SII-SWORD/CoKE huggingface dataset:
CzcE superfamily (CzcE_sf)
Type: Homologous_superfamily

CzcE is involved in heavy-metal resistance . It binds copper , which induces a conformational change. It is thought that CzcE acts both as a Cu(I) and Cu(II) sensor and mediator of the multiple cross-responses of C. metallidurans CH34 against heavy metals by linking copper and cobalt-zinc-cadmium resistance .
Photosystem II Psb28, class 1 superfamily (Psb28_c1_sf)
Type: Homologous_superfamily

This superfamily represents the low molecular weight transmembrane protein Psb28 (PsbW) found in PSII, where it is a subunit of the oxygen-evolving complex. Psb28 appears to have several roles, including guiding PSII biogenesis and assembly, stabilising dimeric PSII , and facilitating PSII repair after photo-inhibition . There appears to be two classes of Psb28, class 1 being found predominantly in algae and cyanobacteria, and class 2 being found predominantly in plants. This entry represents class 1 Psb28.
WIF domain superfamily (WIF_sf)
Type: Homologous_superfamily

Wnt morphogens control embryonic development and homeostasis in adult tissues. In vertebrates the N-terminal WIF domain (WIF-1WD) of Wnt inhibitory factor 1 (WIF-1) binds Wnt ligands.

This entry represents the WIF domain, it is found in the RYK tyrosine kinase receptors and WIF the Wnt-inhibitory-factor. The domain is extracellular and contains two conserved cysteines that may form a disulphide bridge. This domain is Wnt binding in WIF, and it has been suggested that RYK may also bind to Wnt . The WIF domain of WIF-1 was suggested to have a function in inhibiting Wnt signalling .
Spondin, N-terminal domain superfamily (Spondin_N_sf)
Type: Homologous_superfamily

Spondins are multi-domain extracellular matrix (ECM) protein as well as contact-repellent molecules that directs axon outgrowth and cell migration during development. Spondins are involved in patterning axonal growth trajectory through either inhibiting or promoting adhesion of embryonic nerve cells .

This superfamily represents a domain found in the N-terminal half of several Spondin proteins , also called FS domain. It is found in F-spondins (spondin-1), mindins (spondin-2). Its homology to a common Ca2+- and lipid-binding C2 domain suggests that the F-spondin FS domain is responsible for part of the membrane targeting of F-spondin in its regulation of axon development .
Signal transduction protein PmrD superfamily (PmrD_sf)
Type: Homologous_superfamily

PmrA/PmrB and PhoP/PhoQ are a pair of two-component systems (TCSs) that allow the Gram-negative bacteria to survive the cationic antimicrobial peptide polymyxin B. The two TCSs are linked by the polymyxin resistance protein, PmrD . This entry represents a domain found in PmrD. This domain can also be found in anti-adapter protein IraM, a protein which inhibits rpoS proteolysis by regulating rssB activity, thereby increasing the stability of the sigma stress factor rpoS during magnesium starvation .

The Salmonella PmrA/PmrB two-component system is required for resistance to the cationic peptide antibiotic olymyxin B, resistance to Fe(3+)-mediated killing, growth in soil, virulence in mice, and infection of chicken macrophages. PmrA-activated genes encode periplasmic and integral membrane proteins as well as cytoplasmic products mediating the modification of the lipopolysaccharide, suggesting a role for the PmrA/PmrB system in remodeling of the Gram-negative envelope .

The PmrA/PmrB two-component system of Salmonella enterica is activated by Fe(3+), which is sensed by the PmrB protein, and by low Mg(2+), which is sensed by the PhoQ protein. The low Mg(2+) activation requires pmrD, a PhoPPhoQ-activated gene that activates the response regulator PmrA at a posttranscriptional level. However, under conditions that activate the PmrA protein independently of pmrD, such as exposure to Fe3, lower levels of pmrD transcription occur. It has been demonstrated that PmrA binds to the pmrD promoter, suppressing transcription. Negative regulation of the PhoP/PhoQ-activated pmrD gene by the PmrA/ PmrB system closes a regulatory circuit designed to maintain proper cellular levels of activated PmrA protein, and constitutes a singular example of a multicomponent feedback loop .
PAW domain superfamily (PAW_sf)
Type: Homologous_superfamily

The PAW domain (present in PNGases and other worm proteins) is found as a single copy at the C terminus of metazoan peptide:N-glycanase (PNGase) and in multiple copies in hypothetical Caenorhabditis elegans proteins peptide:N-glycanases (PNGases) . The C-terminal PAW domain of PNGase binds to the mannose moieties of N-linked oligosaccharide chains .

The PAW domain is a slightly elongated molecule and displays a β-sandwich architecture, which is composed of two layers, containing nine and eight antiparallel β-strands, respectively, and three additional short helices .
Sf6-type phage tail needle knob superfamily (Phage_tail_NK_sf)
Type: Homologous_superfamily

This entry represents the globular tip protein of some tailed bacteriophages, including Tail needle protein from Shigella phage Sf6. Tailed bacteriophage virions deliver DNA to susceptible cells after adsorbing to specific receptors on the surface of the bacteria. In the Gram-negative bacteria these receptors are surface proteins or polysaccharides. In the phage Sf6-type needle, this distal tip folds into a knob with a TNF-like fold, similar to the fibre knobs of bacteriophage PRD1 and Adenovirus. It contains three bound L-glutamate molecules that are bind tightly in the crevices between the trimers of this trimeric tip .
YrpD-like superfamily (YrpD-like_sf)
Type: Homologous_superfamily

This entry represents bacterial proteins that are typically between 236 and 351 amino acids in length. Members from Bacillus subtilis are named YrpD (

) and YncM (

, PDBe:4hfs).
Interleukin-17 receptor A/B, FnIII-like domain 1 superfamily (IL17RA/B_FnIII-like_1_sf)
Type: Homologous_superfamily

The five IL-17 receptors (IL17RA-IL17RE) exhibit considerable sequence divergence between one another, but all appear to contain extracellular domains composed of fibronectin type-III (FnIII) domains, and cytoplasmic SEF/IL-17R (SEFIR) domains that show loose homology to Toll/IL-1R (TLR) domains.

This is the first of two fibronectin-type domains on interleukin-17 receptor proteins A and B . These two fibronectin-type domains are linked and together bind two molecules of IL-17 at one of its receptor-binding interfaces. This allows the other interface to bind to another receptor, thus allowing the IL-17 family of homodimeric cytokines to coordinate two different receptors .
PAD, N-terminal domain superfamily (PAD_N_sf)
Type: Homologous_superfamily

This superfamily represents the first immunoglobulin-like domain found in protein arginine deiminases.

Protein arginine deiminases (PADs) use a nucleophilic cysteine to hydrolyze guanidinium groups on arginine residues to form citrulline. This reaction, known as citrullination or deimination, results in the loss of positive charge, thereby affecting protein function and altering protein-protein and protein-nucleic acid interactions. Humans encode five PADs, designated PADs 1-4 and PAD6, which regulate numerous cellular processes. PADs are dysregulated in inflammatory diseases and cancer . PAD6 does not bind Ca2+ and is inactive in vitro assays against standard PADs substrate .

The PAD2 monomer consists of two immunoglobulin-like domains, IgG1 (residues 1-115) and IgG2 (residues 116-295), as well as a C-terminal catalytic domain (residues 296-665) .
MIC1, C-terminal superfamily (MIC1_C_sf)
Type: Homologous_superfamily

MIC1 is released as part of a complex by Toxoplasma gondii prior to invasion. The complex, which consists of MIC4-MIC1-MIC6, participates in host cell attachment and penetration, and is critical in invasion . MIC1 is a lactose-binding lectin required for the complex to leave the early compartments of the secretory pathway .

This entry represents the C-terminal domain of MIC1, which has a galectin-like fold that interacts with and stabilises MIC6, providing a mechanism for an exit from the early secretory compartments and trafficking of the complex to micronemes . Members of this group belong to apicomplexa.
Apoptosis regulator, M-T4 superfamily (M-T4_sf)
Type: Homologous_superfamily

Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans . In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.

This entry represents an endoplasmic reticulum-localized apoptosis regulator, M-T4 type. M-T4 has both an N-terminal signal sequence and a C-terminal -RDEL sequence, suggesting that M-T4 resides in the endoplasmic reticulum. M-T4 is an intracellular virulence factor in myxoma virus that functions from within the endoplasmic reticulum and is necessary for the productive infection of lymphocytes . The C-terminal RDEL motif of the myxoma virus M-T4 protein may not be solely responsible for retention of M-T4 in the ER. M-T4 may have a dual function in protecting infected lymphocytes from apoptosis and in modulating the inflammatory response to virus infection . Some members of this entry belong to the pox viruses.
Flavivirus polyprotein propeptide superfamily (Flavi_propep_sf)
Type: Homologous_superfamily

The Flaviviruses are small enveloped animal viruses containing a single positive strand genomic RNA . The genome encodes one large ORF, a polyprotein which undergos proteolytic cleavage of the precursor membrane protein (prM), turning inert virus into infectious particles. This entry consists of a propeptide region of approximately 90 amino acids in length .
Thermostable direct haemolysin superfamily (TDH_sf)
Type: Homologous_superfamily

Thermostable direct haemolysin (TDH) is considered an important virulence factor in Vibrio parahaemolyticus gastroenteritis and is a dimer composed of two identical subunit molecules of approximately 21kDa. The tetrameric form contains a central pore permitting entry and exit of water molecules. A number of biological properties have been attributed to TDH including haemolytic activity, enterotoxicity, cytotoxicity and cardiotoxicity .

Structurally, this superfamily consists of 10 β strands, 1 α helix and 1 3(10)-helix.
NusG, domain 2 superfamily (NusG_2_sf)
Type: Homologous_superfamily

This domain consists of two-sandwiched four-stranded antiparallel sheets. It is found in transcription factor NusG, where it represents domain 2 and is inserted in domain 1 . However, most NusG proteins are missing this domain. In other cases this domain is found in isolation . NusG is a regulator of Rho-dependent transcription termination , but the function of this domain is unknown.
DNA-entry nuclease inhibitor, ComJ superfamily (ComJ_sf)
Type: Homologous_superfamily

Competence is the ability of a cell to take up exogenous DNA from its environment, resulting in transformation. It is widespread among bacteria and is probably an important mechanism for the horizontal transfer of genes. DNA usually becomes available by the death and lysis of other cells. Competent bacteria use components of extracellular filaments called type 4 pili to create pores in their membranes and pull DNA through the pores into the cytoplasm. This process, including the development of competence and the expression of the uptake machinery, is regulated in response to cell-cell signalling and/or nutritional conditions .

The proteins in this entry play a role in the competence of cells to be transformed. They inhibit the activity of the DNA-entry nuclease. DNA-entry nuclease inhibitor is a subunit of a 75kDa protein complex, which governs binding and entry of donor DNA. The complex is a tetramer of two subunits of the DNA-entry nuclease and two subunits of a competence-specific protein ComJ. Only the complex is able to bind ds- and ss-DNA . It is found in the plasma membrane.
Cthe_2751-like superfamily (Cthe_2751_sf)
Type: Homologous_superfamily

This entry includes a group of uncharacterised proteins, including Cthe_2751. The structure of the Cthe_2751 protein (

) from
Clostridium thermocellum
has been solved and shows an all α-helical protein with a central hydrophobic core which provides thermal stability .
Phenylacetyl-CoA epoxidase, subunit B (PaaB_sf)
Type: Homologous_superfamily

This entry represents the 1,2-phenylacetyl-CoA epoxidase, subunit B (also known as PaaB) and related bacterial proteins.

Phenylacetyl-CoA monooxygenase (epoxidase) is a multicomponent enzyme, PaaABC(D)E, responsible for the hydroxylation of phenylacetate-CoA (PA-CoA) as the second catabolic step in phenylacetic acid (PA) degradation . Not only transforms phenylacetyl-CoA into its ring-1,2-epoxide, but also mediates the NADPH-dependent removal of the epoxide oxygen, regenerating phenylacetyl-CoA with formation of water .

The PaaB subunit probably acts as an effector protein .
Superfamily of unknown function DUF427 (DUF427_sf)
Type: Homologous_superfamily

This domain consists of 10 β-strands and 2 short α-helices forming a β-tent fold .
Saro_0823-like superfamily (Saro_0823-like_sf)
Type: Homologous_superfamily

Structures have been solved for homologues from Novosphingobium aromaticivorans (Saro_0823 protein,

) and Rhizobium meliloti (SMc00288 protein,

) and show a β-sheet decorated with helices.
Invasion protein B superfamily (IalB_sf)
Type: Homologous_superfamily

This superfamily consists of several invasion associated locus B (IalB) proteins and related sequences. IalB is known to be a major virulence factor in Bartonella bacilliformis where it was shown to have a direct role in human erythrocyte parasitism. IalB is up-regulated in response to environmental cues signalling vector-to-host transmission. Such environmental cues would include, but not be limited to, temperature, pH, oxidative stress, and haemin limitation. It is also thought that IalB would aide B. bacilliformis survival under stress-inducing environmental conditions .
Tp47, domain C superfamily (PBP_Tp47_domC_sf)
Type: Homologous_superfamily

Domain C is the largest domain in this unusual penicillin-binding protein (PBP), Tp47. This domain is mainly characterised by an immunoglobulin fold with two opposing β-sheets that form the typical barrel-like structure. In contrast to the classical immunoglobulin fold, however, this has an additional β-strand inserted after strand 3. Also, the strands are connected by rather large loops. Helices are inserted between strands 2 and 3 and between strands 4 and 5. Domain C interacts with domain B via a surface that has a slightly concave, goblet-like shape in addition to interacting tightly with domain A and weakly with domain D. Tp47 is unusual in that it displays beta-lactamase activity, so it does not fit the classical structural and mechanistic paradigms for PBPs, and thus Tp47 appears to represent a new class of PBP .
Thiol-activated cytolysin, C-terminal domain superfamily (Thiol_cytolys_C_sf)
Type: Homologous_superfamily

This superfamily represents a domain with an immunoglobulin like fold. It is found at the C terminus of the thiol-activated cytolysin protein.

Thiol-activated cytolysins are toxins produced by a variety of Gram-positive bacteria and are characterised by their ability to lyse cholesterol-containing membranes, their reversible inactivation by oxidation and their capacity to bind to cholesterol. All these proteins contain a single cysteine residue, located in their C-terminal section, which has been shown to be essential for the binding to cholesterol.
ToxA superfamily (ToxA_sf)
Type: Homologous_superfamily

ToxA is produced by particular Pyrenophora triticirepentis races and is a proteinaceous host-selective toxin. It is necessary and sufficient to cause cell death in sensitive wheat cultivars . ToxA adopts a single-domain, β-sandwich fold which has novel topology. The protein is directly involved in recognition events required for ToxA action, which involves several recognition events, is mediated by an important solvent-exposed Arg-Gly-Asp (RGD) containing loop. This structure is remarkably similar to the classic mammalian RGD-containing domain, the fibronectin type III (FnIII) domain. It is thought to be distantly related to mammalian FnIII proteins, gaining entry to the host via an integrin-like receptor in the plant host .
Sodium/potassium-transporting ATPase subunit beta superfamily (Na/K_ATPase_sub_beta_sf)
Type: Homologous_superfamily

This entry represents the sodium/potassium-transporting ATPase subunit beta. This is the non-catalytic component of the active enzyme, which catalyses the hydrolysis of ATP coupled with the exchange of Na
+
and K
+
ions across the plasma membrane. The beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane .
YebF/Cmi superfamily (YebF/Cmi_sf)
Type: Homologous_superfamily

This superfamily includes the colicin M immunity protein Cmi, and the protein of unknown function YebF. Cmi protects cells from the colicin M toxin, though the mechanism by which it achieves this is not known . The protein forms an α-β fold and contains a disulphide bond that is essential for function . Although the function of YbeF is not known, it is secreted by E. coli, and contains the two conserved cysteine residues responsible for the disulphide bond in Cmi .
YEATS superfamily (YEAST_sf)
Type: Homologous_superfamily

This superfamily represents YEATS (Yaf9, ENL, AF9, Taf14, and Sas5) domain, an evolutionarily conserved module present in 4 proteins (ENL, AF9, GAS41, and YEATS2) in humans and 3 proteins (Sas5, Taf14, and Yaf9) in yeast. These proteins are found in major chromatin-remodeling and histone acetyl-transferase (HAT) complexes and implicated in regulation of chromatin structure, histone acetylation and deposition, gene transcription and DNA damage response. The YEATS domain, which as previously shown is found in a number of chromatin-associated proteins, has recently been shown to have the capacity to bind histone lysine acetylation . The ability of the YEATS domains of human AF9 and yeast Taf14 to recognise the histone mark H3K9ac, have shown that these proteins are members of the family of acetyllysine readers .
YabP superfamily (YabP_sf)
Type: Homologous_superfamily

This superfamily represents the YabP protein of the bacterial sporulation program, as found in Bacillus subtilis, Clostridium tetani, and other spore-forming members of the Firmicutes. In B. subtilis, a yabP single mutant appears to sporulate and germinate normally , but is in an operon with yabQ (essential for formation of the spore cortex), it near-universal among endospore-forming bacteria, and is found nowhere else. YabP is involved in spore coat assembly during the process of sporulation .
Type VI secretion protein SciN-like superfamily (Type_VI_SciN-like_sf)
Type: Homologous_superfamily

SciN (also known as Lip) is a lipoprotein tethered to the outer membrane and expressed in the periplasm of E. coli, and is essential for T6SS-dependent secretion of the Hcp-like SciD protein and for biofilm formation .
Conjugal transfer protein TraQ superfamily (TraQ_sf)
Type: Homologous_superfamily

This entry represents the conjugal transfer protein TraQ found in Bacteroides species. The Bacteroides thetaiotaomicron gene coding for this protein is located in a conjugate transposon and appears to be upregulated in the presence of host or other bacterial species compared to growth in pure culture .
Gp34-like superfamily (Gp34-like_sf)
Type: Homologous_superfamily

Proteins in this entry are related to the m04 encoded protein gp34 of pathogenic microorganisms such as Murid herpesvirus 1. m06 and m152 genes are expressed earlier in the intracellular replication phases of these microorganism' life cycles. They function to inhibit MHC-1 loading and export. gp34 is theorized to prevent immune reactions from NK cells which would ordinarily recognise and attack cells lacking MHC .
RNA polymerase sigma-54 factor, core-binding domain superfamily (RpoN_core-bd_sf)
Type: Homologous_superfamily

Bacterial core RNA polymerases (with subunit composition alpha2-β-β') must combine with a sigma subunit to transcribe from specific DNA promoter sequences. This domain, the core-binding domain of sigma factor 54, is a four-helical domain with negative charge that binds and makes a direct interaction with the core RNA polymerase to form an enhancer dependent holoenzyme and triggers the initiation of transcription .
Adenovirus Gp19K superfamily (Adenovirus_Gp19K_sf)
Type: Homologous_superfamily

The 19kDa glycoprotein (GpK19) binds the major histocompatibility (MHC) class I antigens in the endoplasmic reticulum (ER). The ER retention signal at the C terminus of Gp19K causes retention of the complex in the ER, preventing lysis of the cell by cytotoxic T-lymphocytes .
Leucine Rich repeat protein, N-terminal domain superfamily (LRR_N_sf)
Type: Homologous_superfamily

This entry represents a domain found in tandem repeats at the N terminus of secreted Leucine Rich repeat (LRR) proteins from human-associated Bacteroidetes.
PixA-like superfamily (PixA-like_sf)
Type: Homologous_superfamily

This entry represents bacterial proteins that are typically between 173 and 191 amino acids in length. PixA is thought to be specifically produced in Xenorhabdus nematophila. It is an inclusion body protein . This entry also matches AidA.
Terminase small subunit, N-terminal DNA-binding domain, HTH motif superfamily (Terminase_Gp1_N_sf)
Type: Homologous_superfamily

Packaging of double-stranded viral DNA concatemers requires interaction of the prohead with virus DNA. This process is mediated by a phage-encoded DNA recognition and terminase protein. The terminase enzymes described so far, which are hetero-oligomers composed of a small and a large subunit, do not have a significant level of sequence homology. The small terminase subunit is thought to form a nucleoprotein structure that helps to position the terminase large subunit at the packaging initiation site . The small terminase protein is essential for the initial recognition of viral DNA and regulates the motor's ATPase and nuclease activities during DNA translocation and for switching between viral DNA replication and packaging. DNA packaging in tailed bacteriophages and in evolutionarily related herpesviruses is controlled by a viral-encoded terminase. The terminase complex characterised in Bacillus subtilis bacteriophages SF6 and SPP1 consists of two proteins: G1P and G2P .

This entry represents the N-terminal domain of the terminase small subunit, which contains a HTH DNA-binding motif . The first three helices of G1P form the typical helix-turn-helix DNA-binding motif, which is followed by a fourth helix. The fourth helix acts as a linker between the DNA-binding domain and the oligomerization domain .
YfeY-like superfamily (YfeY-like_sf)
Type: Homologous_superfamily

This entry consists of several hypothetical bacterial proteins of unknown function.
RNA polymerase inhibitor superfamily (RNA_pol_inhibitor_sf)
Type: Homologous_superfamily

This entry represents RNA polymerase inhibitor, including Gp2 from T7-like viruses. Bacterial RNA polymerase inhibitor, which is expressed in the late stage of lytic development, is also essential for continuous synthesis of phage DNA and functions in the packaging of the viral genome into the mature phage particle . It inhibits the bacterial host RNA polymerase by interacting with the RpoC subunit and inhibiting the formation of a promoter complex .

Gp2 folds into a compact globular domain consisting of a three-stranded β sheet that packs against an α-helix with a beta1beta2alpha1beta3 topology. The central beta2 strand is flanked by antiparallel beta1 and beta3 strands. Positive and negative charges are at opposite sides on the surface of the molecule. Two conserved arginine residues located on one side are important for binding to and inhibition of host RNA polymerase .