SII-SWORD/CoKE huggingface dataset:
Polyketide synthase-like, ketoreductase domain (PKS_KR)
Type: Domain

This entry represents the ketoreductase domain in polyketides synthase-like and fatty acid related enzymes in fungi and bacteria.

The ketoreductase (KR) domain is a conserved catalytic domain that belongs to the short-chain dehydrogenase/reductase (SDR) superfamily and contains a Rossmann fold, which is crucial for binding the NADPH cofactor . Its primary function is to catalyse the NADPH-dependent reduction of beta-keto groups to beta-hydroxy groups during the biosynthesis of fatty acids, polyketides, and related compounds. The specific substrates and products can vary depending on the enzyme .

Polyketide synthases (PKSs) are large, multifunctional enzyme complexes that catalyse the biosynthesis of diverse secondary metabolites known as polyketides . These enzymes operate in an assembly line-like manner, utilising multiple domains such as acyltransferase (AT)

, and acyl carrier protein (ACP)

to perform stepwise condensation of simple carboxylic acid units . PKSs can be classified into three main types: type I (modular), type II (iterative), and type III, each with distinct structural and functional characteristics . The modular type I PKSs, in particular, contain additional domains like ketoreductase (KR)

, dehydratase (DH)

, and enoylreductase (ER)

that modify the growing polyketide chain .
Oligosaccharide biosynthesis protein Alg14-like (Oligosacch_biosynth_Alg14)
Type: Family

Alg14 is involved dolichol-linked oligosaccharide biosynthesis and anchors the catalytic subunit Alg13 to the ER membrane .
Replication factor A protein 3 (Rfa2)
Type: Family

Rfa3 (also known as RPA14) is a component of the replication protein A (RPA) complex, which binds to and removes secondary structure from ssDNA. The RPA complex is involved in DNA replication, repair, and recombination .
HalX domain (HalX_domain)
Type: Domain

HalX domain protein is a protein of unknown function, previously mis-annotated as HoxA-like transcriptional regulator. The HalX domain is C-terminal to a CheY-like domain (

), which suggests a role as a response regulator.
YcbB domain (YcbB)
Type: Domain

YcbB is a DNA-binding protein .
PglZ domain (PglZ_dom)
Type: Domain

This entry is a member of the Alkaline phosphatase clan. This domain is present in Alkaline phosphatase-like protein PglZ from Bacillus cereus, a putative phosphatase part of a type 1 BREX (bacteriophage exclusion) system that provide immunity against bacteriophage. It has been suggested that proteins containing this domain are involved in phage defense in multiple species .
SAF domain (SAF)
Type: Domain

This entry includes a range of different proteins, such as antifreeze proteins, flagellar FlgA proteins, and CpaB pilus proteins . This domain adopts a β-clip fold .
Transcription regulator BetR, N-terminal (Tscrpt_reg_BetR_N)
Type: Domain

CheY-like phosphoacceptor (or receiver [REC]) domain is a common module in a variety of response regulators of the bacterial signal transduction systems. BetR is one of the many response regulators and is encoded mainly in Burkholderia spp.
It is a N-terminal helix-turn-helix domain (HTH) and has been shown to be related to the XRE-type HTH domain (

), it has been suggested that BetR would have dimerization, protein-protein interaction, and activation/relief-of-inhibition properties .
Metal-dependent hydrolase HDOD (HDOD)
Type: Domain

The HD domain, named after the conserved doublet of predicted catalytic residues, is found in a wide range of bacterial, archaeal and eukaryotic proteins. It defines a superfamily of phosphohydrolases that can catalyze both metal-dependent and -independent phosphomonoesterase and phosphodiesterase reactions for a broad range of substrates . The HD-domain proteins appear to be involved in nucleic acid and nucleotide metabolism, signal transduction and possibly other functions. They are diverse in terms of both domain architecture and phylogenetic distribution; each of the completely sequenced genomes encodes more than one version of this domain.

The HD domain is composed of a bundle of α helices with a 5-helix core. Although all HD domains share key design features, a striking diversity of catalytic centres have been identified, containing no metal, mono-, bi- or trinuclear metal binding sites .

The HD-related output domain (HDOD) is a protein domain of unknown function. Proteins containing the HDOD are widespread in diverse bacteria; it can be present as a stand-alone domain, and also associated with other domains, such as response regulatory (RR), GGDEF, and EAL, suggesting a role in regulation and signaling . Proteins containing this domain include CdgJ from Vibrio cholerae serotype O1. CdgJ is a phosphodiesterase (PDE) that catalyzes the hydrolysis of cyclic diguanylate (c-di-GMP) .
Aminomethyltransferase, C-terminal domain (GcvT_C)
Type: Domain

This entry represents the C-terminal β-barrel domain of aminomethyltransferase, also known as glycine cleavage T-proteins, part of the glycine cleavage multienzyme complex (GcvT)) found in bacteria and the mitochondria of eukaryotes .

The glycine cleavage multienzyme complex (GCV) catalyses the catabolism of glycine in eukaryotes. GcvT (aminomethyltransferase,

) is a folate-dependent enzyme that catalyses the release of ammonia and the transfer of the methylene carbon unit (C1 unit) to tetrahydrofolate (H4folate) from the aminomethyl intermediate attached to the lipoate cofactor of H-protein . GCV is found in bacteria and the mitochondria of eukaryotes. Mutations in the human GcvT gene are known to cause nonketotic hyperglycinemia .
MEKHLA (MEKHLA)
Type: Domain

The MEKHLA domain shares similarity with the PAS domain and is found in the 3' end of plant HD-ZIP III homeobox genes, and bacterial proteins.
Translation initiation factor, beta propellor-like domain (TIF_beta_prop-like)
Type: Domain

This entry contains β-propeller domains found in eukaryotic translation initiation factors and WD domain-containing proteins.
MANSC domain (MANSC_dom)
Type: Domain

The MANSC (motif at N terminus with seven cysteines) domain is a module with a well-conserved seven cysteine motif that is present at the N terminus of higher multicellular animal membrane and extracellular proteins. It is possible that some of the cysteine residues in the MANSC domain form structurally important disulphide bridges. All of the MANSC-containing proteins contain predicted transmembrane regions and signal peptides. It has been proposed that the MANSC domain in HAI-1 might function through binding with hepatocyte growth factor activator and matriptase .

This domain is also found N-terminal in the human Dyslexia-associated protein KIAA0319 and KIAA0319L. KIAA0319 is involved in neuronal migration during development of the cerebral neocortex. This protein is linked to migrational disturbances during brain development, and growth and differentiation of dendrites . KIAA0319L, is capable of rapid endocytosis from the plasma membrane and trafficking to the trans-Golgi network. This protein directly binds to Adeno-associated virus 2 particles and it is involved in the virus infection
Aldehyde ferredoxin oxidoreductase, N-terminal (Ald_Fedxn_OxRdtase_N)
Type: Domain

Enzymes of the aldehyde ferredoxin oxidoreductase (AOR) family contain a tungsten cofactor and an 4Fe4S cluster and catalyse the interconversion of aldehydes to carboxylates . This family includes AOR, formaldehyde ferredoxin oxidoreductase (FOR), glyceraldehyde-3-phosphate ferredoxin oxidoreductase (GAPOR), all isolated from hyperthermophilic archea ; carboxylic acid reductase found in clostridia ; and hydroxycarboxylate viologen oxidoreductase from Proteus vulgaris, the sole member of the AOR family containing molybdenum . GAPOR may be involved in glycolysis , but the functions of the other proteins are not yet clear. AOR has been proposed to be the primary enzyme responsible for oxidising the aldehydes that are produced by the 2-keto acid oxidoreductases .

This entry represents the N-terminal domain of these enzymes. This domain has been shown to interact with the tungsten cofactor .
Aldehyde ferredoxin oxidoreductase, domain 2 (Ald_Fedxn_OxRdtase_dom2)
Type: Homologous_superfamily

Enzymes of the aldehyde ferredoxin oxidoreductase (AOR) family contain a tungsten cofactor and an 4Fe4S cluster and catalyse the interconversion of aldehydes to carboxylates . This family includes AOR, formaldehyde ferredoxin oxidoreductase (FOR), glyceraldehyde-3-phosphate ferredoxin oxidoreductase (GAPOR), all isolated from hyperthermophilic archea ; carboxylic acid reductase found in clostridia ; and hydroxycarboxylate viologen oxidoreductase from Proteus vulgaris, the sole member of the AOR family containing molybdenum . GAPOR may be involved in glycolysis , but the functions of the other proteins are not yet clear. AOR has been proposed to be the primary enzyme responsible for oxidising the aldehydes that are produced by the 2-keto acid oxidoreductases .

This superfamily represents an α-helical domain which is involved in binding the tungsten cofactor, and also contains an iron-sulphur cluster .
Aldehyde ferredoxin oxidoreductase, domain 3 (Ald_Fedxn_OxRdtase_dom3)
Type: Homologous_superfamily

Enzymes of the aldehyde ferredoxin oxidoreductase (AOR) family contain a tungsten cofactor and an 4Fe4S cluster and catalyse the interconversion of aldehydes to carboxylates . This family includes AOR, formaldehyde ferredoxin oxidoreductase (FOR), glyceraldehyde-3-phosphate ferredoxin oxidoreductase (GAPOR), all isolated from hyperthermophilic archea ; carboxylic acid reductase found in clostridia ; and hydroxycarboxylate viologen oxidoreductase from Proteus vulgaris, the sole member of the AOR family containing molybdenum . GAPOR may be involved in glycolysis , but the functions of the other proteins are not yet clear. AOR has been proposed to be the primary enzyme responsible for oxidising the aldehydes that are produced by the 2-keto acid oxidoreductases .

This superfamily represents an α-helical domain involved in binding the tungsten cofactor .
DExx box DNA helicase domain superfamily (DExx_box_DNA_helicase_dom_sf)
Type: Homologous_superfamily

This domain superfamily is found in DExx type DNA helicases, such as the hexameric essential helicases PcrA from Gram-positive bacteria and Rep and UvrD from Gram-negative bacteria . PcrA is essential for cell growth in Bacillus species, as it is required for rolling circle replication, unwinding DNA using an active inchworm mechanism . UvrD from Escherichia coli is a superfamily 1 (SF1) helicase involved in several DNA metabolic processes, including recombination and repair , while Rep affects the rate of replication fork progression in E. coli and is required for the replication of certain phages . The domain is also found in the exodeoxyribonuclease V gamma chain, which has a wide variety of catalytic activities including ATP-dependent exonuclease, ATP-stimulated endonuclease, ATP-dependent helicase and DNA-dependent ATPase activities.
Protein YjdM, N-terminal (YjdM_N)
Type: Domain

This entry represents the N-terminal domain of YjdM, which is predicted to form a zinc-ribbon. YjdM is not involved in phosphonate metabolism .
Protein YjdM, C-terminal (YjdM_C)
Type: Domain

This entry represents the C-terminal domain of YjdM. YjdM is not involved in phosphonate metabolism .
Development/cell death domain (Dev_and_cell_death_domain)
Type: Domain

The DCD (Development and Cell Death) domain is found in plant proteins involved in development and cell death. The DCD domain is an ~130 amino acid long stretch that contains several mostly invariable motifs. These include a FGLP and a LFL motif at the N terminus and a PAQV and a PLxE motif towards the C terminus of the domain. The DCD domain is present in proteins with different architectures. Some of these proteins contain additional recognizable motifs, like the KELCH repeats or the ParB domain . Biological studies indicate a role of these proteins in phytohormone response, embryo development and programmed cell death by pathogens or ozone.

The predicted secondary structure of the DCD domain is mostly composed of β strands and confined by an α-helix at the N- and at the C terminus .

Proteins known to contain a DCD domain are listed below:

Carrot B2 protein.

Pea Gda-1 protein.

Soybean N-rich protein (NRP).
Water stress and hypersensitive response domain (WHy-dom)
Type: Domain

Water Stress and Hypersensitive response (WHy) domain is a region of unknown function found in several plant proteins involved in either the response to water stress or the response to bacterial infection . It is also found in some bacterial and archaeal proteins whose functions are not currently known. This domain is approximately 100 amino acids long and is composed of alternating hydrophobic and hydrophilic residues, with an almost invariant NPN motif at the N terminus. The predicted secondary structure is a novel fold consisting mostly of β strands and a C-terminal α helix.
PhnA protein N-terminal, proteobacterial (PhnaA_N_proteobac)
Type: Domain

The PhnA protein family includes the uncharacterised Escherichia coli protein PhnA and its homologues. The E. coli phnA gene is part of a large operon associated with alkylphosphonate uptake and carbon-phosphorus bond cleavage . The protein is not related to the characterised phosphonoacetate hydrolase designated PhnA .

This entry represents the N-terminal domain of PhnA proteins, which is predicted to form a zinc-ribbon, found in some proteobacteria. It does not include the E. coli sequence.
Adenylate cyclase-associated CAP, N-terminal (Adenylate_cyclase-assoc_CAP_N)
Type: Conserved_site

This entry represents the N-terminal conserved motif of CAP proteins consisting of a single α-helix. CAP proteins are composed of an N-terminal conserved motif followed by an N-terminal (

) and C-terminal (

) domains which are separated by a Pro-rich region.

Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways . In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly . In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity.
Nebulin-like (Nebulin-like)
Type: Family

This entry include nebulin and nebulin-related-anchoring protein (N-RAP).
DNA helicase E1, N-terminal, Papillomavirus (PPV_DNA_helicase_E1_N)
Type: Domain

Papillomaviruses (PPV) are a large family of DNA tumour viruses which give rise to warts in their host species. The helicase E1 protein is an ATP-dependent DNA helicase required for initiation of viral DNA replication . It forms a complex with the viral E2 protein, which is a site-specific DNA-binding transcriptional activator. The E1-E2 complex binds to the replication origin which contains binding sites for both proteins .

The E1 protein is a 70kDa polypeptide with a centrally-located DNA-binding domain and a C-terminal ATPase/helicase domain. It binds specific 18 bp DNA sequences at the origin of replication, melts the DNA duplex and functions as a 3' to 5' helicase . In addition to E2 it also interacts with DNA polymerase alpha and replication protein A to effect DNA replication. The DNA-binding domain forms a five-stranded antiparallel β sheet bordered by four loosely packed α helices on one side and two tightly packed helices on the other . Two structural modules within this domain, an extended loop and a helix, contain conserved residues and are critical for DNA binding. In solution E1 is a monomer, but binds DNA as a dimer. Recruitment of more E1 subunits to the complex leads to melting of the origin and ultimately to the formation of an E1 hexamer with helicase activity .

This entry represents the N-terminal region of E1, which contains the nuclear localisation signal.
Agenet domain, plant type (Agenet_dom_plant)
Type: Domain

This entry represents an agenet domain found in EMSY-like (AtEML) proteins, which have possible roles in chromatin regulation and are related to the BRCA2-interacting human oncoprotein EMSY . Proteins containing this domain also include MRG2 (AT1G02740) from Arabidopsis and PHD finger protein 20-like protein 1 (PHF20L1) from animals. MRG2 binds to the FLOWERING LOCUS T locus and elevates the expression in an H3K36me3-dependent manner . The function of PHF20L1 is not clear.
BBSome complex member BBS5, PH domain (BBS5_PH)
Type: Domain

BBS5 is part of the BBSome complex that may function as a coat complex required for sorting of specific membrane proteins to the primary cilia . Mutations in the BBS5 gene cause Bardet-Biedl syndrome 5 . This entry represents the two tandem PH domains found at the N-terminal of BBS5 .
Transport-associated and nodulation domain, bacteria (Transpt-assoc_nodulatn_dom_bac)
Type: Domain

The BON domain is typically ~60 residues long and has an α/β fold. There is a conserved glycine residue and several hydrophobic regions which suggests a binding function, and, actually, it contains a phospholipid-binding site

,

]. Most proteobacteria seem to possess one or two BON-containing proteins, typically of the OsmY-type proteins ; outside of this group the distribution is more disparate.

The OsmY protein is an Escherichia coli 20kDa outer membrane or periplasmic protein that is expressed in response to a variety of stress conditions, in particular, helping to provide protection against osmotic shock. One hypothesis is that OsmY prevents shrinkage of the cytoplasmic compartment by contacting the phospholipid interfaces surrounding the periplasmic space. The domain architecture of two BON domains alone suggests that these domains contact the surfaces of phospholipids, with each domain contacting a membrane .

In the potassium binding protein Kbp, this domain is able to bind K+ .
Succinate dehydrogenase/fumarate reductase, flavoprotein subunit (Succ_Dhase_FrdA_Gneg)
Type: Family

This entry represents the flavoprotein subunit found in both the SQR and QFR enzymes. This subunit contains an N-terminal domain which binds the FAD cofactor, a central catalytic domain with an unusual fold, and a C-terminal domain whose role is unclear . The dicarboxylate binding site is located between the FAD and catalytic domains.

Succinate:quinone oxidoreductase (

) refers collectively to succinate:quinone reductase (SQR, or Complex II) and quinol:fumarate reductase (QFR) . SQR is found in aerobic organisms, and catalyses the oxidation of succinate to fumarate in the citric acid cycle and donates the electrons to quinone in the membrane. QFR can be found in anaerobic cells respiring with fumarate as terminal electron acceptor. SQR and QFR are very similar in composition and structure, despite catalysing opposite reactions
in vivo
. They are thought to have evolved from a common ancestor, and in Escherichia coli they are capable of functionally replacing each other .

Succinate:quinone oxidoreductases consist of a peripheral domain, exposed to the cytoplasm in bacteria and to the matrix in mitochondria, and a membrane-integral anchor domain that spans the membrane (Fig. 1). The peripheral part, which contains the dicarboxylate binding site, is composed of a flavoprotein subunit, with one covalently bound FAD, and an iron-sulphur protein subunit containing three iron-sulphur clusters. The membrane-integral domain functions to anchor the peripheral domain to the membrane and is required for quinone reduction and oxidation. The anchor domain shows the largest variability in composition and primary sequence, being composed either of one large subunit, or two smaller subunits, which may, or may not, contain protoheme groups.
Acetoin reductase (23BDH)
Type: Family

One member of this family, as characterised in Klebsiella terrigena , is able to interconvert acetoin + NADH with meso-2,3-butanediol + NAD(+). It is also capable of irreversible reduction of diacetyl with NADH to acetoin. There has been a reuctance to classify the enzyme as either

, which is (R,R)-butanediol dehydrogenase, or

, which is acetoin dehydrogenase without a specified stereochemistry . Another member of this family, from Corynebacterium glutamicum (Brevibacterium flavum), is called L-2,3-butanediol dehydrogenase .

This enzyme is a homotetramer in the family of short chain dehydrogenases.
Cobalamin biosynthesis, precorrin-6Y methyltransferase, CbiT subunit (Cbl_synth_MTase_CbiT)
Type: Family

Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase . In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase .

The CbiT subunit of precorrin-6Y C5,15-methyltransferase (

) is a bifunctional enzyme that catalyses two methylations (at C-5 and C-15) in precorrin-6Y, as well as the decarboxylation of the acetate side chain located in ring C, in order to generate precorrin-8X. In the anaerobic pathway, two enzymes are required to produce precorrin-8X: CbiE and CbiT, which can be fused as CbiET (sometimes called CobL) . In the aerobic pathway, the enzyme is a fusion of CbiE and CbiT which is refered to as CobL . CbiT is thought to catalyse one of the methylation reactions, though this has not been completely proven .

This entry represents the CbiT subunit of the aerobic and anaerobic enzymes. In the anaerobic proteins it comproses the entire length of the protein, while in the aerobic enzymes it is fused with CbiE to form the bifunctional CobL protein.
PIK-related kinase, FAT domain (PIK_FAT)
Type: Domain

Phosphatidylinositol kinase (PIK)-related kinases participate in meiotic and V(D)J recombination, chromosome maintenance and repair, cell cycle progression, and cell cycle checkpoints, and their dysfunction can result in a range of diseases, including immunodeficiency, neurological disorder and cancer. The catalytic kinase domain is highly homologous to that of phosphatidylinositol 3- and 4-kinases. Nevertheless, members of the PIK-related family appear functionally distinct, as none of them has been shown to phosphorylate lipids, such as phosphatidylinositol; instead, many have Ser/Thr protein kinase activity. The PI-kinase domain of members of the PIK-related family is wedged between the ~550-amino acid-long FAT (FRAP, ATM, TRRAP) domain and the ~35 residue C-terminal FATC domain .

It has been proposed that the FAT domain could be of importance as a structural scaffold or as a protein-binding domain, or both .
REJ domain (REJ_dom)
Type: Domain

The REJ domain is an extracellular module of ~700 amino acids, which is found associated with other domains, such as EGF, the GPS proteolytic cleavage site, C-type lectin, SUEL-type lectin, LRR, LDL-A, PLAT, PKD . Although its function is unknown, the REJ domain has been shown to be required for cleavage to occur at the GPS . It has been proposed that the REJ domain might function in ion transport homeostasis . REJ domain from Polycystin-1 is required for cleavage at the G-protein coupled proteolytic site (GPS) or the ectodomain, a process that is essential for kidney structure and function .