SII-SWORD/CoKE huggingface dataset:
GOLD domain (GOLD_dom)
Type: Domain

The GOLD (for Golgi dynamics) domain is a protein module found in several eukaryotic Golgi and lipid-traffic proteins. It is typically between 90 and 150 amino acids long. Most of the size difference observed in the GOLD-domain superfamily is traceable to a single large low-complexity insert that is seen in some versions of the domain. With the exception of the p24 proteins, which have a simple architecture with the GOLD domain as their only globular domain, all other GOLD-domain proteins contain additional conserved globular domains. In these proteins, the GOLD domain co-occurs with lipid-, sterol-or fatty acid-binding domains such as PH, CRAL-TRIO, FYVE oxysterol binding-and acyl CoA-binding domains, suggesting that these proteins may interact with membranes. The GOLD domain can also be found associated with a RUN domain, which may have a role in the interaction of various proteins with cytoskeletal filaments. The GOLD domain is predicted to mediate diverse protein-protein interactions . A secondary structure prediction for the GOLD domain reveals that it is likely to adopt a compact all-β-fold structure with six to seven strands. Most of the sequence conservation is centred on the hydrophobic cores that support these predicted strands. The predicted secondary-structure elements and the size of the conserved core of the domain suggests that it may form a β-sandwich fold with the strands arranged in two β-sheets stacked on each other .

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

Eukaryotic proteins of the p24 family.

Animal Sec14-like proteins. They are involved in secretion.

Human Golgi resident protein GCP60. It interacts with the Golgi integral membrane protein Giantin.

Yeast oxysterol-binding protein homologue 3 (OSH3).

Plant Patellin 1-6. It may be involved in membrane-trafficking events .
EAR (EAR)
Type: Repeat

Most of the hereditary idiopathic epilepsies are due to mutation in ion channels expressed in brain. Recently two non-ion channel genes LGI1 and VGLR1 have emerged as important causes of specific epilepsy syndromes. The product of these two genes share a conserved repeated region of about 44 amino acid residues, the EAR domain (for epilepsy-associated repeat) .

The predicted secondary structure (four β-strands) and the numbers of repeated copies (seven) suggest that the EAR domain belongs to the β-propeller fold. A common functional feature found in all characterised domains of this class is a participation in protein-protein interactions. Since the EAR repeat is found in the ectodomain of VLGR1, it is most probably involved in ligand recognition by the receptor .

Proteins known to contain EAR repeats are listed below:

Mammalian LGI1 to LGI4. LGI1 is mutated in autosomal dominant partial epilepsy with auditory features (ADPEAF). The F348C missense mutation is located in the third EAR repeat (7 copies).

Mammalian thrombo-spondin N-terminal domain and EAR repeats containg protein (TSPEAR) (7 copies).

Mammalian very large G protein-coupled receptor 1 (VGLR1) or monogenic audiogenic seizure-susceptible (MASS1) protein. In mouse, mutations in MASS1 gene are associated with generalized epilepsy and seizures in response to loud noises (7 copies) .
Ferritin-like diiron domain (Ferritin-like_diiron)
Type: Domain

This entry represents a group of proteins, containing ferritin-like domain, which is an about 145-residue domain made of a four-helix bundle surrounding a non-heme, non-sulphur, oxo-bridged diiron site. The diiron site is contained within a twisted, left-handed four-helix-bundle constituted of two anti-parallel helix pairs connected through a left-handed crossover connection. Known ligand residues at non-heme, non-sulphur diiron sites in proteins include His, Asp, Glu, and Tyr. Proteins containing a ferritin-like diiron domain possess the ability to catalyse oxidation of Fe2 to Fe3 by O2, i.e. ferroxidase activity. The ferritin-like diiron domain occurs in stand-alone form in ferritin and bacterioferritin or in association with the rubredoxin-like domain in rubrerythrin . Proteins known to contain a ferritin-like diiron domain are listed below:

Ferritin (Ftn), an eukaryotic intracellular protein that stores iron in a soluble, nontoxic, readily available form.

Bacterioferritin (Bfr), a prokaryotic protein which may perform functions in iron detoxification and storage.

Rubrerythrin (Rr), a non-heme protein isolated from anaerobic sulphate- reducing bacteria.

Nigerythrin (Nr), a prokaryotic protein of unknown function.
RNA polymerase sigma-70 region 1.2 (RNA_pol_sigma70_r1_2)
Type: Domain

The bacterial core RNA polymerase complex, which consists of five subunits, is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . RNA polymerase recruits alternative sigma factors as a means of switching on specific regulons. Most bacteria express a multiplicity of sigma factors. Two of these factors, sigma-70 (gene rpoD), generally known as the major or primary sigma factor, and sigma-54 (gene rpoN or ntrA) direct the transcription of a wide variety of genes. The other sigma factors, known as alternative sigma factors, are required for the transcription of specific subsets of genes.

With regard to sequence similarity, sigma factors can be grouped into two classes, the sigma-54 and sigma-70 families. Sequence alignments of the sigma70 family members reveal four conserved regions that can be further divided into subregions eg. sub-region 2.2, which may be involved in the binding of the sigma factor to the core RNA polymerase; and sub-region 4.2, which seems to harbor a DNA-binding 'helix-turn-helix' motif involved in binding the conserved -35 region of promoters recognised by the major sigma factors .

The plastids of higher plants originating from an ancestral cyanobacterial endosymbiont also contain sigma factors that are encoded by a small family of nuclear genes. All plastid sigma factors belong to the superfamily of sigmaA/sigma70 and have sequences homologous to the conserved regions 1.2, 2, 3, and 4 of bacterial sigma factors .
ssDNA-binding transcriptional regulator (ssDNA-bd_transcriptional_reg)
Type: Homologous_superfamily

This superfamily represents a ssDNA-binding transcriptional regulator domain consisting of a helix-swapped dimer of β(4)-α motifs. This domain is found as a C-terminal domain in the transcriptional co-activator PC4 (also known as P15; where it is a dimer of two separate motifs), and in the plant transcriptional regulator PBF-2 (where it is a single chain domain formed by a tandem repeat of two motifs).

Transcriptional regulators play a critical role in controlling the level of transcription from specific genes in response to different stimuli. Members of this family of transcriptional regulators, which preferentially bind single-stranded DNA, include PBF-2 from plants, the mammalian nuclear factor 1-X (NF1-X), and positive cofactor 4 (PC4). These proteins are structurally similar, consisting of a helix-swapped dimer of β(4)-α motifs.

The plant defence transcription factor PBF-2 is comprised of four p24 subunits that interact through a helix-loop-helix motif to produce a central pore . PBF-2 functions as part of the plant's defence system in response to the detection of a pathogen. Upon stimulation, PBF-2 induces several signal transduction pathways leading to changes in the expression of defence genes, including the pathogenesis-related (PR) genes.

NF1-X is one of several NF1 proteins that function as transcription factors. NF1-X consists of two functionally distinct domains: a conserved N-terminal DNA-binding domain and a C-terminal transcriptional regulatory domain. NF1-X binds to the promoter for the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase gene .

PC4 (or P15) possess the ability to co-activate and suppress transcription via its DNA-binding activity. PC4 has been shown to stimulate transcription
in vitro
with diverse activators, including VP16, thyroid hormone receptor, BRCA-1, often involving TFIIA. PC4 and TFIIA are thought to facilitate the assembly of the pre-initiation complex. The repressive activity of PC4 can be alleviated by the transcription factor TFIIH, which protects promoters from PC4 repression . PC4 consists of two domains: an N-terminal regulatory domain and a C-terminal cryptic DNA-binding domain. The protein acts as a dimer with two ssDNA binding channels running in opposite directions to each other .
Peptidase M74/Hedgehog-like, zinc-binding domain superfamily (Zn_M74/Hedgehog-like)
Type: Homologous_superfamily

This entry represents the zinc-binding domain superfamily in peptidases belonging to MEROPS peptidase family M74 (murein endopeptidase MepA), Protein hedgehog, D-D dipeptidase and related proteins.

The structure of the N-terminal signalling domain of hedgehog proteins has been solved and reveals a tetrahedrally coordinated zinc ion that is structurally homologous to the zinc-binding motif in bacterial D-alanyl-D-alanine carboxypeptidases (DD-peptidases) .
Methyl-coenzyme M reductase, alpha subunit, C-terminal (Me_CoM_Rdtase_asu_C)
Type: Domain

This entry represents the C-terminal domain of the alpha subunit, which is comprised of an all-α multi-helical bundle.

Methyl-coenzyme M reductase (MCR) catalyses the reduction of methyl-coenzyme M (CH3-SCoM) and coenzyme B (HS-CoB) to methane and the corresponding heterosulphide CoM-S-S-CoB (

), the final step in methane biosynthesis. This reaction proceeds under anaerobic conditions by methanogenic Archaea , and requires a nickel-porphinoid prosthetic group, coenzyme F430, which is in the EPR-detectable Ni(I) oxidation state in the active enzyme. Studies on a catalytically inactive enzyme aerobically co-crystallized with coenzyme M displayed a fully occupied coenzyme M-binding site with no alternate conformations. The binding of coenzyme M appears to induce specific conformational changes that suggests a molecular mechanism by which the enzyme ensures that methyl-coenzyme M enters the substrate channel prior to coenzyme B, as required by the active-site geometry .

MCR is a hexamer composed of 2 alpha, 2 beta, and 2 gamma subunits with two identical nickel porphinoid active sites, which form two long active site channels with F430 embedded at the bottom .
Alpha-macroglobulin, receptor-binding (A-macroglobulin_rcpt-bd)
Type: Domain

This entry represents the receptor-binding domain (RBD) of alpha-2-macroglobulin and related proteins. The RBD is located at the C terminus, its structure having an immunoglobulin-like fold consists of a sandwich of nine strands in two sheets with a Greek-key topology .

The alpha-macroglobulin (aM) family of proteins includes protease inhibitors , typified by the human tetrameric a2-macroglobulin (a2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' and a thiol ester, (iii) a similar protease inhibitory mechanism and (iv) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. aM protease inhibitors inhibit by steric hindrance . The mechanism involves protease cleavage of the bait region, a segment of the aM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the aM collapses about the protease. In the resulting aM-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation . Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified .
Argininosuccinate lyase (Argininosuccinate_lyase)
Type: Family

Argininosuccinate lyase (ASL or ASAL,

) participates in arginine synthesis in all organisms catalysing the reversible breakdown of argininosuccinate to arginine and fumarate. The reaction is also part of the urea cycle . The crystal structures of ASLs from several species have been studied, in particular the duck delta1 and delta2 eye lens crystallins, which are inactive and active homologues of ASL, respectively . ASL is a member of the Lyase class I family, these proteins are active as tetramers. The four active sites of the homotetrameric enzyme are each formed by residues from three different subunits. In humans, mutations in ASAL result in the autosomal recessive disorder argininosuccinic aciduria .

This entry represents argininosuccinate lyase and includes avian delta crystallins whose biological role is to provide the optically clear cellular protein of the eye lens.
Alpha-helical ferredoxin (Helical_ferredxn)
Type: Homologous_superfamily

The α-helical ferredoxin domain contains two Fe4-S4 clusters, typical of bacterial ferredoxin. Iron-sulphur proteins play an important role in electron transfer processes and in various enzymatic reactions. In eukaryotes, the mitochondria are the major site of Fe-S cluster biosynthesis in the cell, used for the assembly of mitochondrial and non-mitochondrial Fe-S proteins. The α-helical ferredoxin domain is present in several proteins involved in redox reactions, including the C-terminal of the respiratory proteins succinate dehydrogenase (SQR) in bacteria/mitochondria, and fumarate reductase (QFR) in bacteria. SQR is analogous to the mitochondrial respiratory complex II, and is involved in the electron transport pathway from succinate as a donor to the acceptor ubiquinone. SQR helps prevent the formation of reactive oxygen species and is used during aerobic respiration, whereas QFR does not and, consequently, is used to catalyse the final step of anaerobic respiration using the acceptor fumarate .

The α-helical ferredoxin domain is also present in the N-terminal of the cytosolic protein dihydropyrimidine dehydrogenase, (DPD) which catalyses the NADPH-dependent, rate-limiting step in pyrimidine degradation, converting pyrimidines to 5,6-dihydro compounds . DPD catalysis involves electron transfer from NADPH to the substrate via the Fe4-S4 centre and FAD. In mammals, this pathway produces the neurotransmitter beta-alanine.
DNA polymerase III-theta, bacterial (DNA_pol_III_theta_bac)
Type: Family

This entry represents the theta subunit of DNA polymerase III from bacteria, whose core structure consists of an irregular array of three helices .

DNA polymerase III (Pol III) is the primary enzyme responsible for replication of Escherichia coli chromosomal DNA. The holoenzyme consists of 17 proteins and contains two core polymerases. The Pol III catalytic core has three tightly associated subunits: alpha, epsilon and theta. The alpha subunit is responsible for the DNA polymerase activity, while the epsilon subunit is the 3'-5' proofreading exonuclease. The epsilon subunit binds to both the alpha and theta subunits in the linear order α-ε-theta. The theta subunit is the smallest, and may act to enhance the proofreading activity of epsilon, especially under extreme conditions .
Prefoldin (Prefoldin)
Type: Homologous_superfamily

The Prefoldin/GimC family of proteins are found in eukaryotes and archaea . Prefoldin is part of a molecular chaperone system that promotes the correct folding of nascent polypeptide chains. Prefoldin/GimC interacts with the nascent chain to stabilise it prior to its folding within the central cavity of a chaperonin. Prefoldin/GimC is a hexamer consisting of two types of subunits, alpha and beta. Archaeal prefoldin contains one type of alpha and one type of beta subunit , while eukaryotic prefoldin/GimC contains two different but related alpha subunits and four related beta subunits .

The unconventional prefoldin RPB5 interactor-like protein from Drosophila (also known as URI) is a serine/threonine phosphatase inhibitor and required for germ line cell viability and differentiation. It binds to protein phosphatase 1 alpha subunits with higher affinity than the beta subunits .
Cytochrome c-like domain (Cyt_c-like_dom)
Type: Domain

After cytochrome c is synthesized in the cytoplasm as apocytochrome c, it is transported through the outer mitochondrial membrane to the intermembrane space, where haem is covalently attached by thioester bonds to two cysteine residues located in the cytochrome c centre. Cytochrome c is required during oxidative phosphorylation as an electron shuttle between Complex III (cytochrome c reductase) and IV (cytochrome c oxidase). In addition, cytochrome c is involved in apoptosis in more complex organisms such as Xenopus, rats and humans. Cellular stress can induce cytochrome c release from the mitochondrial membrane. In mammals, cytochrome c triggers the assembly of the apoptosome, consisting of cytochrome c, Apaf-1 and dATP, which activates caspase-9, leading to cell death . There are several different members of the cytochrome c family with different functional roles, for instance cytochrome c549 is associated with photosystem II .
Homedomain-like superfamily (Homeodomain-like_sf)
Type: Homologous_superfamily

Homeodomain (HD)-containing proteins are transcription factors that share a related DNA binding domain . HD was first identified in a number of Drosophila homeotic and segmentation proteins, but is now known to be well conserved in organisms from all domains in life. The domain binds DNA through a helix-turn-helix (HTH) structure. The HTH motif is characterised by two α-helices, which make intimate contacts with the DNA and are joined by a short turn. The second helix binds to DNA via a number of hydrogen bonds and hydrophobic interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA. The first helix helps to stabilise the structure. Many proteins contain homeodomains, including Drosophila Engrailed, yeast mating type proteins, hepatocyte nuclear factor 1a and HOX proteins.

The homeodomain motif is very similar in sequence and structure to domains in a wide range of DNA-binding proteins, including recombinases, Myb proteins, GARP response regulators, human telomeric proteins (hTRF1), paired domain proteins (PAX), yeast RAP1, centromere-binding proteins CENP-B and ABP-1, transcriptional regulators (TyrR), AraC-type transcriptional activators, and tetracycline repressor-like proteins (TetR, QacR, YcdC) .
UBA-like superfamily (UBA-like_sf)
Type: Homologous_superfamily

UBA domains are a commonly occurring sequence motif of approximately 45 amino acid residues that are found in diverse proteins involved in the ubiquitin/proteasome pathway, DNA excision-repair, and cell signalling via protein kinases . HHR23A, the human homologue of yeast Rad23A is a nucleotide excision-repair protein that contains both an internal and a C-terminal UBA domain. The fold of the UBA domain consists of a compact three-helical bundle with a right-handed twist, and have a conserved hydrophobic surface patch for protein-protein interactions. UBA-like domains can be found in other proteins as well, such as the TS-N domain in the elongation factor Ts (EF-Ts), which catalyses the recycling of the GTPase EF-Tu required for the binding of aminoacyl-tRNA top the ribosomal A site ; and the C-terminal domain of TAP/NXF1, which functions in nuclear export through the interaction of its UBA-like domain with FG nucleoporins .
Putative DNA-binding domain superfamily (DNA-bd_dom_put_sf)
Type: Homologous_superfamily

A putative DNA-binding domain with a conserved structure is found in several different protein families. The core structure of the domain consists of a three-helical fold that is architecturally similar to that of the "winged-helix" fold, but is topologically distinct. Representatives of this domain can be found in domains B1 and B5 from the beta subunit of phenylalanine-tRNA synthetases , the C-terminal region of the DNA/RPA-binding domain of the DNA excision repair factor XPA , the N-terminal domain of the transcriptional activators BmrR and MtaN , the most conserved domain of the retinal development protein Dachshund , and the DNA-binding domain of the gpNU1 subunit from the bacteriophage lambda viral packing protein terminase .
Smac/DIABLO-like superfamily (Smac/DIABLO-like_sf)
Type: Homologous_superfamily

Smac (Second Mitochondria-derived Activator of Caspase) and DIABLO (Direct IAP-Binding protein with Low PI) are 29kDa mitochondrial precursor proteins. Apoptosis, or programmed cell death, is an essential process in metazoan development and homeostasis. Apoptosis is carried out by caspases, which are under tight regulatory control. Inhibitor-of-apoptosis proteins (IAP) suppress apoptosis by inhibiting caspases, while the mitochondrial protein Smac/Diablo promotes apoptosis by suppressing IAPs. The N-terminal four sequences in Smac/Diablo are responsible for the protein's interaction with IAPs . The crystal structure of Smac/Diablo reveals a closed, three-helical bundle structure with a left-handed twist, and that the protein homodimerises through an extensive hydrophobic interface .
Immunoglobulin/albumin-binding domain superfamily (Ig/albumin-bd_sf)
Type: Homologous_superfamily

This superfamily represents immunoglobulin and albumin-binding (GA module) domains from various bacterial proteins, which share a common fold consisting of a left-handed three-helical bundle (mirror topology to spectrin-like fold).

The Staphylococcus aureus virulence factor protein A (SpA) contains five highly homologous Ig-binding domains in tandem (designated domains E, D, A, B and C) that share this common structure. Protein A can exist in both secreted and membrane-bound forms, and has two distinct Ig-binding activities: each domain can bind Fc-gamma (the constant region of IgG involved in effector functions) and Fab (the Ig fragment responsible for antigen recognition) .

Protein G-related albumin-binding (GA) modules occur on the surface of numerous Gram-positive bacterial pathogens. Protein G of group C and G Streptococci interacts with the constant region of IgG and with human serum albumin. The GA module is found in a range of bacterial cell surface proteins . GA modules may promote bacterial growth and virulence in mammalian hosts by scavenging albumin-bound nutrients and camouflaging the bacteria. Variations in sequence give rise to differences in structure and function between GA modules in different proteins, which could alter pathogenesis and host specificity due to their varied affinities for different species of albumin . Proteins containing a GA module include PAB from Peptostreptococcus magnus .
Pheromone, protozoan (Pheromone_protoz)
Type: Family

Protozoan pheromones are cell-type specific protein signals. This entry represents a family of mating ciliate pheromones (or gamones) from the protozoan Euplotes raikovi, including Er-1, Er-2, Er-10, Er11 and Er22. These pheromones are diffusible extracellular communication signals that distinguish different intra-specific classes of cells commonly referred to as 'mating types'. Pheromones prepare these cells for conjugation by changing their cell surface properties. The mitogenic activity induced by Er pheromone autocrine signalling can be inhibited by cAMP . The NMR structure of several pheromones have been determined, revealing a closed up-and-down bundle of three helices with a left-handed twist . In some cases, different pheromones can compete with each other in binding to their cell-surface receptors.