SII-SWORD/CoKE huggingface dataset:
CCG-binding protein 1 (CBP1)
Type: Family

CBP1 is regulator of transcription initiation in plants that shows no homology to animal or yeast proteins. CBP1, via interaction with CCG and the Mediator complex, connects transcription factors and the Pol II machinery to regulate pollen tube attraction .
rRNA-processing protein Fcf1, PIN domain (Fcf1_PIN)
Type: Domain

Fcf1 (also known as Utp24) is an essential protein involved in pre-rRNA processing and 40S ribosomal subunit assembly . As a component of the small subunit (SSU) processome, Fcf1 is an essential nucleolar protein required for processing of the 18S pre-rRNA at sites A0-A2 .

The PIN (PilT N terminus) domain is a compact RNA-binding protein domain found in all domains of life. Typically, the PIN domain contains three or four conserved acidic residues (putative metal-binding, active site residues) . The Fcf1 PIN domain has four of these putative active site residues and the Fcf1-Utp23 homologue PIN domain has three of them. Point mutation studies of the conserved acidic residues in the putative active site of Saccharomyces cerevisiae Fcf1 determined they were essential for pre-rRNA processing at sites A1 and A2, whereas the presence of the Fcf1 protein itself is also required for cleavage at site A0 .
[PSI+] induction protein 2 (PSI_induc_2)
Type: Family

Budding yeast Pin2 was identified as a protein that when overexpressed can induce the [PIN+] prion phenotype, which is a prerequisite for prion formation by Sup35, referred to as the [PSI+] prion . Pin2 localization is dependent on both exo- and endocytosisis. It is an exomer-dependent cargo that localizes at the plasma membrane of the bud early in the cell cycle, and the bud neck at cytokinesis. The prion-like domain (PLD) in Pin2 serves as a Pin2 retention signal in the trans-Golgi network (TGN) and may act as stress-response element. Under environmental stress, Pin2 is endocytosed, and the PLD aggregates and causes sequestration of Pin2. This aggregation is reversible upon stress removal and Pin2 can be re-exported to the plasma membrane . Why Pin2 needs to be retain under stress is not clear, but it may be related to the observation that Pin2 interacts with various components of the cell-wall integrity pathway.
pH-response regulator protein palC (pH-resp_palC)
Type: Family

PalC is found in fungi and is required for the proteolytic cleavage of the transcription factor pacC in response to alkaline ambient pH .
Large ribosomal subunit protein mL59 (Ribosomal_mL59)
Type: Family

This entry represents the large ribosomal subunit protein mL59 (also known as MrpL25) which is a yeast mitochondria-specific ribosomal (mitoribosome) protein. mL59 may be located near the tunnel exit site .
Meiotically up-regulated protein Msb1/Mug8 (Msb1/Mug8)
Type: Family

The function of this family of yeast proteins is not known. Mug8 may have a role in meiosis and septation in Schizosaccharomyces pombe . The Saccharomyces cerevisiae homologue Msb1 may be involved in positive regulation of 1,3-beta-glucan synthesis and the Pkc1p-MAPK pathway .
Phosphomethylpyrimidine synthase (ThiC)
Type: Family

This entry includes phosphomethylpyrimidine synthases, including thiC from prokaryotes and AtTHIC from Arabidopsis. thiC is found within the thiamin biosynthesis operon and is involved in thiamin biosynthesis . ThiC catalyzes the synthesis of the hydroxymethylpyrimidine phosphate (HMP-P) moiety of thiamine from aminoimidazole ribotide (AIR) in a radical S-adenosyl-L-methionine (SAM)-dependent reaction .

AtTHIC is involved in pyrimidine synthesis in the thiamine biosynthesis pathway of Arabidopsis. Heterologous expression of AtTHIC could functionally complement the thiC knock-out mutant of E. coli .
4-hydroxythreonine-4-phosphate dehydrogenase (PdxA)
Type: Family

PdxA is an NAD+-dependent 4-hydroxythreonine 4-phosphate dehydrogenase (

) active in pyridoxal phosphate biosynthesis .
Phosphoglycolate phosphatase, prokaryotic (PGPase_prok)
Type: Family

This family represents 2-phosphoglycolate phosphatase (PGP) and is limited to prokaryotes. PGP is an essential enzyme in the glycolate salvage pathway in higher organisms (photorespiration in plants). Phosphoglycolate results from the oxidase activity of RubisCO in the Calvin cycle when concentrations of carbon dioxide are low relative to oxygen. In Ralstonia eutropha and Rhodobacter sphaeroides, the PGP gene (CbbZ) is located on an operon along with other Calvin cycle enzymes including RubisCO . In E. coli, however, there does not appear to be a functional Calvin cycle (RubisCO is absent), although the E. coli PGP gene (gph) is on the same operon (dam) with ribulose-5-phosphate-3-epimerase (rpe), a gene in the pentose-phosphate pathway (along with other, unrelated genes) . The E. coli enzyme catalyzes the dephosphorylation of 2-phosphoglycolate and it is involved in salvage in the metabolism of a two-carbon compound generated by the cellular DNA repair machinery .

This enzyme is a member of the Haloacid Dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolase enzymes.
NAD(P)H dehydrogenase (quinone), prokaryotic (NQO)
Type: Family

WrbA (tryptophan (W) repressor-binding protein) was discovered in Escherichia coli, where it was proposed to play a role in regulation of the tryptophan operon , which has been put in question since then . Instead, WrbA has been shown to have FMN-dependent NAD(P)H:quinone oxidoreductase activity . A role in quinone detoxification has been proposed, supported by evidence suggesting its involvement in oxidative defence and/or cell signalling .
Ribose-phosphate pyrophosphokinase, archaea (Rib-P_diPkinase_arc)
Type: Family

Ribose-phosphate diphosphokinase, also known as ribose-phosphate pyrophosphokinase (RPPK), or phosphoribosyldiphosphate synthetase (

), catalyses the transfer of an intact diphosphate (PP) group from ATP to ribose-5-phosphate (R-5-P), which results in the formation of AMP and 5-phospho-D-ribosyl--1-diphosphate (PRPP).

This family consists of archaeal enzymes. PRPP from Methanocaldococcus jannaschii differ from previously characterised bacterial PRPP synthases by its tetrameric quaternary structure and the simultaneous phosphate ion-activation and lack of allosteric inhibition, and constitute a novel class of PRPP synthases .
Ribose-phosphate pyrophosphokinase, bacterial-type (Rib-P_diPkinase_bac)
Type: Family

This family consists of bacterial and some eukaryotic enzymes. The crystal structure of the PRPP synthetase from Bacillus subtilis has been determined; the functional form of the enzyme is an hexamer .

Ribose-phosphate diphosphokinase, also known as ribose-phosphate pyrophosphokinase (RPPK), or phosphoribosyldiphosphate synthetase (

), catalyses the transfer of an intact diphosphate (PP) group from ATP to ribose-5-phosphate (R-5-P), which results in the formation of AMP and 5-phospho-D-ribosyl--1-diphosphate (PRPP).
Tripartite DENN domain (Tripartite_DENN)
Type: Domain

This entry represents the full tripartite DENN domain.

The tripartite DENN (Differentially Expressed in Normal and Neoplastic Cells) domain is an evolutionarily conserved protein module found in several proteins involved in Rab-mediated processes and, in some cases, regulation of MAPK (Mitogen-Activated Protein Kinase) signalling pathways and related proteins in eukaryotic organisms. The DENN domain consists of three subdomains: uDENN (upstream DENN)

, the core DENN domain

, and dDENN (downstream DENN)

, which are structurally distinct but functionally interconnected due to their roles in Rab GTPase activation. Recent studies have confirmed the DENN domain's function as a guanine nucleotide exchange factor (GEF) for Rab GTPases, facilitating the exchange of GDP for GTP to activate Rabs. This activity has been demonstrated for various DENN proteins, such as DENND1A and DENND1B, which specifically activate Rab35, and DENND2B, which serves as a GEF for Rab10 and Rab13, influencing processes like primary ciliogenesis and epithelial cancer development .

The tripartite structure of the DENN domain, comprising uDENN, DENN itself, and dDENN, features distinct patterns of sequence conservation and variable interdomain lengths that suggest functional specialisation. Structural studies have revealed conserved residues critical for Rab binding and catalytic activity, emphasising the role of DENN domains in spatially and temporally regulating membrane trafficking events . Additionally, DENN domains are often associated with other domains such as RUN

, PLAT

, which may further enhance their functional versatility in cellular signalling pathways .

Some proteins known to contain a tripartite DENN domain include:

Human mitogen-activated protein kinase activating protein containing death domain (MADD)

, orthologous to Rab3GEP

Human SET domain-binding factor 1 (SBF1)

Human DENN domain-containing protein 2B

Human C-myc promoter-binding protein

In Arabidopsis, SCD1 is a unique gene encoding for the only protein containing a complete DENN domain. SCD1 is part of a protein complex that interacts with the exocyst complex and the RabE1 family of GTPases. It is also involved in activating innate immune responses against bacteria .

Recent findings highlight the broader target spectrum of DENN domains than previously appreciated. For example, DENND2B interacts with Rab35 as both an effector and a GEF at intercellular bridges during cytokinesis. These discoveries underscore the importance of DENN domain proteins in regulating diverse cellular processes such as vesicle trafficking, signal transduction, ciliogenesis, and cancer progression .
Hepatitis delta antigen (HDAg) domain (HDAG_dom)
Type: Domain

Transcription elongation by RNA polymerase II (RNAPII) is negatively regulated by the human factors DRB-sensitivity inducing factor (DSIF) and negative elongation factor (NELF). NELF is a transcription factor composed of four subunits, NELF-A, -B, -C (or its variant -D), and -E, that are conserved from Drosophila to humans. Certain subunits have been implicated in numerous diseases ranging from neurological disorders to cancer. The N-terminal segment of NELF-A shows sequence similarity to the hepatitis delta antigen (HDAg), the viral protein required for replication of hepatitis delta virus (HDV) [E1]. Replication of HDV RNA appears to involve the host RNAPII and requires the presence of HDAg. HDAg binds RNAPII directly and stimulates transcription by displacing NELF and promoting RNAPII elongation. HDAg directly binds RNAPII and inhibits NELF-RNAPII association, possibly because HDAg competes with NELF-A for a common surface on RNAPII .

The C terminus of the HDAg domain forms the RNAPII-binding motif conserved in humans and virus, while the NELF-C (or NELF-D)-binding region of NELF-A is localized in the middle of the HDAg domain. The region of HDAg corresponding to the NELF-C (or NELF-D)-binding region of NELF-A contains two arginine-rich motifs responsible for RNA-binding activity .

The HDAg domain is composed of a long N-terminal helix, interrupted by a sharp bend and continuing on into another short helix . The middle part of the HDAg domain makes an 'extended region' that forms four helices . The structure of the C-terminal section is not yet known.
MPN domain (MPN)
Type: Domain

The MPN (Mpr1, Pad1 N-terminal) domain (also known as the Mov34, JAB, PAD-1, or JAMM (JAB1/MPN/Mov34 metalloenzyme) domain) is a widespread 120 amino acid protein module found in archaea, bacteria and eukaryotes. In eukaryotes the MPN domain is found in subunits of several multiprotein complexes, including the proteasome, whereas in eubacteria and archaea, the MPN domain is usually found in single domain proteins .

Within the MPN domain super-family, two main subclasses have been characterised: the MPN+ and MPN- domain-containing proteins. MPN+ domain-containing proteins are classified as metalloenzymes responsible for isopeptidase activity. These proteins contain a conserved glutamate (E) and a JAMM (Jab1/MPN/Mov34 metalloenzyme) motif, typically consisting of a canonical sequence (H-x-H-x-S-x-D) and coordinating a zinc ion. The E and JAMM motifs specify a catalytic centre essential for selective hydrolysis of linkages, contained between ubiquitin/ubiquitin-like proteins and target proteins or between ubiquitin monomers within a polymeric chain. MPN- domains are recognisable by the absence of essential Zn(2+)-coordinating residues that are required for catalytic function. In protein complexes, an MPN+ domain can associate with MPN- domains for purposes that are not well understood .

The MPN domain is composed of a five-stranded mixed β-sheet with strand order 21345 sandwiched between two α-helices. There is a second, smaller three-stranded parallel β-sheet formed by residues at the N and C termini and in the loop between the first two strands of the main sheet. MPN domains often form part of larger proteins. The N and C termini of the structure are close in space, allowing it to be easily inserted into a multidomain protein. The histidine and aspartate residues of the JAMM motif coordinate a zinc ion .

Some proteins known to contain an MPN domain are listed below:

Eukaryotic COP9 signalosome complex subunit 5 (CSN5).

Eukaryotic COP9 signalosome complex subunit 6 (CSN6).

Eukaryotic 26S proteasome regulatory subunit RPN11.

Eukaryotic 26S proteasome non-ATPase subunit 7 (PSMD7), also known as Mov34.

Eukaryotic AMSH (associated molecule with the SH3 domain of STAM) proteins, zinc metalloproteases that specifically cleave ubiquitin chains.

Eukaryotic pre-mRNA-splicing factor 8 (PRP8), a component of the U5 small nuclear RNA-protein (snRNP) complex.

Eukaryotic translation initiation factor 3 (eIF3) subunits f and h (also known as subunits p47 and p40, respectively).

Animal BRCC36 family proteins, Lys-63-specific deubiquitinases.

Animal BRCA1-A complex subunit Abraxas.

Animal BRISC complex subunit Abro1.

Bacterial UPF0758 protein.

Bacteriophage lambda tail assembly protein 'K' (vtak).
LITAF domain containing protein (LITAF_fam)
Type: Family

LITAF (LPS-induced TNF-activating factor) (also known as SIMPLE; small integral membrane protein of the late endosome) is an endosome-associated integral membrane protein important for multivesicular body (MVB) sorting. It is a monotypic membrane protein with both termini exposed to the cytoplasm and is anchored to membranes via an in-plane helical membrane anchor, present within the highly conserved C-terminal region known as the 'LITAF domain' or 'SIMPLE-like domain'. The LITAF domain consists of conserved cysteines separated by a 22 residue hydrophobic region. LITAF domains are found throughout the eukaryotes, suggesting ancient conserved functions, with multiple instances of expansion, especially in the metazoa .

Proteins containing the LITAF domain include:

Vertebrate lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF). In human, several mutations in LITAF cause the autosomal dominant inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 1 (CMT1). These mutations map to the LITAF domain .

Eukaryotic cell death-inducing p53-target protein 1 (CDIP1) .

Arabidopsis thaliana GSH-induced LITAF domain protein (GILP), acts as a membrane anchor, bringing other regulators of programmed cell death (PCD) to the plasma membrane .
Folliculin/SMCR8, longin domain (Folliculin/SMCR8_longin)
Type: Domain

Folliculin (FLCN) is a tumor suppressor that enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) Activating Protein (GAP) activity. It belong to the DENN module family of proteins and contains a divergent DENN module comprised of a N-terminal longin domain (also known as upstream DENN domain, u-DENN), followed by a DENN domain. It forms a complex with its partners, FNIP1 or FNIP2 (Folliculin interacting protein 1 or 2), which directly contacts the Rag GTPases RagC/D to stimulate GTP hydrolysis and thus promote the conversion to the GDP-bound state. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. They contain longin domains that heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, and C-terminal DENN domains which interact at the distal end of the structure .

This is the N-terminal domain of folliculin, the longin domain . An arginine residue located in this domain (Arg164) is catalytic residue for GAP activity . This domain can also be found in SMCR8, a component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy .
Folliculin/SMCR8, tripartite DENN domain (FLCN/SMCR8_DENN)
Type: Domain

The tripartite DENN (after differentially expressed in neoplastic versus normal cells) domain is found in several proteins that share common structural features and have been shown to be guanine nucleotide exchange factors (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. The tripartite DENN domain is composed of three distinct modules which are always associated due to functional and/or structural constraints: upstream DENN or uDENN (also known as longin domain), the better conserved central or core or cDENN, and downstream or dDENN regions. The tripartite DENN domain is found associated with other domains, such as RUN, PLAT, PH, PPR, WD-40, GRAM or C1. The function of DENN domain remains to date unclear, although it appears to represent a good candidate for a GTP/GDP exchange activity .

The DENN domain forms a heart-shaped structure, with the N-terminal residues forming one and the C-terminal residues forming the second one. The N-terminal half forms the uDENN domain and consists of a central antiparallel β-sheet layered between one helix and two helices. A long random-coil region links the two lobes. The C-terminal lobe is composed of the cDENN and dDENN domains. The cDENN domain is an α/β three layered sandwich domain with a central sheet of 5-strands. The dDENN domain is an all-α helical domain, whose core contains two α-hairpins which diverge rapidly in sequence .

Divergent types of the tripartite DENN domain have also been detected in other protein families , such as folliculin (FLCN), a tumour suppressor protein disrupted in various cancers and the Birt-Hogg-Dube syndrome, and Smith-Magenis syndrome chromosomal region candidate eight protein (SMCR8), which has been implicated in autophagy .
HD-GYP domain (HD_GYP_dom)
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 .

A distinct version of this domain, HD-GYP, contains a number of additional highly conserved residues. The spectrum of the domains that are associated with HD-GYP in multidomain proteins suggests that it is probably involved in signal transduction. The HD-GYP domain is likely to be a conserved scaffold whose main role is to allow protein-protein interactions with partner GGDEF domains while achieving (a) different function(s) through diversification of the active-site cavity and the N-terminal regulatory domains . In addition to the HD domain 5-helix core, the HD-GYP domain contains two extra C-terminal helices .
Vicinal oxygen chelate (VOC), core domain (VOC_core)
Type: Domain

This entry represents the core domain in Vicinal oxygen chelate (VOC) proteins. The core domain has topological symmetry, being comprised of two β-α-β-β-β units that form an incompletely closed barrel of β-sheet about the metal ion . This domain mediates the reactions via its structure and protein-chelating residues that secure and localise a metal ion.

The vicinal oxygen chelate (VOC) family of enzymes is a diverse group of proteins found across all domains of life, including bacteria, archaea, and eukarya. These enzymes catalyse a wide range of chemical reactions through a common mechanistic feature: bidentate coordination to a divalent metal centre via vicinal oxygen atoms in the substrate, intermediate, or transition state . The widespread presence of VOC enzymes across all domains of life highlights their evolutionary significance and critical roles in diverse metabolic pathways and cellular functions .

Some members of this family include:

Bacillus thuringiensis, Metallothiol transferase FosB

Caenorhabditis elegans, 4-hydroxyphenylpyruvate dioxygenase

Arabidopsis thaliana, Lactoylglutathione lyase

Homo sapiens, Glyoxalase domain-containing protein 5

.
PA14/GLEYA domain (PA14/GLEYA)
Type: Domain

The ~150-amino acid PA14 domain, named after its location in the protective antigen of anthrax toxin, is found in a variety of bacterial and eukaryotic proteins such as glycosidases, glycosyltransferases, proteases, amidases, toxins, adhesins and signaling molecules. The PA14 domain is combined in a mosaic manner with various catalytic or non-catalytic domains directly or indirectly implicated in binding carbohydrate or peptidoglycan. It could be a carbohydrate-binding module .

The PA14 domain is a β-barrel structure comprising two β-sheets. The N and C termini of the domain are close together in space, presumably, thereby facilitating the insertion of the PA14 domain into other recognized domains without structural disruption .

This entry also recognizes the related GLEYA domain (

), which is a carbohydrate-binding domain found in fungal adhesins (also referred to as agglutinins or flocculins) .
Velvet domain (Velvet_dom)
Type: Domain

The fungus-specific velvet family of regulatory proteins plays a key role in coordinating secondary metabolism and differentiation processes such as asexual or sexual sporulation and sclerotia or fruiting body formation. These velvet regulators are present in most parts of the fungal kingdom from chytrids to basidiomycetes. Velvet proteins interact with each other, alone ("homodimers"), in various combinations ("heterodimers"), and also with other proteins. The velvet proteins share a homologous region comprising about 150 amino acids, which lack significant sequence similarity to any other known proteins. The velvet domain is involved in specific DNA binding as well as in the dimerization of the different velvet proteins, resulting in the formation of homo- and heterodimers .

The velvet domain is an RHD-like domain related to NF-kappaB. It folds into a highly twisted β-sandwich composed of seven antiparallel β-strands. One side of the β-sandwich is involved in dimer formation, whereas the other one is flanked by several loops of which two fold into an α-helix. These α-helical fragments are located between β-strands 2 and 3 and at the C terminus .
Envelope glycoprotein Gp160 (Gp160)
Type: Family

The envelope glycoprotein Gp160 of HIV1 and simian immunodeficiency virus (SIV) is cleaved into the surface protein Gp120 and the transmembrane protein Gp41 . This entry represents the full length Gp160. Gp160 oligomerizes in the host endoplasmic reticulum into predominantly trimers. In a second time, Gp160 transits in the host Golgi, where glycosylation is completed. The precursor is then proteolytically cleaved in the trans-Golgi and thereby activated by cellular furin or furin-like proteases to produce Gp120 and Gp41 .