SII-SWORD/CoKE huggingface dataset:
DPH-type metal-binding domain (DPH_MB_dom)
Type: Domain

This entry represents the DPH-type metal binding domain consists of a three-stranded β-sandwich with one sheet comprising two parallel strands: (i) β1 and (ii) β6 and one antiparallel strand: β5. The second sheet in the β-sandwich is comprised of strands β2, β3, and β4 running anti-parallel to each other. The two β-sheets are separated by a short stretch α-helix. It can be found in proteins such as DPH3 and DPH4. This domain is also found associated with N-terminal domain of heat shock protein DnaJ

domain .

Diphthamide is a unique post-translationally modified histidine residue found only in translation elongation factor 2 (eEF-2). It is conserved from archaea to humans and serves as the target for diphteria toxin and Pseudomonas exotoxin A. These two toxins catalyse the transfer of ADP-ribose to diphtamide on eEF-2, thus inactivating eEF-2, halting cellular protein synthesis, and causing cell death . The biosynthesis of diphtamide is dependent on at least five proteins, DPH1 to -5, and a still unidentified amidating enzyme. DPH3 and DPH4 share a conserved region, which encode a putative zinc finger, the DPH-type or CSL-type (after the the final conserved cysteine of the zinc finger and the next two residues) MB domain contains a Cys-X-Cys...Cys-X2-Cys motif which tetrahedrically coordinates both Fe and Zn. The Fe containing DPH-type MBD has an electron transfer activity .
Glycosyltransferase, ALG3 (Glycosyltransferase_ALG3)
Type: Family

The formation of N-glycosidic linkages of glycoproteins involves the ordered assembly of the common Glc3Man9GlcNAc2 core-oligosaccharide on the lipid carrier dolichyl pyrophosphate. Whereas early mannosylation steps occur on the cytoplasmic side of the endoplasmic reticulum with GDP-Man as donor, the final reactions from Man5GlcNAc2-PP-Dol to Man9GlcNAc2-PP-Dol on the lumenal side use Dol-P-Man . The ALG3 gene encodes the Dol-P-Man:Man5GlcNAc2-PP-Dol mannosyltransferase.
Septum formation inhibitor MinC, N-terminal (MinC_N)
Type: Domain

In Escherichia coli FtsZ (

) assembles into a Z ring at midcell. Its assembly at polar sites is prevented by the min system. MinC

, a component of this system, is an inhibitor of FtsZ assembly that is positioned within the cell by interaction with the MinDE proteins. MinC is an oligomer, probably a dimer . The C-terminal half of MinC is the most conserved and interacts with MinD. The N-terminal half is thought to interact with FtsZ. MinC rapidly oscillates between the poles of the cell to destabilise FtsZ filaments that have formed before they mature into polar Z rings.
Sprouty (Sprouty)
Type: Family

Sprouty (Spry) and Spred (Sprouty related EVH1 domain) proteins have been identified as inhibitors of the Ras/mitogen-activated protein kinase (MAPK) cascade, a pathway crucial for developmental processes initiated by activation of various receptor tyrosine kinases . These proteins share a conserved, C-terminal cysteine-rich region, the SPR domain. This domain has been defined as a novel cytosol to membrane translocation domain . It has been found to be a PtdIns(4,5)P2-binding domain that targets the proteins to a cellular localization that maximizes their inhibitory potential . It also mediates homodimer formation of these proteins .

The SPR domain can occur in association with the WH1 domain (see

) (located in the N-terminal part of the proteins) in the Spred proteins.
Neuraminyllactose-binding hemagglutinin (NeuraminylLac-bd_hemagglutn)
Type: Family

This family is comprised of several flagellar sheath adhesin proteins also called neuraminyllactose-binding haemagglutinin precursor (NLBH or HpaA) or N-acetylneuraminyllactose-binding fibrillar haemagglutinin receptor-binding subunits. NLBH is found exclusively in Helicobacter which are gut colonising bacteria and bind to sialic acid rich macromolecules present on the gastric epithelium . The sialic acid-sensitive agglutination of erythrocytes by certain strains of Helicobacter pylori has been attributed to the NLBH protein .
Protein of unknown function DUF707 (DUF707)
Type: Family

This family consists of uncharacterised proteins from Arabidopsis thaliana.
Coronavirus NS2A (Coronavirus_NS2A)
Type: Family

This entry is represented by Coronavirus non-structural protein 2A (32kDa); it is a family of uncharacterised viral proteins.

Members have a phosphoesterase module (2H) and are predicted to be involved in RNA modification. The viral group of 2H phosphoesterases contains proteins from two unrelated virus types: the type C rotaviruses (VP3 protein,

) that are double stranded multipartite RNA viruses and the coronaviruses (NS2 protein, this group) that are positive strand RNA viruses. Given that these viruses have vertebrate hosts, it is likely that the 2H phosphoesterase domain was derived from the host by one of virus groups followed by rapid sequence divergence . Subsequently, it may have been exchanged between the viral families. Although the direction of the exchange is not clear, it is possible that a double stranded replicative form of a subgenomic RNA transcript of the coronavirus NS2 was stabilised by a rotavirus and incorporated into its multiple double stranded RNA genome . These proteins can be utilised as novel drug targets because of their predicted RNA modification role.
FAD-linked sulfhydryl oxidase (Baculo_p33)
Type: Family

This family consists of a series of baculoviral 33kDa early protein homologues. Autographa californica nuclear polyhedrosis virus (AcMNPV) p33 has been shown to be a functional FAD-linked sulfhydryl oxidase .
Spiralin (Spiralin)
Type: Family

This family includes Spiralin from Spiroplasma citri and similar proteins from Tenericutes. The surface of spiroplasma bacteria is crowded with the membrane-anchored lipoprotein spiralin, whose structure and function are unknown, although its cellular function is thought to be a structural and mechanical one rather than catalytic .
UNC-50 (UNC-50)
Type: Family

This family contains several eukaryotic transmembrane proteins which are related to the Caenorhabditis elegans protein UNC-50

. A mammalian homologue, UNCL is a novel inner nuclear membrane protein that associates with RNA and is involved in the cell-surface expression of neuronal nicotinic receptors. UNCL plays a broader role because UNCL homologues are present in two yeast and a plant species, none of which express nicotinic receptors and it is also found in tissues that lack nicotinic receptors.
Microtubule-associated protein 6 (MAP6)
Type: Family

Microtubule-associated protein 6 (MAP6) is a calmodulin binding protein that is involved in microtubule stabilisation .

Neurons contain abundant subsets of highly stable microtubules that resist de-polymerising conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. MAP6 is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity . It regulates axonal growth during neuron polarisation, which is controlled by a palmitoylation cycle . MAP6 interacts with TMEM106B, and this interaction is crucial for controlling dendritic trafficking of lysosomes, presumably by acting as a molecular brake for retrograde transport . TMEM106B is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology.
Protein of unknown function DUF713 (DUF713)
Type: Family

This family contains proteins of unknown function.
Protein-L-histidine N-pros-methyltransferase (METL9)
Type: Family

This family contains protein-histidine N-methyltransferases (also known as DORA reverse strand protein DREV) that specifically catalyse 1-methylhistidine (pros-methylhistidine) methylation of target proteins, such as S100A9, NDUFB3, SLC39A5, SLC39A7, ARMC6 and DNAJB12 . They mediate methylation of proteins with a His-x-His (HxH) motif (where 'x' is preferably a small amino acid), in which the 1-methylhistidine modification may affect the binding of zinc and other metals . These proteins constitute the main methyltransferase for the 1-methylhistidine modification in cell .
MgpC adhesin (MgpC)
Type: Family

This family contains several Mycoplasma MgpC-like proteins. MgpC encode antigenic
proteins associated with attachment . The structure of MGP3 shows that this entry is a partial match to a large β propeller domain that binds to sialic acid .
Alanine dehydrogenase/pyridine nucleotide transhydrogenase, N-terminal (AlaDH/PNT_N)
Type: Domain

Alanine dehydrogenase catalyses the NAD-dependent reversible reductive amination of pyruvate into alanine. Pyridine nucleotide transhydrogenase catalyses the reduction of NADP
+
to NADPH with the concomitant oxidation of NADH to NAD
+
. This enzyme is located in the plasma membrane of prokaryotes and in the inner membrane of the mitochondria of eukaryotes. The transhydrogenation between NADH and NADP is coupled with the translocation of a proton across the membrane. In prokaryotes the enzyme is composed of two different subunits, an alpha chain (gene pntA) and a beta chain (gene pntB), while in eukaryotes it is a single chain protein.

The sequence of alanine dehydrogenase from several bacterial species is related to the alpha subunit of bacterial pyridine nucleotide transhydrogenase and the N-terminal half of the eukaryotic enzyme. The two most conserved regions correspond respectively to the N-terminal domain of these proteins, represented in this entry, and to a central glycine-rich domain which is part of the NAD(H)-binding site . The N-terminal domain is also found in lysine 2-oxoglutarate reductases .
NTF2-like N-terminal transpeptidase (MecA_N)
Type: Domain

The multiple antibiotic resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) has become a major clinical problem worldwide. Methicillin resistance in MRSA strains is due to the acquisition of the mecA gene via horizontal transfer from an unidentified species which encodes penicillin-binding protein 2a (PBP2a).
DNA binding HTH domain, Psq-type (HTH_Psq)
Type: Domain

The psq-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of about 50 amino acids present in eukaryotic proteins of the Pipsqueak family. This family is named after the Drosophila pipsqueak protein, containing a DNA-binding domain that consists of four tandem repeats of the psq motif . Proteins of the Pipsqueak family occur in vertebrates, insects, nematodes, and fungi.
CHASE2 (CHASE2)
Type: Domain

CHASE2 is an extracellular sensory domain, which is present in various classes of transmembrane receptors that are upstream of signal transduction pathways in bacteria. Specifically, CHASE2 domains are found in histidine kinases, adenylate cyclases, serine/threonine kinases and predicted diguanylate cyclases/phosphodiesterases. The environmental factors that are recognised by
CHASE2 domains are not currently known .
CHASE3 (CHASE3)
Type: Domain

CHASE3 is an extracellular sensory domain, which is present in various classes of transmembrane receptors that are upstream of signal transduction pathways in bacteria. Specifically, CHASE3 domains are found in histidine kinases, adenylate cyclases, methyl-accepting chemotaxis proteins and predicted diguanylate cyclases/phosphodiesterases . This domain recognises pyrene (Matilla et.al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
CHASE4 (CHASE4)
Type: Domain

CHASE4 is an extracellular sensory domain, which is present in various classes of transmembrane receptors that are upstream of signal transduction pathways in prokaryotes. Specifically, CHASE4 domains are found in histidine kinases in archaea and in predicted diguanylate cyclases/phosphodiesterases in bacteria. Environmental factors that are recognised by CHASE4 domains are not known at this time .
Spore coat protein U/FanG (Spore_coat_U/FanG)
Type: Domain

This domain is found in protein U, a spore coat protein produced at the late stage of development of Myxococcus xanthus. Protein U is produced as a secretory precursor, pro-protein U, which is then secreted across the membrane to assemble on the spore surface . This domain is also found in a number of the genes within a conserved polycistronic operon that encodes a novel chaperone-usher pili assembly system. Examples are CsuA/B of Acinetobacter baumannii, and the CsuA, CsuB and CsuE of Vibrio parahaemolyticus and the related genes of Yersinia pestis. Protein FanG from E.coli is also included in this entry, which is involved in the initiation of K99 fimbriae formation .
MASE2 (MASE2)
Type: Domain

This domain of unknown function is often found adjacent to the GGDEF domain in bacteria (

).
MASE1 (MASE1)
Type: Domain

This domain has been reported to bind aspartate and participate in protein-protein interactions .
Chlorhexidine efflux transporter (BTP_bacteria)
Type: Domain

This entry represents a conserved pair of two transmembrane α-helices. All members carry the two pairs of TMs. BTP is a form of drug efflux pump, that actively tranports chlorhexidine out of the cell. Chlorhexidine, a bisbiguanide antimicrobial agent, is commonly used as an antiseptic and disinfectant in hospitals, and there is an increasing problem with resistance to it in some pathogenic bacteria. BTP is localised in the cytoplasmic membrane .
PHB accumulation regulatory (PHB_accumulat)
Type: Domain

The proteins this domain is found in are typically involved in regulating polymer accumulation in bacteria, for example the production of poly-beta-hydroxybutyrate (PHB) which is formed via the polymerisation of D(-)-3-hydroxybutyryl-CoA . The function of this domain is unknown.
RNA polymerase I-specific transcription initiation factor Rrn10, Saccharomycetes (Rrn10_Saccharomycetes)
Type: Family

The protein Rrn10 has been identified as a component of the Upstream Activating Factor
(UAF), an RNA polymerase I (pol I) specific transcription stimulatory factor that recognises the upstream ribosomal RNA
(rRNA) gene promoter in a sequence specific manner and which stimulates rRNA synthesis .

This entry represents Rrn10 from budding yeasts.
CHAD domain (CHAD_dom)
Type: Domain

The CHAD (conserved histidine α-helical) domain has been identified as a specific binding module for inorganic polyphosphates (polyPs), linear polymers of orthophosphate units linked by phosphoanhydride bonds. This binding has been observed in bacterial, archaeal, and eukaryotic CHAD domains, which are formed by two four-helix bundles and possess a central pore surrounded by conserved basic surface patches. Different CHAD domains have been found to bind polyPs with dissociation constants ranging from the nano- to mid-micromolar range, but not nucleic acids. The binding of polyPs to CHAD domains occurs across the central pore and along the two basic patches, and mutational analysis of CHAD-polyP interface residues has validated the complex structure. The presence of a CHAD domain in the polyPase ygiF has been shown to enhance its enzymatic activity. Additionally, a CHAD protein from the plant Ricinus communis has been found to localize to the nucleus/nucleolus when expressed in Arabidopsis and tobacco, suggesting that plants may harbor polyPs in these compartments. It has been proposed that CHAD domains may be used to engineer the properties of polyP-metabolizing enzymes and to specifically localize polyP stores in eukaryotic cells and tissues .

Although the CHAD domain was originally defined as a 'conserved histidine α-helical domain' with histidines acting as metal chelators and/or phosphoacceptors, it has been found that the histidines contributing to Zn2 ion coordination in the RcCHAD structure were not conserved among CHAD family proteins. Therefore, CHAD domains are unlikely to be metal-binding proteins .
Transcription initiation factor TFIID component TAF4, C-terminal (TAF4_C)
Type: Domain

Accurate transcription initiation at protein-coding genes by RNA polymerase II requires the assembly of a multiprotein complex around the mRNA start site. Transcription factor TFIID is one of the general factors involved in this process. Yeast TFIID comprises the TATA binding protein and 14 TBP-associated factors (TAFIIs), nine of which contain histone-fold domains. The C-terminal region of the TFIID-specific yeast TAF4 (yTAF4) containing the HFD shares strong sequence similarity with Drosophila (d)TAF4 and human TAF4. A structure/function analysis of yTAF4 demonstrates that the HFD, a short conserved C-terminal domain (CCTD), and the region separating them are all required for yTAF4 function. This region of similarity is found in Transcription initiation factor TFIID component TAF4 .
Centromere protein Chl4/mis15/CENP-N (Chl4/mis15/CENP-N)
Type: Family

This family includes Chl4 from budding yeasts, mis15 from fission yeasts and centromere protein N (CENP-N) from animals.

In Saccharomyces cerevisiae, Chl4 is an outer kinetochore structural component required for chromosome stability . Chl4 is a component of the Ctf19 kinetochore complex that interacts with Ctf19p, Ctf3p, Iml3p and Mif2p . It is required for establishing bipolar spindle-microtubule attachments and proper chromosome segregation .
Emopamil-binding protein (EBP)
Type: Family

Emopamil binding protein (EBP) is a nonglycosylated type I integral membrane protein of endoplasmic reticulum and shows high level expression in epithelial tissues. The EBP protein has emopamil binding domains, including the sterol acceptor site and the catalytic centre, which show Delta8-Delta7 sterol isomerase activity. Human sterol isomerase, a homologue of mouse EBP, is suggested not only to play a role in cholesterol biosynthesis, but also to affect lipoprotein internalisation. In humans, mutations of EBP are known to cause the genetic disorder of X-linked dominant chondrodysplasia punctata (CDPX2). This syndrome of humans is lethal in most males, and affected females display asymmetric hyperkeratotic skin and skeletal abnormalities .
Glycosylation-dependent cell adhesion molecule 1 (GLYCAM-1)
Type: Family

This family consists of the lactophorin precursors proteose peptone component 3 (PP3) and glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1). GlyCAM-1 functions as a ligand for L-selectin, a saccharide-binding protein on the surface of circulating leukocytes, and mediates the trafficking of blood-born lymphocytes into secondary lymph nodes. In this context, sulphatation of the carbohydrates of GlyCAM-1 has been shown to be a critical structural requirement to be recognised by L-selectin. GlyCAM-1 is also expressed in pregnant and lactating mammary glands of mouse and in an unknown site in the lung, in the bovine uterus and rat cochlea .
Outer membrane protein 2, Brucella (OMP2_Brucella)
Type: Family

This family consists of several outer membrane proteins (2a and 2b) from Brucella abortus. B. abortus is Gram-negative, facultative intracellular bacteria that can infect many species of animals and Homo sapiens .
Protein of unknown function DUF735 (DUF735)
Type: Family

This family consists of several uncharacterised Borrelia burgdorferi proteins of unknown function.
Adenovirus E3A (Adeno_E3A)
Type: Family

Adenoviruses have evolved multiple mechanisms to evade the host immune response. Several of the immunomodulatory adenoviral proteins are encoded in early transcription unit 3 (E3). The E3A/19K protein interferes with antigen presentation and T cell recognition .
Uncharacterised protein family UPF0193 (UPF0193)
Type: Family

This family of proteins is functionally uncharacterised.
Oligosaccharyltransferase complex subunit (TMEM258/Ost5)
Type: Family

This entry includes Ost5 from budding yeasts and TMEM258 from animals. Ost5 is an essential subunit of the N-oligosaccharyl transferase (OST) complex which catalyses the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains .
Mitochondrial distribution/morphology family 35/apoptosis (MDM35_apoptosis)
Type: Family

This is a family of small highly conserved proteins. In Saccharomyces cerevisiae (Baker's yeast) the gene YKL053C-A (MDM35)

is one of the genes essential for maintenance of normal mitochondrial distribution and morphology (MDM) ; wherease in Homo sapiens (Human), p53CSV,

is a direct transcriptional target for p53 and appears to be a cell-survival mediator in response to genotoxic stress including low-levels of DNA damage. It is suggested that p53CSV modulates the apoptotic pathway through interaction with HSP70 and Apaf-1 thereby inhibiting activation of procaspase-3 and procaspase-9 .
Uncharacterised protein family UPF0220 (UPF0220)
Type: Family

This family of proteins is functionally uncharacterised.
Protein of unknown function UPF0223 (UPF0223)
Type: Family

This family of proteins is functionally uncharacterised.
CHAP domain (CHAP_dom)
Type: Domain

The CHAP (cysteine, histidine-dependent amidohydrolases/peptidases) domain is a region between 110 and 140 amino acids that is found in proteins from bacteria, bacteriophages, archaea and eukaryotes of the Trypanosomidae family. Many of these proteins are uncharacterised, but it has been proposed that they may function mainly in peptidoglycan hydrolysis. The CHAP domain is found in a wide range of protein architectures; it is commonly associated with bacterial type SH3 domains and with several families of amidase domains. It has been suggested that CHAP domain containing proteins utilise a catalytic cysteine residue in a nucleophilic-attack mechanism .

The CHAP domain contains two invariant residues, a cysteine and a histidine. These residues form part of the putative active site of CHAP domain containing proteins. Secondary structure predictions show that the CHAP domain belongs to the α+β structural class, with the N-terminal half largely containing predicted α-helices and the C-terminal half principally composed of predicted β-strands .

Some proteins known to contain a CHAP domain are listed below:

Bacterial and trypanosomal glutathionylspermidine amidases.

A variety of bacterial autolysins.

A Nocardia aerocolonigenes putative esterase.

Streptococcus pneumoniae choline-binding protein D.

Methanosarcina mazei protein MM2478, a putative chloride channel.

Several phage-encoded peptidoglycan hydrolases.

Cysteine peptidases belonging to MEROPS peptidase family C51 (D-alanyl-glycyl endopeptidase, clan CA).
DciA-like (DciA-like)
Type: Family

This family include DciA from Pseudomonas aeruginosa (

) and similar sequences mainly found in bacteria. DciA is a replicative helicase operator essential for bacterial replication initiation .
Herpesvirus glycoprotein L, N-terminal (Herpes_gL_N)
Type: Domain

Herpesviruses are enveloped by a lipid bilayer that contains at least a dozen glycoproteins. The virion surface glycoproteins mediate recognition of susceptible cells and promote fusion of the viral envelope with the cell membrane, leading to virus entry. No single glycoprotein associated with the virion membrane has been identified as the fusogen .

Glycoprotein L (gL) forms a non-covalently linked heterodimer with glycoprotein H (gH). This heterodimer is essential for virus-cell and cell-cell fusion since the association of gH and gL is necessary for correct localisation of gH to the virion or cell surface. gH anchoring the heterodimer to the plasma membrane through its transmembrane domain. gL lacks a transmembrane domain and is secreted from cells when expressed in the absence of gH .

This entry represents Herpesvirus glycoprotein L (gL), which is a virion associated envelope glycoprotein . Heterodimer formation between gH and gL has been demonstrated in both virions and infected cells . Heterodimer formation between gL and gH is important for the proper folding of gH and its insertion into the membrane because the anti-gH conformation-dependent monoclonal antibodies (mAbs) 53S and LP11 bind gH only when gL is present .