the proposed protease active site is not conserved. Peptidase family C39 mostly contains bacteriocin-processing endopeptidases from bacteria . The cysteine peptidases in family C39 cleave the 'double-glycine' leader peptides from the precursors of various bacteriocins (mostly non-lantibiotic). The cleavage is mediated by the transporter as part of the secretion process. Bacteriocins are antibiotic proteins secreted by some species of bacteria that inhibit the growth of other bacterial species. The bacteriocin is synthesized as a precursor with an N-terminal leader peptide, and processing involves removal of the leader peptide by cleavage at a Gly-Gly bond, followed by translocation of the mature bacteriocin across the cytoplasmic membrane. Most endopeptidases of family C39 are N-terminal domains in larger proteins (ABC transporters) that serve both functions .
Deltex, C-terminal (Deltex_C)
Type: Domain

The deltex family of proteins is involved in the regulation of Notch signaling, and therefore may play roles in cell-to-cell communications that regulate mechanisms determining cell fate . They have a central RING-type zinc finger domain and contain a C-terminal domain that is also found in other domain architectures. Deltex-1 (DTX1) contains a RING finger and two WWE domains, indicating that it may be an E3 ubiquitin ligase . Human deltex 3-like, which contains an additional N-terminal domain (presumably with ubiquitin ligase activity) is also described as E3 ubiquitin-protein ligase DTX3L, B-lymphoma- and BAL-associated protein (BBAP), or rhysin-2. DTX3L mediates monoubiquitination of K91 of histone H4 in response to DNA damage .

This entry represents the C-terminal domain of the Deltex proteins.
RagA/B (RagA/B)
Type: Family

RagA and RagB are closely related Rag GTPases (ras-related GTP-binding protein A and B) that constitute a unique subgroup of the Ras superfamily , and are functional homologues of
Saccharomyces cerevisiae
Gtr1 . They function by forming heterodimers with RagC or RagD, and similarly, Gtr1 dimerizes with Gtr2, through the carboxy-terminal segments. They play an essential role in regulating amino acid-induced target of rapamycin complex 1 (TORC1) kinase signaling , exocytic cargo sorting at endosomes, and epigenetic control of gene expression. In response to amino acids, the Rag GTPases guide the TORC1 complex to activate the platform containing Rheb proto-oncogene by driving the relocalization of mTORC1 from discrete locations in the cytoplasm to a late endosomal and/or lysosomal compartment that is Rheb-enriched and contains Rab-7 .
Deltex family (Deltex_fam)
Type: Family

The deltex family of proteins is involved in the regulation of Notch signaling, and therefore may play roles in cell-to-cell communications that regulate mechanisms determining cell fate . They have a central RING-type zinc finger domain and contain a C-terminal domain that is also found in other domain architectures. Deltex-1 (DTX1) contains a RING finger and two WWE domains, indicating that it may be an E3 ubiquitin ligase . Human deltex 3-like, which contains an additional N-terminal domain (presumably with ubiquitin ligase activity) is also described as E3 ubiquitin-protein ligase DTX3L, B-lymphoma- and BAL-associated protein (BBAP), or rhysin-2. DTX3L mediates monoubiquitination of K91 of histone H4 in response to DNA damage .
Deltex, C-terminal domain superfamily (Deltex_C_sf)
Type: Homologous_superfamily

The deltex family of proteins is involved in the regulation of Notch signaling, and therefore may play roles in cell-to-cell communications that regulate mechanisms determining cell fate . They have a central RING-type zinc finger domain and contain a C-terminal domain that is also found in other domain architectures. Deltex-1 (DTX1) contains a RING finger and two WWE domains, indicating that it may be an E3 ubiquitin ligase . Human deltex 3-like, which contains an additional N-terminal domain (presumably with ubiquitin ligase activity) is also described as E3 ubiquitin-protein ligase DTX3L, B-lymphoma- and BAL-associated protein (BBAP), or rhysin-2. DTX3L mediates monoubiquitination of K91 of histone H4 in response to DNA damage .

This entry represents the C-terminal domain of the Deltex proteins. It contains a fold composed of central β-sheet lined with two long parallel α-helices .
RagC/D (RagC/D)
Type: Family

RagC and RagD are closely related Rag GTPases (ras-related GTP-binding protein C and D) that constitute a unique subgroup of the Ras superfamily , and are functional homologues of
Saccharomyces cerevisiae
Gtr2. They form heterodimers with RagA or RagB , and similarly, Gtr2 dimerizes with Gtr1 in order to function. They play an essential role in regulating amino acid-induced target of rapamycin complex 1 (TORC1) kinase signaling , exocytic cargo sorting at endosomes, and epigenetic control of gene expression. In response to amino acids, the Rag GTPases guide the TORC1 complex to activate the platform containing Rheb proto-oncogene by driving the relocalization of mTORC1 from discrete locations in the cytoplasm to a late endosomal and/or lysosomal compartment that is Rheb-enriched and contains Rab-7 .
Ribosomal biogenesis NSA2 family (NSA2_fam)
Type: Family

NSA2 is required for the maturation of 27S pre-rRNA in yeast . It has been characterised in mammalian cells as a nucleolar protein that might play a role in the regulation of the cell cycle and in cell proliferation .
Cathepsin C (CatC)
Type: Domain

Cathepsin C (also known as Dipeptidyl Peptidase I or DPPI (

) MEROPS identifier C01.070) is an atypical papain-like cysteine peptidase with chloride dependency and dipeptidyl peptidase activity, resulting from its tetrameric structure which limits substrate access. Each subunit of the tetramer is composed of three peptides: the heavy and light chains, which together adopts the papain fold and forms the catalytic domain; and the residual propeptide region, which forms a β barrel and points towards the substrate's N terminus . The subunit composition is the result of the unique characteristic of procathepsin C maturation involving the cleavage of the catalytic domain and the non-autocatalytic excision of an activation peptide within its propeptide region . By removing N-terminal dipeptide extensions, cathepsin C activates granule serine peptidases (granzymes) involved in cell-mediated apoptosis, inflammation and tissue remodelling . Loss-of-function mutations in cathepsin C are associated with Papillon-Lefevre and Haim-Munk syndromes, rare diseases characterised by hyperkeratosis and early-onset periodontitis .
RON, Sema domain (RON_Sema)
Type: Domain

RON receptor tyrosine kinase is a macrophage-stimulating protein (MSP) receptor. Upon binding of MSP, RON is activated via autophosphorylation within its kinase catalytic domain, resulting in a wide range of effects, including proliferation, tubular morphogenesis, angiogenesis, cellular motility and invasiveness. By interacting with downstream signaling molecules, it regulates macrophage migration, phagocytosis, and nitric oxide production . RON has been implicated in cancers of the breast, colon, pancreas and ovaries because both splice variants and receptor overexpression have been identified in these tumours .

The Sema domain is located at the N terminus and contains four disulfide bonds formed by eight conserved cysteine residues. It serves as ligand recognition and binding model. RON is composed of an α-β heterodimer. The extracellular alpha chain is disulfide linked to the beta chain, which contains an extracellular ligand-binding region with a Sema domain, a PSI domain and four IPT repeats, a transmembrane segment, and an intracellular catalytic tyrosine kinase domain. The Sema domain of RON may be necessary for receptor dimerization and activation .
SMG1, PIKK catalytic domain (SMG1_PIKKc)
Type: Domain

SMG-1 plays a critical role in the mRNA surveillance mechanism known as non-sense mediated mRNA decay (NMD). NMD protects the cells from the accumulation of aberrant mRNAs with premature termination codons (PTCs) generated by genome mutations and by errors during transcription and splicing. SMG-1 phosphorylates Upf1, another central component of NMD, at the C terminus upon recognition of PTCs. The phosphorylation/dephosphorylation cycle of Upf1 is essential for promoting NMD .
Ubiquitin-like protein FUBI (FUBI)
Type: Domain

Fubi is a ubiquitin-like protein encoded by the fau gene which has an N-terminal ubiquitin-like domain (also referred to as FUBI) fused to the ribosomal protein S30. Fubi is thought to be a tumour suppressor protein and the FUBI domain may act as a substitute or an inhibitor of ubiquitin or one of ubiquitin's close relatives UCRP, FAT10, and Nedd8 .
Papain-like cysteine endopeptidase (Peptidase_C1A_papain-like)
Type: Domain

This entry represents homologues of papain, from peptidase family C1 subfamily A, including the mammalian CPs (cathepsins F, H, L, K, O, S, V, X and W) . Cathepsins B and C, which differ in their activation peptides, are not included here . Papain is an endopeptidase with specific substrate preferences, primarily for bulky hydrophobic or aromatic residues at the S2 subsite, a hydrophobic pocket in papain that accommodates the P2 sidechain of the substrate (the second residue away from the scissile bond). Most members of the papain subfamily are endopeptidases. Some exceptions to this rule can be explained by specific details of the catalytic domains like the occluding loop in cathepsin B which confers an additional peptidyl-dipeptidase activity and the mini-chain of cathepsin H resulting in an N-terminal exopeptidase activity .
LexA-like (LexA-like)
Type: Domain

Peptidase S24 LexA-like proteins are involved in the SOS response leading to the repair of single-stranded DNA within the bacterial cell . Proteins containing this domain includes LexA, MucA and UmuD. LexA (

) is the diverse family of bacterial transcription factors that repress genes in the cellular SOS response to DNA damage .

The LexA-like proteins contain two-domains: an N-terminal DNA binding domain and a C-terminal domain (CTD) that provides LexA dimerization as well as cleavage activity . They undergo autolysis, cleaving at an Ala-Gly or a Cys-Gly bond, separating the DNA-binding domain from the rest of the protein .

The LexA, UmuD and MucD proteins interact with RecA, which activates self cleavage either derepressing transcription in the case of LexA or activating the lesion-bypass polymerase in the case of UmuD and MucA. UmuD'2, is the homodimeric component of DNA pol V, which is produced from UmuD by RecA-facilitated self-cleavage. The first 24 N-terminal residues of UmuD are removed; UmuD'2 is a DNA lesion bypass polymerase . MucA , like UmuD, is a plasmid encoded a DNA polymerase (pol RI) which is converted into the active lesion-bypass polymerase by a self-cleavage reaction involving RecA .
Transcriptional regulatory protein WalR-like (WalR-like)
Type: Family

This family contains proteins that have a signal transduction response regulator receiver domain at the N terminus and a OmpR/PhoB-type DNA-binding domain at the C terminus. Homologues are predominantly from bacteria, but also eukaryotes and archaea. Members of the family are frequently part of a two-component regulatory system, including:

Transcriptional regulatory protein WalR, a member of the two-component regulatory system with WalK involved in the regulation of the ftsAZ operon and others . It plays a role in the regulation of fatty acid biosynthesis

Heme response regulator HssR, a member of the two-component regulatory system with HssS involved in intracellular heme homeostasis and tempering of staphylococcal virulence.

Response regulator protein GraR, a member of the two-component regulatory system with GraS involved in resistance against cationic antimicrobial peptides

Response regulator MprA, a member of the two-component regulatory system with MprB which contributes to maintaining a persistent infection in the host

Response regulator ArlR, a member of the two-component regulatory system with ArlS involved in the regulation of adhesion, autolysis, multidrug resistance and virulence

Response regulator SaeR, a member of the two-component regulatory system with SaeS involved in the regulation of staphylococcal virulence factors

Transcriptional regulatory protein CpxR, a member of the two-component regulatory system CpxA/CpxR which responds to envelope stress response by activating or, in some cases, repressing expression of downstream genes .
Type 1 protein exporter (Type_1_exporter)
Type: Family

Proteins in this entry are required for type I protein secretion and have an N-terminal ABC transporter type 1 transmembrane domain and a C-terminal P-loop containing nucleoside triphosphate hydrolase domain. The transmembrane domain forms a pore in the inner membrane and the ATP-binding domain is responsible for energy generation. Sequences are mainly from bacteria, but there are homologues from eukaryotes and archaea. Proteins in this entry include the following:

Lipid A export ATP-binding/permease protein MsbA, which is required for lipid A and possibly glycerophospholipid transport, and for biogenesis of the outer membrane in bacteria

Beta-(1-->2)glucan export ATP-binding/permease protein NdvA from nitrogen-fixing bacteria, which is required for beta-(1-->2)glucan export, essential for nodule formation in legume roots

Iron-sulfur clusters transporter ATM1, a yeast mitochondrial protein that exports Fe/S cluster-containing protein precursors and other mitochondrially synthesized proteins to the cytoplasm . The mammalian equivalents are the ATP-binding cassette sub-family B members 6, 7, 8 and 9, which are required for the transport of heme and porphyrin from the cytoplasm to the mitochondrion

Leukotoxin translocation ATP-binding protein LktB, required for leukotoxin export in
Mannheimia haemolytica

Multidrug resistance protein 1, which exports xenobiotics, such as cytotoxic drugs, out of cells leading to tumour cell resistance to multiple drugs . The bacterial equivalents include multidrug resistance-like ATP-binding protein MdlA

Alpha-hemolysin translocation ATP-binding protein HlyB from
E. coli
, a component of the ABC transporter complex HlyBD required for the export of hemolysin

Phosphatidylcholine translocator ABCB4, required for lipid secretion in the bile, transporting phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes

Bile salt export pump, required for the secretion of bile salts into the canaliculus of hepatocytes

Antigen peptide transporter 1, which is required for the transport of antigens from the cytoplasm to the endoplasmic reticulum for association with MHC class I molecules

P-glycoprotein 14 which exports polar lipids into the developing pharyngeal cuticle to protect against xenobiotic insult . PGP-14 has an internal duplication and two copies of the constituent domains.