SII-SWORD/CoKE huggingface dataset:
BH3-interacting domain death agonist (BID)
Type: Family

Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes . At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.

Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 . Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily . Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.

BID is a member of the Bcl-2 superfamily of proteins that are key regulators of programmed cell death, hence this family is related to the Apoptosis regulator Bcl-2 protein BH domain. BID is a pro-apoptotic member of the Bcl-2 superfamily and as such posses the ability to target intracellular membranes and contains the BH3 death domain. The activity of BID is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, which causes a change of cellular localisation .
Pepsin inhibitor-3-like repeated domain (Pepsin-I3)
Type: Domain

Pepsin inhibitor-3 consists of two domains, each comprising an antiparallel β-sheet flanked by an α-helix. In the enzyme-inhibitor complex, the N-terminal β-strand of PI-3 pairs with one strand of the active site flap region of pepsin . The two domains are tandem repeats of sequence, and has therefore been termed repeated domain.
Cdc24/Scd1, N-terminal (Cdc24/Scd1_N)
Type: Domain

This domain can be found in budding yeast Cdc24 and fission yeast Scd1. They are guanine nucleotide exchange factor (GEF) for Cdc42 .
TECPR1-like, DysF domain (TECPR1-like_DysF)
Type: Domain

This entry represents the DysF domain found twice in human Tectonin β-propeller repeat-containing protein 1 (TECPR1) and similar animal sequences. TECPR1 is a tethering factor involved in autophagy, autophagosome maturation and selective autophagy against bacterial pathogens . This protein has two 5-bladed β-propeller domains (

). The DysF domain lies inserted between the first and second blades of each propeller. It consists of a central pair of antiparallel β-strands connected via a long loop that wraps around the β-sheet and covers large parts of the elongated finger-shaped domain surface. The N-terminal DysF domain of TECPR1 detects and binds sphingomyelin .

This domain is also found towards the N-terminal of Pex23 from Drosophila melanogaster, which shows structural similarity with Tectonin beta-propeller repeat-containing proteins but is involved in peroxisome biogenesis .

Yeast peroxisomal proteins of the PEX28-32 family and at the N-terminal of Meiotically up-regulated gene 65 protein from Schizosaccharomyces pombe (Mug65) are also members of this group. PEX28/29 are involved in the regulation of peroxisome number, size and distribution . Mug65 has a role in meiosis .
Alpha-2-macroglobulin RAP, C-terminal (Alpha_2_MRAP_C)
Type: Domain

The alpha-2-macroglobulin receptor-associated protein (RAP) is a intracellular glycoprotein that binds to the 2-macroglobulin receptor and other members of the low density lipoprotein receptor family. The protein inhibits binding of all currently known ligands of these receptors . Two different studies have provided conflicting domain boundaries.
HNS-dependent expression A/B (HNS-dep_expression_A/B)
Type: Family

HNS (histone-like nucleoid structuring)-dependent expression A (HdeA) protein is a stress response protein found in highly acid resistant bacteria such as Shigella flexneri and Escherichia coli, but which is lacking in mildly acid tolerant bacteria such as Salmonella . HdeA is one of the most abundant proteins found in the periplasmic space of E. coli, where it is one of a network of proteins that confer an acid resistance phenotype essential for the pathogenesis of enteric bacteria . HdeA is thought to act as a chaperone, functioning to prevent the aggregation of periplasmic proteins denatured under acidic conditions. The HNS protein, a chromatin-associated protein that influences the gene expression of several environmentally-induced target genes, represses the expression of HdeA. HdeB, which is encoded within the same operon, may form heterodimers with HdeA. HdeA is a single domain α-helical protein with an overall fold that is similar to the fold of the N-terminal subdomain of the GluRS anticodon-binding domain.

This entry represents HdeA and HdeB which are also known as acid stress chaperones.
Neugrin/Rrg9 (NGRN/Rrg9)
Type: Family

This entry include neugrin from mammals and Rrg9 from fungi. Neugrin is mainly expressed in neurons and may play an important role in the process of neuronal differentiation . Rrg9 is required for respiratory activity and maintenance and expression of the mitochondrial genome .
Zeta toxin domain (Zeta_toxin_domain)
Type: Domain

This entry represents a domain originally identified in bacterial zeta toxin proteins, where it comprises the whole protein . It has subsequently been found in a number of other proteins, such as polynucleotide kinase and 2',3'-cyclic-nucleotide 3'-phosphodiesterase. It appears to function as a kinase domain .
Effector protein NleG (Effector_NleG)
Type: Family

Many bacterial pathogens deliver effector proteins into host cells via a type III secretion system, enabling them to manipulate host cell biology in ways that benefit the pathogen. In enterohaemorrhagic Escherichia coli O157:H7, the NleG protein and its homologues represent the largest family of effector proteins, with 14 members identified in the Sakai strain alone . Members of the NleG family share a conserved C-terminal domain that adopts a structure similar to the RING finger/U-box domain found in eukaryotic ubiquitin ligases . These domains allow NleG proteins to selectively interact with human E2 ubiquitin-conjugating enzymes and exhibit in vitro activity characteristic of eukaryotic E3 ligases, although the precise role of this activity in pathogenesis remains unclear. Effector proteins such as NleG are believed to alter host cell physiology and promote bacterial survival within host tissues. This particular protein is likely an E3 ubiquitin-protein ligase that interferes with the host ubiquitination pathway, directing host proteins towards proteasomal degradation. Supporting its role in virulence, mice infected with a bacterial strain lacking this gene display less severe diarrhoea .
Conserved oligomeric Golgi complex subunit 6 (COG6)
Type: Family

COG6 is a component of the peripheral membrane COG (conserved oligomeric Golgi) complex that is involved in intra-Golgi protein trafficking. COG is located at the cis-Golgi, regulates tethering of retrograde intra-Golgi vesicles and is required for normal Golgi morphology and localisation . COG subunits belong to the CATCHR (complexes associated with tethering containing helical rods) family which includes subunits of the GARP/EARP, exocyst, and Dsl1 complexes, all evolutionary related and have a conserved structural fold consisting of α-helical bundles in tandem at the C-terminal and a coiled-coil region at the N-terminal .
PRP1 splicing factor, N-terminal (PRP1_N)
Type: Domain

This domain is specific to the N-terminal part of the prp1 splicing factor, which is involved in mRNA splicing (and possibly also poly(A)+ RNA nuclear export and cell cycle progression). This domain is specific to the N terminus of the RNA splicing factor encoded by prp1 . It is involved in mRNA splicing and possibly also poly(A)and RNA nuclear export and cell cycle progression.
GINS complex, subunit Psf3 (GINS_Psf3)
Type: Family

DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the pre-replication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.

A novel replication complex, GINS (for Go, Ichi, Nii, and San; meaning 5-1-2-3 in Japanese, after the four related subunits of the complex Sld5, Psf1, Psf2 and Psf3), has been identified . The GINS complex is conserved in eukaryotic cells and is essential for DNA replication. When the DNA replication fork is opened, GINS is required to maintain the association between the MCM and Cdc45 in the large replicator complex . The GINS complex acts as a replicative helicase that unlocks the double-stranded DNA prior to the moving replication fork .

Psf2's expression is up regulated in many diseases, especially tumors, and adversely affects prognosis .

The GINS complex is essential for initiation of DNA replication in Xenopus egg extracts . This 100kDa stable complex includes Sld5, Psf1, Psf2, and Psf3. Homologues of these components are found also in other eukaryotes. This family of proteins represents the Psf3 component.

Electron microscopy of GINS shows that it forms a ring-like structure , reminiscent of the structure of PCNA , the DNA polymerase delta replication clamp. The eukaryotic GINS subunits are homologous. The four subunits of the complex consist of two domains each, termed the α-helical (A) and β-strand (B) domains. The A and B domains of Sld5/Psf1 are permuted with respect to Psf1/Psf3 .
Serine acetyltransferase, N-terminal (Ser_AcTrfase_N)
Type: Domain

The N-terminal domain of serine acetyltransferase has a sequence that is conserved in plants and bacteria .
Repeat of unknown function DUF1079 (DUF1079)
Type: Repeat

This entry represents several repeats of 31 residues in length and seems to be exclusive to Moraxella catarrhalis UspA proteins. The UspA1 and UspA2 proteins of M. catarrhalis are structurally related and are exposed on the bacterial cell surface where can function adhesins . This repeat is commonly found with the

.
Haem-binding HasA (HasA_haem-bd)
Type: Family

Free iron is limited in vertebrate hosts, thus an alternative to siderophores has been developed by pathogenic bacteria to access host iron bound in protein complexes. HasA is a secreted haemophore that has the ability to obtain iron from haemoglobin. Once bound to HasA, the haem is shuttled to the receptor HasR, which releases the haem into the bacterium .
3-keto-alpha-glucoside-1,2-lyase/3-keto-2-hydroxy-glucal hydratase domain (AL/BT2_dom)
Type: Domain

This domain has structural similarity to an endo-1,3-1,4-beta glucanase belonging to glycoside hydrolase family 16

. A member containing this domain, BT2157 from B. thetaiotaomicron, was initially described as a 3-keto trehalose hydrolase involved in trehalose degradation . However, members of this group of proteins, previously known as DUF1080, have been reported to be 3-keto-α-glucoside-1,2-lyases and 3-keto-2-hydroxy-glucal hydratases and named AL/BT2 enzymes .
Epoxide hydrolase, N-terminal (Epoxide_hydro_N)
Type: Domain

This entry represents the N-terminal region of the eukaryotic epoxide hydrolase protein. Epoxide hydrolases (

) comprise a group of functionally related enzymes that catalyse the addition of water to oxirane compounds (epoxides), thereby usually generating vicinal trans-diols. EHs have been found in all types of living organisms, including mammals, invertebrates, plants, fungi and bacteria. In animals, the major interest in EH is directed towards their detoxification capacity for epoxides since they are important safeguards against the cytotoxic and genotoxic potential of oxirane derivatives that are often reactive electrophiles because of the high tension of the three-membered ring system and the strong polarisation of the C--O bonds. This is of significant relevance because epoxides are frequent intermediary metabolites, which arise during the biotransformation of foreign compounds . This domain is often found in conjunction with

.
Fimbrial protein SefA (SefA)
Type: Family

The sefABC genes make up part of a complex sef operon responsible for the expression and assembly of SEF14 fimbriae. sefA encodes a fimbrin, the structural subunit of SEF14 fimbriae . Possession of SEF14 fimbriae alone do not appear to play a significant role in the pathogenesis of Salmonella enteritidis .

This family also includes adhesin CS22 and CS15 (antigen 8786) which share homology with fimbria SEF14 of Salmonella enteritidis .
Bacterial transcription activator, effector binding (AraC_E-bd)
Type: Domain

This domain is found in the probable effector binding domain of a number of different bacterial transcription activators and is also present in some DNA gyrase inhibitors. The absence of a HTH motif in the DNA gyrase inhibitors is thought to indicate the fact that these do not bind DNA.

It is also found in Transcriptional regulator Rob which binds to regulatory regions and represses transcription of genes belonging to the flagellar regulon, including flhD, flhB and fliC .
Hepcidin (Hepcidin)
Type: Family

Hepcidin is a antibacterial and anti-fungal protein expressed in the liver and is also a signalling molecule in iron metabolism. The hepcidin protein is cysteine-rich and forms a distorted β-sheet with an unusual disulphide bond found at the turn of the hairpin .
Carbohydrate-binding domain, family 9 (Carb-bd_dom_fam9)
Type: Domain

This entry represents the family 9 carbohydrate-binding module (CBD9), which exhibit an immunoglobulin-like β-sandwich fold, with an additional β-strand at the N terminus .

Bacterial extracellular cellulases and hemicellulases are involved in the hydrolysis of the major structural polysaccharides of plant cell walls. These are usually modular enzymes that contain catalytic and non-catalytic domains. The CBD9 domain binds to cellulose, xylan, as well as to a range of soluble di- and mono-saccharides, and is found in cellulose- and xylan-degrading enzymes, such as endo-1,4-beta-xylanase (

) .
Type II heat-labile enterotoxin, B subunit (LT-IIB)
Type: Family

These are B subunits from the type II heat-labile enterotoxin. The B subunits form a pentameric ring, which interacts with one A subunit. Thus, the structural arrangement of type I and type II heat-labile enterotoxins are very similar .
Arfaptin homology (AH) domain (AH_dom)
Type: Domain

The arfaptin homology (AH) domain is a protein domain found in a range of proteins, including arfaptins, protein kinase C-binding protein PICK1 and mammalian 69kDa islet cell autoantigen (ICA69) . The AH domain of arfaptin has been shown to dimerise and to bind Arf and Rho family GTPases , including ARF1, a small GTPase involved in vesicle budding at the Golgi complex and immature secretory granules.

The AH domain consists of three α-helices arranged as an extended antiparallel α-helical bundle. Two arfaptin AH domains associate to form a highly elongated, crescent-shaped dimer .
Molybdenum cofactor biosynthesis protein A-like, twitch domain (MoaA_twitch)
Type: Domain

This entry represents the iron-sulfur cluster-binding twitch domain of GTP 3',8-cyclase, which is also known as molybdenum cofactor biosynthesis protein A (MoaA) in bacteria and archaea, molybdenum cofactor biosynthesis protein 1 (MOCS1) in most eukaryotes, and molybdenum cofactor biosynthesis enzyme CNX2 in plants . They belong to a family of enzymes involved in the synthesis of metallo-cofactors (

). Each subunit of the MoaA dimer is comprised of an N-terminal SAM domain (

) that contains the [4Fe-4S] cluster typical for this family of enzymes, as well as an additional [4Fe-4S] cluster in the C-terminal domain that is unique to MoaA proteins, involved in substrate binding . The unique Fe site of the C-terminal [4Fe-4S] cluster is thought to be involved in the binding and activation of 5'-GTP .

Mutations in the human MoCF biosynthesis proteins MOCS1, MOCS2 or GEPH cause MoCF Deficiency type A (MOCOD), causing the loss of activity of MoCF-containing enzymes, resulting in neurological abnormalities and death .

The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism .
DMAP1-binding domain (DMAP1-bd)
Type: Domain

This is a ~120-amino acid protein-protein interaction module that binds DMAP1 (DNA methyltransferase-associated protein 1), a transcriptional co-repressor. It is found at the N terminus of DNMT1 (DNA methyltransferase 1) and animal disco-interacting protein 2 (DIP-2), a protein that maintains morphology of mature neurons . This domain is also found in N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTA) and gamma (GNPTG) from animals, which are members of a complex that catalyses the initial step in the formation of the mannose 6-phopsphate targeting signal on newly synthesized lysosomal acid hydrolases. The DMAP1-binding domain mediates the selective binding GlcNAc-1-phosphotranferase to acid hydrolases .

The DMAP1-binding domain is predicted to adopt a long helix-turn-helix structure that is rich in leucine residues .
Zinc finger, MYM-type (Znf_MYM)
Type: Domain

MYM-type zinc fingers were identified in MYM family proteins . Human protein

is involved in a chromosomal translocation and may be responsible for X-linked retardation in XQ13.1 .

is also involved in disease. In myeloproliferative disorders it is fused to FGF receptor 1 ; in atypical myeloproliferative disorders it is rearranged . Members of the family generally are involved in development. This Zn-finger domain functions as a transcriptional trans-activator of late vaccinia viral genes, and orthologues are also found in all nucleocytoplasmic large DNA viruses, NCLDV. This domain is also found fused to the C termini of recombinases from certain prokaryotic transposons .

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
Neurobeachin-like, DUF1088 (NBEA-like_DUF1088)
Type: Domain

This domain is found in the neurobeachins (NBEAs) and BEACH domain-containing proteins (BDCPs). NBEAs are localised near Golgi apparatus and are involved in vesicular trafficking, intracellular transport, membrane dynamics, endosomal recycling, and receptor signalling. BDCPs are associated with lysosome size, apoptosis, autophagy, granule size, or synapse formation. Although the function of this domain is unknown, its mutations have been related to autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency, responsible for common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS) . NBEAs deficiency may induce spine loss with defects in synaptic efficacy and plasticity, being associated with autism spectrum disorder (ASD) and ASD-related syndromes .
FGF binding 1 (FGF1-bd)
Type: Family

This family consists of several mammalian FGF binding protein 1. Fibroblast growth factors (FGFs) play important roles during foetal and embryonic development . Fibroblast growth factor-binding protein (FGF-BP) 1 is a secreted protein that can bind fibroblast growth factors (FGFs) 1 and 2 .
Lytic murein transglycosylase D , lipid attachment domain (MltD_lipid-attach)
Type: Domain

This entry represents the MltD lipid attachment domain. It is a short N-terminal domain found in membrane-bound lytic murein transglycosylase D (Mltd).
Protein of unknown function DUF1091 (DUF1091)
Type: Family

This entry contains a number of proteins from Drosophila melanogaster and other insects. Their function is unknown. Based on its distant similarity to

and conserved pattern of cysteine residues it is possible that these domains are also lipid binding.
KEN domain (KEN_dom)
Type: Domain

The proteins listed below share a common architecture with a protein kinase homology domain (see

) followed by an ~135-residue globular kinase-extension nuclease (KEN) domain made of eight helices :

Mammalian 2-5A-dependent RNase or RNase L (EC 3.1.26.-), an interferon-induced enzyme implicated in both the molecular mechanisms of interferon action and the fundamental control of RNA stability. 2-5A-dependent RNase is a unique enzyme in that it requires 2-5A, unusual oligoadenylates with 2',5'-phosphodiester linkages. RNase L is catalytically active only after binding to an unusual activator molecule containing a 5'-phosphorylated 2', 5'-linked oligoadenylate (2-5A), in the N-terminal half. RNase L consists of three domains, namely the N-terminal ankyrin repeat domain (see

), the protein kinase homology domain, and the C-terminal KEN domain .

Eukaryotic Ire1/Ern1, an ancient transmembrane sensor of endoplasmic reticulum (ER) stress with dual protein kinase and ribonuclease activities. In response to ER stress Ire1/Ern1 catalyzes the splicing of target mRNAs in a spliceosome-independent manner. Ire1/Ern1 is a type 1 transmembrane receptor consisting of an N-terminal ER luminal domain, a transmembrane segment and a cytoplasmic region. The cytoplasmic region encompasses a protein kinase domain followed by a C-terminal KEN domain .

The dimerisation of the kinase domain activates the ribonuclease function of the KEN domain .
COX aromatic rich motif (COX_ARM)
Type: Domain

COX2 (Cytochrome O ubiquinol OXidase 2) is a major component of the respiratory complex during vegetative growth. It transfers electrons from a quinol to the binuclear centre of the catalytic subunit 1. The function of this region is not known.