SII-SWORD/CoKE huggingface dataset:
D-glucuronyl C5-epimerase (C5-epimerase)
Type: Family

D-glucuronyl C5-epimerase converts D-glucuronic acid to L-iduronic acid to increase heparan sulfate (HS) flexibility . The structure of D-glucuronyl C5-epimerase has been determined .
Nonsense-mediated mRNA decay protein 3 (Upf3)
Type: Family

This entry includes nonsense-mediated mRNA decay protein 3 (Upf3) and its homologues. In budding yeasts, Upf3 is involved in the nonsense-mediated mRNA decay (NMD) pathway . Human Upf3a and Upf3b are components of the exon-junction complex (EJC), which promotes nonsense-mediated mRNA decay (NMD) and regulate translation efficiency .
Vps71/ZNHIT1 (Vps71/ZNHIT1)
Type: Family

This entry includes Vps71 from yeasts and ZNHIT1 (also known as Hamlet or p18) from animals.
WD repeat-containing protein 91 (WDR91)
Type: Family

This entry represents WDR91 and its homologues. WDR91 is part of the WDR81-WDR91 complex that functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex. WDR91 has been shown to be recruited to endosomes by interacting with active guanosine triphosophate-Rab7 and inhibits Rab7-associated phosphatidylinositol 3-kinase activity .

This entry also includes Sorf-1, a WDR91 homologue from C. elegans. Sorf-1 and Sorf-2 form a complex with Beclin1 and inhibit the activity of the PI3K complex .
Coiled-coil and C2 domain-containing protein 1 (CC2D1A/B)
Type: Family

This entry includes coiled-coil and C2 domain-containing protein 1A/B (CC2D1A/B, also known as Freud-1/2). CC2D1A is involved in many pathways, including nuclear factor kappaB, PDK1/Akt, cAMP/PKA, Notch and bone morphogenetic protein . It is a calcium-regulated repressor of serotonine receptor 5-HT1A and dopamine-D2 receptor expression . CC2D1B binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons .

CC2D1A and CC2D1B have also been shown to interact with the CHMP4 family of proteins, the major subunit of the ESCRT-III complex. They may regulate degradation and signaling of EGFR and TLR4 .

CC2D1A and CC2D1B share conserved domains, including several DM14 domains that are specific to this protein family, a C-terminal helix-loop-helix domain, and a C2 domain. The CC2D1A C2 domain is thought to be calcium insensitive and it lacks several acidic residues that mediate calcium binding of the PKC C2 domain. In addition, it contains a poly-basic insert that is not present in calcium-dependent C2 domains and may function as a nuclear localization signal . The CC2D1B C2 domain appears to be essential for its DNA binding and repressor function; it may mediate protein-protein interactions .
Pre-mRNA-processing factor Prp40 (Prp40-like)
Type: Family

This entry represents a group of pre-mRNA-processing proteins, including budding yeast Prp40, and its homologues. Prp40 is required for pre-spliceosome formation, which is the first step of pre-mRNA splicing . In human, there are two Prp40 homologues, PRP40A and PRP40B. They are also involved in pre-mRNA splicing .
SERRATE/Ars2 (SE/Ars2)
Type: Family

This entry includes SERRATE (SE) from plants and its homologues, Ars2, from animals and Pir2 from Schizosaccharomyces pombe . These proteins play a role in nuclear RNA metabolism. They interact with the nuclear cap-binding complex (CBC) and mediates interactions with diverse RNA processing and transport machineries in a transcript-dependent manner. Interestingly, the plant SERRATE does not have the RNA recognition motif (RRM) domain found in metazoans and S. pombe .

In Arabidopsis, SE acts as a mediator between the cap-binding complex (CBC) and both the pre-mRNA splicing and primary microRNAs (miRNAs) processing machinery . Drosophila Ars2 has been shown to regulate both miRNA- and siRNA- dependent silencing and suppress RNA virus infection .
Golgi apparatus protein 1 (GLG1)
Type: Family

The Golgi apparatus protein 1 (GLG1), which is located in Golgi cisterns of various cell types, can bind fibroblast growth factor and E-selectin. Sixteen cysteine-rich GLG1 repeats form the core of the protein and are located in the lumen. The C-terminal part of GLG1 is composed of a transmembrane region and a short cytoplasmic tail. The Cys-rich GLG1 repeat is a ~60 amino acid module that contains 4 Cys residues, which can form intrachain disulphide bridges .
DNA fragmentation factor 40 (DFF40)
Type: Family

One of the hallmarks of the terminal stages of apoptosis is internucleosomal DNA breakdown. DNA fragmentation factor (DFF) and endonuclease G (Endo G) are responsible for this process. DFF exists in the nucleus as a heterodimer composed of a 45kDa chaperone and inhibitor subunit (DFF45, also called ICAD-L) and a 40kDa latent nuclease subunit (DFF40/CAD). Apoptotic activation of caspase-3 or -7 results in the cleavage of DFF45 and release of active DFF40 nuclease, which forms homo-oligomers. DFF40's nuclease activity is further activated by proteins such as histone H1, HMGB1/2, and topoisomerase II .

This entry represents DFF40 (also known as DNA fragmentation factor subunit beta), which is an apoptotic nuclease that digests chromatin to yield 3'-hydroxyl groups and 5'-phosphate residues .
Jlp2/Ccd25 (Jlp2/Ccd25)
Type: Family

This entry includes Jlp2 from budding yeasts and coiled-coil domain-containing protein 25 (Ccd25) from animals. Their functions are not clear.
CAAX prenyl protease 2, eukaryotes (Rce1)
Type: Family

Rce1 is an integral membrane, metal-dependent endoprotease localized to the endoplasmic reticulum that mediates the cleavage of the carboxyl-terminal three amino acids from CaaX proteins, such as Ras family of small GTPases, the gamma-subunit of heterotrimeric GTPases, nuclear lamins, and protein kinases and phosphatase . It is classified as type II CAAX prenyl protease and is included in peptidase family M79. Its structure has been solved .
Ubiquitin-like modifier Hub1/Ubl5 (Hub1/Ubl5)
Type: Family

This entry includes Hub1 from yeasts and Ubl5 from animals. Hub1 is an ubiquitin-like protein that lacks the C-terminal Gly, which is essential for covalent attachment to target protein(s) of ubiquitin and other ubiquitin-like (UBL) modifiers . Hub1 binds non-covalently to a conserved element termed HIND, which is present in the spliceosomal protein Snu66 in yeast and mammals, and Prp38 in plants . Hub1 does not affect general splicing, instead, it acts as a modulator of spliceosome performance and facilitator of alternative splicing . It has been shown to bind to the DEAD-box helicase Prp5 and mediates enhanced, but error-prone splicing .
Protein N-terminal glutamine amidohydrolase (NTAQ1)
Type: Family

The N-end rule pathway is an ubiquitin (Ub)-dependent proteolytic system that mediates and regulates the degradation of intracellular proteins through the recognition of their N-terminal residues. NTAQ1 (also known as Nta1 in fungi) is an N-terminal amidohydrolase, which converts N-terminal Asn and Gln to the N-terminal residues Asp and Glu, the first step of the hierarchically organized N-end rule pathway . The structure of Nta1 has been determined .
Cysteine-rich hydrophobic domain-containing protein 1/2 (CHIC1/2)
Type: Family

The function of cysteine-rich hydrophobic domain-containing protein 1/2 (CHIC1/2) is not clear. CHIC1, also known as brain X-linked gene (BRX), is preferentially expressed in the brain and is a potential candidate for one of the X-linked mental retardation syndromes mapped within the pericentromeric region of the human X chromosome . A chromosomal aberration involving CHIC2 is found in a form of acute myeloid leukemia; the mutation prevents palmitoylation and the protein does not associate with the membrane .
RNA-directed RNA polymerase L, C-terminal (L_poly_C)
Type: Domain

This entry represents a common C-terminal region shared by paramyxovirus-like RNA-dependent RNA polymerases. These are often called L protein (large polymerase protein). Capping of mRNA requires RNA triphosphatase and guanylyl transferase activities, demonstrated for the rinderpest virus L protein .
Type I inositol 1,4,5-trisphosphate 5-phosphatase (INPP5A)
Type: Family

Type I inositol 1,4,5-trisphosphate 5-phosphatase (INPP5A) catalyzes the removal of the 4-position phosphate from inositol 3,4-bisphosphate (Ins(3,4)P2), inositol 1,3,4-triphosphate (Ins(1,3,4)P3), and phosphatydlinositol 3,4-bisphosphate (PtdIns(3,4)P2) . In mice, a frame shift mutation in the INPP5A gene causes the weeble mutant phenotype, which is characterised by an early onset cerebellar ataxia and neurodegeneration, especially apparent in the Purkinje cells .
RING-finger protein MAG2/RNF10 (MAG2/RNF10)
Type: Family

This entry represents a group of E3 ubiquitin-protein ligases including MAG2 from budding yeasts and RNF10 from animals, which contain a RING-finger. RNF10 has been shown to be involved in transcriptional regulation of the myelin-associated glycoprotein gene and myelin formation in Schwann cells . It catalyses monoubiquitination of 40S ribosomal proteins RPS2/us5 and RPS3/us3 in response to ribosome stalling .

MAG2 is E3 ubiquitin-protein ligase involved in the degradation of non-functional 18S rRNAs in response to stalled ribosomes .
CCR4-NOT transcription complex subunit 10 (CNOT10)
Type: Family

CNOT10 is part of the CCR4-NOT complex, a major cellular mRNA deadenylase linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. CNOT10 is essential for the integrity of the CCR4-NOT complex and for degradation of many mRNAs .
UDP-sugar pyrophosphorylase (UDP-sugar_pyrophosphorylase)
Type: Family

This entry includes UDP-sugar phosphorylases such as UDP-N-acetylglucosamine pyrophosphorylase, UDP-N-acetylhexosamine pyrophosphorylase (UAP1) and UDP-N-acetylglucosamine diphosphorylase, all of which catalyse the transfer of an uridylyl group. UAP1 has two catalytic domains, UDP-N-acetylgalactosamine pyrophosphorylase (

) and UDP-N-acetylglucosamine pyrophosphorylase (

) . UDP-N-acetylglucosamine diphosphorylase is required for the biosynthesis of UDP-glucosamine, an essential precursor for glycoprotein and glycolipid synthesis and can utilize UDP-glucosamine or UDP-galactosamine .
Protein Shq1 (Shq1)
Type: Family

The box H/ACA ribonucleoproteins (RNPs) are protein-RNA complexes responsible for pseudouridylation, the most abundant post-transcriptional modification of cellular RNAs . Each distinct H/ACA RNA assembles with a common set of four proteins, Cbf5 (NAP57 in rodents and dyskerin in humans), Nop10, Nhp2 (L7Ae in archaea) and Gar1 .
Endo-beta-1,6-galactanase/Exo-beta-1,6-galactobiohydrolase (6GAL/EXGAL)
Type: Family

In Trichoderma viride, endo-beta-1,6-galactanase (6GAL) hydrolyzes galactooligomers with a degree of polymerization higher than 3 . This family also includes Exo-beta-1,6-galactobiohydrolase (EXGAL) from Bifidobacterium longum, which specifically releases the non-reducing terminal beta-1,6-galactobiose of beta-1,6-galactooligosaccharides . 6GAL and EXGAL are members of Glycoside Hydrolase Family 30 (GH30), subfamily 5 .
Small ribosomal subunit protein uS14, eukaryotes/archaea (RIbosomal_uS14_euk_arc)
Type: Family

This entry includes the small ribosomal subunit protein uS14 from eukaryotes (also known as 40S ribosomal protein S29, the cytosolic form) and archaea (also known as 30S ribosomal protein S14 type Z). They belong to the zinc-binding subfamily of ribosomal protein uS14. They bind 1 zinc ion per subunit and bind to the 16S rRNA . uS14 is required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site.
Vacuolar protein sorting-associated protein 54 (Vps54)
Type: Family

Vacuolar protein sorting-associated protein 54 (Vps54) is a component of the GARP (Vps52/53/54) complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN) . Mammalian GARP complex has been shown to play a general role in the delivery of retrograde cargo into the TGN .
FOG family (FOG)
Type: Family

This entry represents the FOG (Friend of GATA) family, whose members are zinc finger cofactors that regulate GATA factor-activated gene transcription. There are two FOG proteins in mammals, FOG1 and FOG2. They are essential cofactors that act via the formation of a heterodimer with transcription factors of the GATA family GATA1, GATA2 and GATA3 . In mice, FOG1 is expressed predominantly within the hematopoietic system, while FOG2 is expressed outside of blood, mostly in heart, brain, gonads, and liver .

This entry also includes the FOG homologue from fruit flies, U-shaped (Ush), which is expressed in circulating and lymph gland hemocytes, where it plays a critical role in controlling blood cell proliferation and differentiation .
DNA-directed RNA polymerases I, II, and III subunit RPABC4 (RPABC4)
Type: Family

DNA-directed RNA polymerases

(also known as DNA-dependent RNA polymerases) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-directed RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. The core RNA polymerase complex consists of five subunits (two alpha, one beta, one beta-prime and one omega) and 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 . The core RNA polymerase complex forms a "crab claw"-like structure with an internal channel running along the full length . The key functional sites of the enzyme, as defined by mutational and cross-linking analysis, are located on the inner wall of this channel.

RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (>100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.

This family includes the DNA-directed RNA polymerases I, II, and III subunit RPABC4 (also known as RPC10 and ABC10-alpha) .
DNA-directed RNA polymerase III subunit RPC3 (RPC3)
Type: Family

This entry represents RPC3, a subunit of the DNA-directed RNA polymerase III. In yeast this subunit is also known as Rpc82, and in animals as Rpc62. Human Rpc62 has been shown to bind ssDNA (single-stranded DNA) .
NEDD8 ultimate buster 1 (NUB1)
Type: Family

NUB1 is an adaptor protein which negatively regulates the ubiquitin-like protein Nedd8 as well as neddylated proteins levels through proteasomal degradation . It has been shown to be regulated by Mdm2 (E3 ubiquitin ligase) through ubiquitination on its lysine 159 .
Dynein regulatory complex protein (DRC1/DRC2)
Type: Family

DRC1 is a key component of the nexin-dynein regulatory complex (N-DRC), essential for N-DRC integrity. It is required for the assembly and regulation of specific classes of inner dynein arm motors. It may also function to restrict dynein-driven microtubule sliding, thus aiding in the generation of ciliary bending . Mutations of DRC1 gene cause Ciliary dyskinesia, primary, 21 (CILD21), which is a disorder characterised by abnormalities of motile cilia .

DRC2, also known as CCDC65, is an essential component of the nexin-dynein regulatory complex (N-DRC). DRC2 is necessary for the co-assembly of DRC2 and DRC1 to form the base plate of N-DRC.
Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 /2 (HERPUD1/2)
Type: Family

HERPUD1, also known as HERP, is a key component of the ERAD multiprotein complex which helps to stabilize the complex and facilitate the efficient degradation of unfolded proteins . This entry also includes HERPUD2, whose function is not clear, but has been associated with hyperuricemia .
F-box only protein (F-box_only)
Type: Family

Proteins in this entry contain an N-terminal F-box and a C-terminal F-box associated (FBA) domain. The F-box is a conserved domain that is present in numerous proteins with a bipartite structure . Through the F-box, these proteins are linked to the Skp1 protein and the core of SCFs (Skp1-cullin-F-box protein ligase) complexes. SCFs complexes constitute a new class of E3 ligases . They function in combination with the E2 enzyme Cdc34 to ubiquitinate G1 cyclins, Cdk inhibitors and many other proteins, to mark them for degradation. The binding of the specific substrates by SCFs complexes is mediated by divergent protein-protein interaction motifs present in F-box proteins, like WD40 repeats, leucine rich repeats or ANK repeats.
mRNA cap guanine-N7 methyltransferase (RG7MT1)
Type: Family

This entry represents mRNA (guanine-N(7))-methyltransferase, which can either be found as a single domain protein, or as a domain within the mRNA-capping enzyme catalytic subunit.

mRNA (guanine-N(7))-methyltransferase methylates the N7 position of the added guanosine to the 5'-cap structure of mRNAs. It binds RNA containing 5'-terminal GpppC . Viral mRNA capping enzymes, meanwhile, are multidomain proteins that catalyse the first two reactions in the mRNA cap formation pathway . They are heterodimers consisting of a large (catalytic) and small subunit.
Pre-rRNA-processing protein Esf1 (Esf1)
Type: Family

Pre-rRNA-processing protein Esf1 is required for the biogenesis of 18S rRNA in Saccharomyces cerevisiae. It has a role in early pre-rRNA processing because it associates with U3 and U14 snoRNAs but not the SSU processome . Homologues are found in other fungi, animals and plants.
TBC1 domain family member 23 (TBC1D23)
Type: Family

TBC1 domain family member 23 (TBC1D23) is a catalytically inactive member of a family of Rab GTPase-activating proteins (GAPs) which plays a role in endosome-to-Golgi trafficking and is important for normal brain development, especially in axonal and dendritic growth. It functions as a bridging factor between golgin-97/245 and the FAM21 subunit of the WASH (Wiskott-Aldrich syndrome protein and SCAR homologue) complex on endosomal vesicles . Mutations of the TBC1D23 gene cause pontocerebellar hypoplasia and alter cortical development .
Type II phosphatidylinositol 4-kinase Lsb6/PI4K2 (Lsb6/PI4K2)
Type: Family

This entry represents a group of type II phosphatidylinositol 4-kinases, including Lsb6 from yeasts and PI4K2alpha/beta from animals . PI4K2alpha catalyzes the phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P), a lipid that plays important roles in endocytosis, Golgi function, protein sorting and membrane trafficking and is required for prolonged survival of neurons. The structure of PI4K2alpha has been revealed .
Eukaryotic translation initiation factor 2D (EIF2D)
Type: Family

Proteins in this entry contain at least an N-terminal PUA (PseudoUridine synthase and Archaeosine transglycosylase) domain and a C-terminal SUI1 domain. Proteins with this architecture include:

Eukaryotic translation initiation factor 2D (EIF2D; formerly and erroneously known as ligatin): a factor that initiates translation by delivering tRNA to the P-site, where the initiating AUG codon binds, of the eukaryotic ribosome in a GTP-independent manner . EIF2D recruits aminoacylated initiator tRNA (Met-tRNA(Met)(i)) to 40S/mRNA complexes and promotes release of deacylated tRNA and mRNA from recycled 40S subunits after ABCE1-mediated dissociation of post-termination ribosomes .

Translation machinery-associated protein 64 (Tma64) from the yeast
Saccharomyces cerevisiae
, which is uncharacterised but also interacts with the 40S ribosomal subunit .
N-acetyl-D-glucosamine kinase NAGK-like (NAGK-like)
Type: Family

This entry includes N-acetyl-D-glucosamine kinases (NAGKs) from prokaryotes and eukaryotes. NAGK converts endogenous N-acetylglucosamine (GlcNAc), a major component of complex carbohydrates, from lysosomal degradation or nutritional sources into GlcNAc 6-phosphate . It has been shown to play an enzyme activity-independent role in human neurons .
Eukaryotic translation initiation factor 2D, SUI1 domain (eIF2D_SUI1)
Type: Domain

This entry represents the SUI1 domain found at the C terminus of eukaryotic translation initiation factor 2D (eIF2D).
Ribosome biogenesis protein Bms1/Tsr1 (Bms1/Tsr1)
Type: Family

Bms1p and Tsr1p represent a new family of factors required for ribosome biogenesis. They are each independently required for 40S ribosomal subunit biogenesis. Bms1p, a protein required for pre-rRNA processing, contains an evolutionarily conserved guanine nucleotide-binding (G) domain with five conserved polypeptide loops designated G1 through G5, which form contact sites with the guanine nucleotide or coordinate the Mg(2+) ion. Sequences resembling G1 (consensus [GA]-x(4)-G-K-[ST]; also known as a P-loop), G4 (consensus [NT]-K-x-D), and G5 (consensus S-[AG] are present in all Bms1 proteins, and either fully conform with the consensus or contain, at most, single conservative substitutions. The G2 motif (consensus G-P-[IV]-T) contains a T residue involved in the coordination of the Mg(2+) required for GTP hydrolysis. The G3 motif diverges from the consensus found in G proteins, D-x(2)-G; however, the D residue is replaced with the conserved E residue. In contrast, Tsr1p lacks a P-loop and is not predicted to bind GTP. It functions at a later step of 40S ribosome production, possibly in assembly and/or export of 43S pre-ribosomal subunits to the cytosol .
Nonsense-mediated mRNA decay protein Nmd2/UPF2 (Nmd2/UPF2)
Type: Family

This entry includes Nmd2 from yeasts and UPF2 from animals. They are involved in the nonsense-mediated mRNA decay (NMD) pathway . In the human UPF complex (composed of UPF1/2/3), UPF2 and UPF3b cooperatively stimulate both ATPase and RNA helicase activities of UPF1 .
Damage-control phosphatase ARMT1 (ARMT1)
Type: Family

This family represents Damage-control phosphatases ARMT1, including YMR027W from S. cerevisiae (

) and human ARMT1 (C6orf211, previously known as Protein-glutamate O-methyltransferase) . Despite a first characterization of human ARMT1 as a carboxyl methyltransferase, a second study suggests that these proteins are metal-dependent phosphatases implicated in metabolite damage-control, whose function is to limit potentially harmful buildups of phosphometabolites , in processes termed "damage pre-emption" or "housecleaning".