SII-SWORD/CoKE huggingface dataset:
Flagellum site-determining protein FlhG (FlhG)
Type: Domain

FlhG (also annotated FleN/YlxH) is an ATPase that regulates location and number of bacterial flagella . FlhG acts antagonistically with FlhF/FleQ to regulate the number of polar flagella, with FlhF promoting flagellar assembly and FlhG inhibiting it. FlhG interacts with FlhF and influences its GTPase activity .

FlhG and FlhF are responsible for generating the single polar flagellum of Pseudomonas sps and Vibrio cholerae. In these bacteria, FlhG represses the activity or expression of a master transcriptional regulator , FleQ in the case of Pseudomonas . Campylobacter jejuni FlhG likely influences a flagellar biosynthetic step to control flagellar number, rather than suppressing activators of flagellar gene transcription as in Vibrio and Pseudomonas species . On the peritrichous bacterium Bacillus subtilis, FlhF and FlhG function together to spatially organize flagella in a defined grid-like pattern around the cellular midpoint, but not at polar regions .
Secreted aspartic endopeptidase (SAP-like)
Type: Domain

SAPs (Secreted aspartic proteinases) are secreted from a group of pathogenic fungi, predominantly Candida species. They are secreted from the pathogen to degrade host proteins. SAP is one of the most significant extracellular hydrolytic enzymes produced by C. albicans. SAP proteins, encoded by a family of 10 SAP genes. All 10 SAP genes of C. albicans encode preproenzymes, approximately 60 amino acid longer than the mature enzyme, which are processed when transported via the secretory pathway. The mature enzymes contain sequence motifs typical for all aspartyl proteinases, including the two conserved aspartate residues other active site and conserved cysteine residues implicated in the maintenance of the three-dimensional structure. Most Sap proteins contain putative N-glycosylation sites, but it remains to be determined which Sap proteins are glycosylated .

A variety of fungal secreted aspartic peptidases are included in this entry:

barrierpepsin (MEROPS identifier A01.015)

candidapepsin SAP1 (A01.014)

candidapepsin SAP2 (A01.060)

candidapepsin SAP3 (A01.061)

candidapepsin SAP4 (A01.062)

candidapepsin SAP5 (A01.063)

candidapepsin SAP6 (A01.064)

candidapepsin SAP7 (A01.065)

candidapepsin SAP8 (A01.066)

candidapepsin SAP9 (A01.067)

candidapepsin SAP10 (A01.085)

candiparapsin (A01.038)

canditropsin (A01.037)

yapsin-1 (A01.030)

yapsin-2 (A01.031)

These are not all products secreted by pathogenic fungi. Barrierpepsin and yapsins are secreted by Sacchomyces cervisiae. Barrierpepsin is secreted by yeasts of mating type a and processes the alpha-mating factor at the Leu-Lys bond, thereby inactivating it. This is mechanism for optimizing the concentration of the mating factor . Yapsin-1 releases alpha-mating factor from its precursor .

Aspartyl proteases (APs), also known as acid proteases, ([ec:3.4.23.-]) are a widely distributed family of proteolytic enzymes known to exist in vertebrates, fungi, plants, retroviruses and some plant viruses. APs use an Asp dyad to hydrolyze peptide bonds.

APs found in eukaryotic cells are α/β monomers composed of two asymmetric lobes ("bilobed"). Each of the lobes provides a catalytic Asp residue, positioned within the hallmark motif Asp-Thr/Ser-Gly, to the active site. The N- and C-terminal domains, although structurally related by a 2-fold axis, have only limited sequence homology except the vicinity of the active site. This suggests that the enzymes evolved by an ancient duplication event. The enzymes specifically cleave bonds in peptides which have at least six residues in length with hydrophobic residues in both the P1 and P1' positions. The active site is located at the groove formed by the two lobes, with an extended loop projecting over the cleft to form an 11-residue flap, which encloses substrates and inhibitors in the active site. Specificity is determined by nearest-neighbour hydrophobic residues surrounding the catalytic aspartates, and by three residues in the flap. The enzymes are mostly secreted from cells as inactive proenzymes that activate autocatalytically at acidic pH. Eukaryotic APs form peptidase family A1 of clan AA.
Nitroreductase Frm2/Hbn1-like (Frm2/Hbn1)
Type: Family

Nitroreductases comprise a group of FMN- or FAD-dependent enzymes that reduce nitrosubstituted compounds by using NAD(P)H, and are found in bacterial species and yeast. In Saccharomyces cerevisiae, two nitroreductase proteins have been described, Frm2 and Hbn1, that are involved in the oxidative stress defense system . Frm2 primarily utilizes NADH to reduce 4-nitroquinoline-N-oxide (4-NQO) .
Oxygen-insensitive NAD(P)H nitroreductase NfsB-like (NfsB-like)
Type: Domain

Nitroreductases are flavin-associated oxidoreductase enzymes that reduce nitro substituents on aromatic rings. They can be divided in two functional classes. Type I nitroreductases are oxygen-insensitive, i.e. can generate nitroso, hydroxylamine and/or amine end-products in the presence of molecular oxygen, whereas type II nitroreductases are oxygen-sensitive and can only generate these products when oxygen is absent .

This family includes type I oxidoreductases such as NfsB from Escherichia coli , RdxA and FrxA from Helicobacter pylori , and FRase I in Vibrio fischeri , which reduces FMN into FMNH2 as part of the bioluminescent reaction . This type of nitroreductase can be used in cancer chemotherapy to activate a range of prodrugs .
Undecaprenyl-diphosphatase (UPP_Pase)
Type: Domain

Several members of this family have been annotated as bacitracin transport permeases, as it was suspected that they form the permease component of an ABC transporter system. It was shown, however, that BcrC from Bacillus subtilis posesses undecaprenyl pyrophosphate (UPP) phospatase activity, and it is hypothesized that it competes with bacitracin for UPP, increasing the cell's resistance to bacitracin . YbjG from E. coli may function in the recycling of periplasmic undecaprenyl pyrophosphate .
SPFH domain, YdjI-like (SPFH_YdjI)
Type: Domain

This is found in an uncharacterised family of proteins similar to stomatin, prohibitin, flotillin, HflK/C (SPFH) and podocin. The conserved domain common to the SPFH superfamily has also been referred to as the Band 7 domain .
von Willebrand factor domain BatA-type (vWA_BatA_type)
Type: Domain

Members of this subgroup are bacterial in origin. They are typified by the presence of a MIDAS motif .

The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders
. In von Willebrand factor, the type A domain (vWF) is the prototype for a protein superfamily. The vWF domain is found in various plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins . Although the majority of VWA-containing proteins are extracellular, the most ancient ones present in all eukaryotes are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport and the proteasome. A common feature appears to be involvement in multiprotein complexes. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands . A number of human diseases arise from mutations in VWA domains.
DNA damage inducible protein 1 ubiquitin-like domain (DDI1_N)
Type: Domain

DDI1 (DNA damage inducible protein 1) has an amino-terminal ubiquitin-like domain, an retroviral protease-like (RVP-like) domain, and a UBA (ubiquitin-associated) domain. This entry represents the amino-terminal ubiquitin-like domain of DDI1 .

Ubiquitin is a globular protein, the last four C-terminal residues (Leu-Arg-Gly-Gly) extending from the compact structure to form a 'tail', important for its function. The latter is mediated by the covalent conjugation of ubiquitin to target proteins, by an isopeptide linkage between the C-terminal glycine and the ε-amino group of lysine residues in the target proteins.
Calpain subdomain III (C2_III)
Type: Domain

This group of cysteine peptidases belong to the MEROPS peptidase family C2 (calpain family, clan CA). A type example is calpain, which is an intracellular protease involved in many important cellular functions that are regulated by calcium . The protein is a complex of 2 polypeptide chains (light and heavy), with eleven known active peptidases in humans and two non-peptidase homologues known as calpamodulin and androglobin . These include a highly calcium-sensitive (i.e., micro-molar range) form known as mu-calpain, mu-CANP or calpain I; a form sensitive to calcium in the milli-molar range, known as m-calpain, m-CANP or calpain II; and a third form, known as p94, which is found in skeletal muscle only .

All forms have identical light but different heavy chains. Both mu- and m-calpain are heterodimers containing an identical 28kDa subunit and an 80kDa subunit that shares 55-65% sequence homology between the two proteases . The crystallographic structure of m-calpain reveals six "domains" in the 80kDa subunit :

A 19-amino acid NH2-terminal sequence;

Active site domain IIa;

Active site domain IIb. Domain 2 shows
low levels of sequence similarity to papain; although the catalytic His has
not been located by biochemical means, it is likely that calpain and papain
are related .

Domain III;

An 18-amino acid extended sequence linking domain III to domain IV;

Domain IV, which resembles the penta EF-hand family of polypeptides, binds calcium and regulates activity . Ca
2+
-binding causes a rearrangement of the protein backbone, the net effect of which is that a Trp side chain, which acts as a wedge between catalytic domains IIa and IIb in the apo state, moves away from the active site cleft allowing for the proper formation of the catalytic triad .

Calpain-like mRNAs have been identified in other organisms including bacteria, but the molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in these organisms cells is still unclear In metazoans, the activity of calpain is controlled by a single proteinase inhibitor, calpastatin (

). The calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. The calpains ostensibly participate in a variety of cellular processes including remodelling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma .

This entry includes subdomain III of typical and atypical calpains.
Calpain C2 domain (C2_Calpain)
Type: Domain

A single C2 domain is found in calpains (EC 3.4.22.52, EC 3.4.22.53), calcium-dependent, non-lysosomal cysteine proteases.

The C2 domain is a Ca
2+
-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain . Regions with significant homology to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding and in membrane targetting processes such as subcellular localisation.

The 3D structure of the C2 domain of synaptotagmin has been reported , the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key . Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca
2+
-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
Alkane/xylene monooxygenase (AlkB/XylM)
Type: Family

Alkane hydroxylase AlkB catalyzes the terminal hydroxylation of alkanes and the omega-hydroxylation of fatty acids in the presence of a NADH-rubredoxin reductase and rubredoxin . It is an integral membrane di-iron enzyme that shares a requirement for iron and oxygen for activity in a manner similar to that of the non-heme integral membrane desaturases . Alcanivorax borkumensis has two alkane hydroxylases, AlkB1 and AlkB2, with AlkB1 being responsible for the degradation of short-chain n-alkanes .

Also included in this family is xylene/toluene monooxygenase, a related enzyme with broad specificity that oxidizes toluene and xylenes to (methyl)benzyl alcohols .
Dihydroorotate dehydrogenase, class 1A (DHOD_1A)
Type: Family

Dihydroorotate dehydrogenase (DHOD) catalyzes the oxidation of (S)-dihydroorotate to orotate. This is the fourth step and the only redox reaction in the de novo biosynthesis of UMP, the precursor of all pyrimidine nucleotides. DHOD requires FMN as co-factor. DHOD is divided into class 1 and class 2 based on their amino acid sequences and cellular location. Members of class 1 are cytosolic enzymes and multimers, while class 2 enzymes are membrane associated and monomeric. The class 1 enzymes can be further divided into subtypes 1A and 1B which are homodimers and heterotetrameric proteins, respectively .

This entry represents class 1A.
PTS system mannose/sorbose specific IIA subunit (PTS_IIA_man)
Type: Domain

The bacterial phosphoenolpyruvate: sugar phosphotransferase system (PTS) is a multi-protein system involved in the regulation of a variety of metabolic and transcriptional processes. This family is one of four structurally and functionally distinct group IIA PTS system cytoplasmic enzymes, necessary for the uptake of carbohydrates across the cytoplasmic membrane and their phosphorylation. IIA subunits receive phosphoryl groups from HPr and transfer them to IIB subunits, which in turn phosphorylate the substrate .
Dihydroorotate dehydrogenase, class 1B (DHOD_1B)
Type: Family

Dihydroorotate dehydrogenase catalyzes the oxidation of (S)-dihydroorotate to orotate. This is the fourth step and the only redox reaction in the de novo biosynthesis of UMP, the precursor of all pyrimidine nucleotides. DHOD requires FMN as co-factor. DHOD divides into class 1 and class 2 based on their amino acid sequences and cellular location. Members of class 1 are cytosolic enzymes and multimers while class 2 enzymes are membrane associated and monomeric. The class 1 enzymes can be further divided into subtypes 1A and 1B which are homodimers and heterotetrameric proteins, respectively .

This entry represents DHOD class 1B .
Type I lantibiotic biosynthesis cyclase (LanC)
Type: Family

Lantibiotics form a class of antimicrobial peptides that are ribosomally synthesized as precursor peptides and then post-translationally modified . Lantibiotics are post-translationally modified to contain thioether cross-links called lanthionines (Lans) or methyllanthionines (MeLans) in addition to 2,3-didehydroalanine (Dha) and (Z)-2,3-didehydrobutyrine (Dhb). These unusual amino acids are introduced by the dehydration of serine and threonine residues, followed by thioether formation via addition of cysteine thiols, catalysed by LanB and LanC or LanM. Class I lantibiotics possess two modification enzymes, i.e. a dehydratase LanB and a cyclase LanC. Class II lantibiotics are modified by a bi-functional enzyme called LanM, which is able to perform both the dehydration and the cyclization reactions.

LanC is the cyclase enzyme of the lanthionine synthetase. Lanthinoine is a class I lantibiotic. LanC, the cyclase component, is a zinc metalloprotein, whose bound metal has been proposed to activate the thiol substrate for nucleophilic addition. This family also contains the cyclases involved in the biosynthesis of subtilin (SpaC) , nisin (NisC) and homologues.
GDP-mannose 3,5-epimerase (GDP-Man_epi)
Type: Domain

This subgroup of NDP-sugar epimerase/dehydratases are extended short-chain dehydrogenase/reductases (SDRs); they have the characteristic active site tetrad, and an NAD-binding motif: TGXXGXX[AG], which is a close match to the canonical NAD-binding motif. Members include Arabidopsis thaliana GDP-mannose-3',5'-epimerase which catalyzes the epimerization of GDP-alpha-D-mannose to form GDP-beta-L-galactose . It also catalyses an epimerization reaction that releases GDP-L-gulose, an intermediate that could be dedicated for the de novo biosynthesis of vitamin C in plants .

Extended SDRs are distinct from classical SDRs. In addition to the Rossmann fold (α/β folding pattern with a central β-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids .
Tetratricopeptide repeat protein 38 (TTC38)
Type: Family

Members of this family are annotated as tetratricopeptide repeat protein 38. The function is not known. Proteins containing tetratricopeptide (TPR) repeats may indicate mostly α-helical secondary structure.
Ferredoxin--NADP reductase, bacteria (FNR_bac)
Type: Family

Ferredoxin-NADP+ (oxido)reductase is an FAD-containing enzyme that catalyzes the reversible electron transfer between NADP(H) and electron carrier proteins such as ferredoxin and flavodoxin. Isoforms of these flavoproteins (i.e. having a non-covalently bound FAD as a prosthetic group) are present in chloroplasts, mitochondria, and bacteria in which they participate in a wide variety of redox metabolic pathways. The C-terminal domain contains most of the NADP(H) binding residues and the N-terminal domain interacts non-covalently with the isoalloxazine rings of the flavin molecule which lies largely in a large gap betweed the two domains. Ferredoxin-NADP+ reductase first accepts one electron from reduced ferredoxin to form a flavin semiquinone intermediate. The enzyme then accepts a second electron to form FADH2 which then transfers two electrons and a proton to NADP+ to form NADPH .

This family consists of Ferredoxin--NADP reductase from bacteria .
Heat shock protein beta-3 (HSPB3)
Type: Domain

This entry represents the alpha crystallin domain (ACD) found in heat shock protein beta-3 (HspB3) from vertebrates, also known as heat-shock protein 27-like protein (HSPL27, 17kDa) . Small heat shock proteins (sHSP) are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits . HspB3 is expressed in adult skeletal muscle, smooth muscle, and heart, and in several other fetal tissues. In muscle cells HspB3 forms an oligomeric 150kDa complex with myotonic dystrophy protein kinase-binding protein (MKBP/ HspB2), this complex may comprise one of two independent muscle-cell specific chaperone systems. The expression of HspB3 is induced during muscle differentiation controlled by the myogenic factor MyoD . HspB3 may also interact with Hsp22 (HspB8).
UDP-GlcNAc-dolichyl-phosphate GlcNAc phosphotransferase (GPT)
Type: Family

UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase (GPT) catalyzes the transfer of GlcNAc-1-P from UDP-GlcNAc to dolichol-P to form GlcNAc-P-P-dolichol . The reaction is the first step in the assembly of dolichol-linked oligosaccharide intermediates and is essential for eukaryotic N-glycosylation . GPT activity has been identified in all eukaryotic cells examined to date. A series of six conserved motifs designated A through F, ranging in length from 5 to 13 amino acid residues, has been identified in this family. They have been determined to be important for stable expression, substrate binding, or catalytic activities .
MADS MEF2-like, N-terminal (MEF2-like_N)
Type: Domain

This entry represents the N-terminal domain of MEF2 (myocyte enhancer factor 2)-like/Type II subfamily of MADS (MCM1, Agamous, Deficiens, and SRF (serum response factor)) box family of eukaryotic transcriptional regulators . It binds DNA and exists as hetero and homo-dimers. This protein differs from SRF-like/Type I subgroup mainly in position of the α helix responsible for the dimerisation interface . It is important in homeotic regulation in plants and in immediate-early development in animals and is also found in fungi .
SRF-like, MADS-box (SRF-like_MADS-box)
Type: Domain

SRF-like/Type I subfamily of MADS (MCM1, Agamous, Deficiens, and SRF (serum response factor)) box family of eukaryotic transcriptional regulators . Binds DNA and exists as hetero- and homo-dimers . Differs from the MEF-like/Type II subgroup mainly in position of the α 2 helix responsible for the dimerization interface. Important in homeotic regulation in plants and in immediate-early development in animals . Also found in fungi .

Human serum response factor (SRF) is a ubiquitous nuclear protein important for cell proliferation and differentiation. SRF function is essential for transcriptional regulation of numerous growth-factor-inducible genes, such as c-fos oncogene and muscle-specific actin genes. A core domain of around 90 amino acids is sufficient for the activities of DNA-binding, dimerisation and interaction with accessory factors. Within the core is a DNA-binding region, designated the MADS box , that is highly similar to many eukaryotic regulatory proteins: among these are MCM1, the regulator of cell type-specific genes in fission yeast; DSRF, a Drosophila trachea development factor; the MEF2 family of myocyte-specific enhancer factors; and the Agamous and Deficiens families of plant homeotic proteins.

In SRF, the MADS box has been shown to be involved in DNA-binding and dimerisation . Proteins belonging to the MADS family function as dimers, the primary DNA-binding element of which is an anti-parallel coiled coil of two amphipathic α-helices, one from each subunit. The DNA wraps around the coiled coil allowing the basic N-termini of the helices to fit into the DNA major groove. The chain extending from the helix N-termini reaches over the DNA backbone and penetrates into the minor groove. A 4-stranded, anti-parallel β-sheet packs against the coiled-coil face opposite the DNA and is the central element of the dimerisation interface.
The MADS-box domain is commonly found associated with K-box region see (

).
DNA-directed RNA polymerases I and III subunit AC19 (RNAP_AC19)
Type: Family

The eukaryotic AC19 subunit (also known as RPAC2 in mammals and RPC19 in yeast) of RNA polymerase (RNAP) I and RNAP III is involved in the assembly of RNAP subunits . RNAP is a large multi-subunit complex responsible for the synthesis of RNA. It is the principal enzyme of the transcription process, and is a final target in many regulatory pathways that control gene expression in all living cells. At least three distinct RNAP complexes are found in eukaryotic nuclei: RNAP I, RNAP II, and RNAP III. RNAP I is responsible for the synthesis of ribosomal RNA precursor, while RNAP III functions in the synthesis of 5S and tRNA . The AC19 subunit is the equivalent of the RPB11 subunit of RNAP II . The RPB11 subunit heterodimerizes with the RPB3 subunit, and together with RPB10 and RPB12, anchors the two largest subunits, RPB1 and RPB2, and stabilizes their association. The homology of AC19 to RPB11 suggests a similar function. The AC19 subunit is likely to associate with the RPB3 counterpart, AC40, to form a heterodimer, which stabilizes the association of the two largest subunits of RNAP I and RNAP III .