SII-SWORD/CoKE huggingface dataset:
SAC3/GANP/THP3 (SAC3/GANP/THP3)
Type: Family

This family includes the yeast nuclear export factor Sac3 , and mammalian GANP/MCM3-associated protein, which facilitates the nuclear localisation of MCM3, a protein that associates with chromatin in the G1 phase of the cell-cycle . It also includes yeast Thp3 (THO-related protein 3), which may have a role in transcription elongation .
Thioredoxin domain-containing protein 17-like (TXNDC17-like)
Type: Family

This entry represents a group of thioredoxin domain-containing proteins, including TXNDC17 from animals, SPBC21C3.12c from fission yeasts and AtClot from Arabidopsis. TXNDC17, also known as TRP14, is a highly conserved and ubiquitously expressed oxidoreductase involved in controlling of cellular redox signalling pathways. TXNDC17 has been shown to efficiently reduce l-cystine and can directly reactivate oxidized protein-tyrosine phosphatase PTP1B .
Lysine-specific demethylase LSDs-like (LSDs-like)
Type: Family

This entry represents a group of lysine-specific demethylases (LSDs) 3A and 3B. It also describes a group of JmjC-containing proteins, including JHDM2A/B/C (also known as KDM3A/B and JMJD1C), and hairless (HR) proteins. They have histone demethylase (HDM) activity that specifically demethylates 'Lys-9' of histone H3 . This entry also includes IBM1 (also known as JMJ25, At3g07610), JMJ24, and JMJ26-29 from Arabidopsis. IBM1 is a histone demethylase directly associated with chromatin of two siRNA biogenesis factors, RDR2 and DCL3 .
XMAP215 (XMAP215)
Type: Family

XMAP215 proteins, such as Alp14 and XMAP215 (also known as CKAP5), increase microtubules dynamic polymerization rates by recruiting soluble alpha/beta-tubulin via their conserved TOG domains to polymerizing microtubule plus ends . The TOG domain contains HEAT repeats, forming a oblong paddle-like structure. CKAP5 plays a major role in organizing spindle poles and acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibres of the mitotic spindle by acting as inter-microtubule bridge .

Proteins in this family also includes the XMAP215 homologue, Stu2 from budding yeasts and Alp14/Dis1 from fission yeasts .
Vacuolar protein sorting-associated protein Vps41/Vps8 (Vps41/Vps8)
Type: Family

This entry includes Vps41 and Vps8.

Vps8 is one of the Golgi complex components necessary for vacuolar sorting . Eukaryotic cells contain a highly dynamic endomembrane system, in which individual organelles keep their identity despite continuous vesicle generation and fusion. Vesicles that bud from a donor membrane are targeted and delivered to each individual organelle, where they release their cargo after fusion with the acceptor membrane. Vps8 is the core component of the endosomal tethering complex CORVET (class C core vacuole/endosome tethering). Vps8 co-operates with Vps21-GTP to mediate endosomal clustering in a reaction that is dependent on Vps3. Vps8 is the only CORVET subunit that is enriched on late endosomes, suggesting that it is a marker for the maturation of late endosomes. Late endosomes form intraluminal vesicles, and the resulting multivesicular bodies fuse with the vacuole to release their cargoes .

Vsp41 is a subunit of the homotypic vacuole fusion and vacuole protein sorting (HOPS) complex, which is essential for membrane docking and fusion at the Golgi-to-endosome and endosome-to-vacuole stages of protein transport . This protein interacts with Caspase-8, which plays a key role in apoptosis and development . Vsp41 consists of a β-propeller at the N-terminal (

), represented in this entry, followed by an α-solenoid (TPR-like) domain, a CHCR domain and a RING zinc finger (

).
Protein Peter Pan-like (PPAN-like)
Type: Family

Peter Pan (PPAN) was initially identified in Drosophila melanogaster. PPAN is highly conserved and essential for maintaining growth and survival . Human PPAN localizes to nucleoli and to mitochondria. It can shuttle between the nucleus and the cytoplasm in response to nucleolar stress and apoptosis induction . PPAN knockdown has been linked to mitochondrial damage and stimulates autophagy . The yeast homologues of PPAN, Ssf1 and Ssf2, are nucleolar ribosome biogenesis factors required for maturation of the large ribosomal subunit .
RNA polymerase subunit Rpb7-like (Rpb7-like)
Type: Family

The eukaryotic RNA polymerase subunits RPB4 and RPB7 form a heterodimer that reversibly associates with the RNA polymerase II core, being involved in initiation complex formation . Archaeal cells contain a single RNAP made up of about 12 subunits, displaying considerable homology to the eukaryotic RNAPII subunits. The RPB4 and RPB7 homologues are called subunits F and E, respectively, and have been shown to form a stable heterodimer. While the RPB7 homologue is reasonably well conserved, the similarity between the eukaryotic RPB4 and the archaeal F subunit is barely detectable .

This entry includes RPB7 and its homologues.
Csn12 family (Csn12-like)
Type: Family

This entry includes a group of mRNA export factors, including Csn12 and Thp1 from budding yeasts and their homologues from fungi, animal and plants. Csn12 is part of the THO complex involved in transcription elongation and mRNA processing and export . Thp1 is a component of the TREX-2 complex (Sac3-Thp1-Sus1-Cdc31) involved in transcription elongation and mRNA export from the nucleus . The animal homologue, PCID2, is part of the TREX-2 complex (consists of PCID2, GANP, CENP and DSS1) .
BolA-like protein 2 (BOL2)
Type: Family

BOLA2 is part of the [2Fe-2S] chaperone complex that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins .
Clp1/Grc3 (Clp1/Grc3)
Type: Family

This entry includes Clp1 and Grc3/NOL9.

Polyribonucleotide 5-hydroxyl-kinase Clp1 is a component of the cleavage factor IA (CF IA) complex, which is involved in the endonucleolytic cleavage during polyadenylation-dependent pre-mRNA 3'-end formation . It is involved in both the endonucleolyitc cleavage and polyadenylation steps of mRNA 3'-end maturation . Human Clp1 can also function as a tRNA splicing enzyme . In human, mutations in Clp1 affect tRNA biogenesis and lead to impairment of both peripheral and central nervous system function, causing severe motor-sensory defects, cortical dysgenesis and microcephaly . Clp1 contains three domains, a small N-terminal β sandwich domain involved in DNA binding , a C-terminal domain containing a novel α/β-fold and a central domain that binds ATP .

NOL9 and its orthologue Gre3 are polynucleotide 5'-kinases involved in rRNA processing . NOL9 can phosphorylate single-stranded and double-stranded RNA and DNA substrates .
Ataxin2-like (ATXN2-like)
Type: Family

This entry represents a group of RNA-binding proteins , including Ataxin-2 from animals, Pbp1 from fungi and Cid3/4 from Arabidopsis.

Ataxin-2 has many functions, such as endocytic receptor cycling , translational regulation, embryonic development , energy metabolism and weight regulation . Mutations of the Ataxin-2 gene cause spinocerebellar ataxia 2 (SCA2), a neurodegenerative disorder leading to predominant loss of Purkinje cells in the cerebellum and impairment of motor coordination . In SCA2, expansion of a CAG repeat in exon 1 of the Ataxin-2 (ATXN2) gene causes expansion of a polyQ domain in the ATXN2 protein . ATXN2 has been shown to interact with many proteins. It interacts with multiple RNA-binding proteins (RBPs), staufen, IP3R, RGS8 mRNA, endophilins and CIN85 .

Pbp1 interacts with Pab1 to regulate mRNA polyadenylation . It promotes mating-type switching in mother cells by positively regulating HO mRNA translation and forms a condensate in response to respiratory status to regulate TORC1 signalling . It is also involved in P-body-dependent granule assembly .

Cid3/4 may have a role in developmental pathways throughout the life cycle of plants .
SUN domain-containing protein 1-5 (SUN1-5)
Type: Family

Sad1/UNC-84 (SUN)-domain proteins are inner nuclear membrane (INM) proteins that are part of bridging complexes linking cytoskeletal elements with the nucleoskeleton. Originally identified based on an ~150-amino acid region of homology between the C terminus of the Schizosaccharomyces pombe Sad1 protein and the Caenorhabditis elegans UNC-84 protein, SUN proteins are present in the proteomes of most eucaryotes. In addition to the SUN domain, these proteins contain a transmembrane sequence and at least one coiled-coil domain and localise to the inner nuclear envelope. SUN proteins are anchored in the inner nuclear envelope by their transmembrane segment and oriented in the membrane such that the C-terminal SUN domain is located in the space between the inner and outer nuclear membrane. Here, the SUN domain can interact with the C-terminal tail of an outer nuclear envelope protein that binds to the cytoskeleton, including the centrosome .
SUN domain-containing Suco/Slp1-like (Suco/Slp1-like)
Type: Family

This entry represents a group of SUN domain-containing proteins, including Suco (SUN domain-containing ossification factor) from animals and Slp1 from yeasts. SUN-domain containing proteins contain three structural features: a transmembrane, a coiled-coil, and a SUN domain.

Suco regulates type I collagen synthesis in osteoblasts during their postnatal maturation . Slp1 is required for localization of MPS3 (a SUN domain-containing protein) to the nuclear envelope .
Coenzyme A pyrophosphatase (CoAse)
Type: Family

Coenzyme A pyrophosphatase (CoAse), a member of the Nudix hydrolase superfamily, functions to catalyse the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved Nudix fold and requires a single divalent cation for catalysis. In addition to a signature Nudix motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition . CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid synthesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules .

Proteins in this family include Nudt7 and Nudt8. Nudt7 mediates the cleavage of CoA, CoA esters and oxidized CoA with similar efficiencies, yielding 3',5'-ADP and the corresponding 4'-phosphopantetheine derivative as products. Preferentially hydrolyzes medium-chain acyl-CoAs and bile acid-CoAs . This entry also includes yeast Pcd1, which act as peroxisomal pyrophosphatase with specificity for coenzyme A and CoA derivatives .
Calcium permeable stress-gated cation channel 1-like (Csc1-like)
Type: Family

Csc1 is a cation channel that is permeable to calcium and gated by physical signals such as hyperosmotic stress .
N6-adenosine-methyltransferase non-catalytic subunit METTL14-like (METTL14-like)
Type: Family

In humans, the METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N6 position of some mRNAs and regulates the circadian clock, differentiation of embryonic stem cells and cortical neurogenesis . This entry also includes Kar4 from budding yeasts. Kar4 is a phosphoprotein required for expression of karyogamy-specific genes during mating and that it also acts during mitosis and meiosis . N6-adenosine-methyltransferase non-catalytic subunit MTB is another member of this family which associates with MTA, FIP37, VIR and HAKAI to form the so-called 'm6A writer complex' which is essential for adenosine methylation at specific mRNA sequences .
Protein suppressor of sable-like (Su(sable)-like)
Type: Family

This entry includes protein suppressor of sable (also known as Su(s)) from flies and related proteins from eukaryotes. They contain closely related CCCH zinc finger (ZF) motifs. Su(s) is a nuclear RNA-binding protein that inhibits the accumulation of certain aberrant mRNAs . It has been shown to interact with Wdr82, and together they inhibit Pol II elongation through Hsp70-alphabeta elements .
RNA polymerase II transcriptional coactivator Sub1/Tcp4-like (Sub1/Tcp4-like)
Type: Family

This entry represents a group of RNA polymerase II transcriptional coactivators, including Sub1 from budding yeasts, Tcp4 from animals and KIWI/KELP from plants.

Tcp4, also known as p15, is a coactivator that functions cooperatively with TAFs and mediates functional interactions between upstream activators and the general transcriptional machinery. It has a bipartite structure composed of an amino-terminal regulatory domain and a carboxy-terminal cryptic DNA-binding domain . The DNA-binding activity of the carboxy-terminal is disguised by the amino-terminal p15 domain. Activity is controlled by protein kinases that target the regulatory domain.

Sub1 facilitates elongation by influencing enzymes that modify RNAP II (RNA polymerase II) . It is required for NHEJ repair of DSBs in plasmid DNA, but not in chromosomal DNA .

KELP has been shown to bind to movement protein (MP) of tomato mosaic virus (ToMV) and interferes with virus cell-to-cell movement .
Trafficking protein particle complex subunit TRAPPC10/Trs130 (TRAPPC10/Trs130)
Type: Family

This entry includes human Trafficking protein particle complex subunit 10 (TRAPPC10), yeast Trafficking protein particle complex II-specific subunit 130 (Trs130) and similar eukaryotic proteins.

The trafficking protein particle complex TRAPP is a multi-protein complex needed in the early stages of the secretory pathway. To date, two kinds of TRAPP complexes have been studied, TRAPPI and TRAPP II. These complexes differ in subunit composition . TRAPP I binds vesicles derived from the endoplasmic reticulum bringing them closer to the acceptor membrane. TRAPPII activates GTPase Ypt31/Ypt32 as the guanine nucleotide exchange factor in the trans-Golgi network to determine the maturation of Golgi cisternae into post-Golgi carriers in yeast .

The TRAPPC10/Trs130 subunit of the TRAPP II complex functions in late Golgi trafficking as a membrane tether. TRAPPII binds the Ypt1 GTPase and probably uses the TRAPPI catalytic core to promote guanine nucleotide exchange. TRS130 plays a role in the YPT GEF activity of TRAPP II .
Transcription initiation factor TFIID subunit 11-like (TAF11-like)
Type: Family

TFIID is a multiprotein complex composed of the TATA binding protein and TBP-associated factors (TAFs), and is required for accurate and regulated initiation of transcription by RNA polymerase II. This entry represents TAF11, which together with TAF13 and TBP, play key roles during promoter binding by the TFIID and TFIIA transcription factor complexes .
Proteasome inhibitor PI31-like (PI31-like)
Type: Family

PI31 is a regulatory subunit of the immunoproteasome which is an inhibitor of the 20S proteasome in vitro. PI31 is also an Fbxo7.Skp1 binding partner. Fbxo7 is an F-box protein, which are the substrate-recognition components of the Skp1-Cul1-F box protein (SCF) E3 ubiquitin ligases. The interaction between PI31 and Fbxo7.Skp1 occurs via the β sheets of a N-terminal domain present in both proteins and known as FP(Fbxo7/PI31) domain. The structure of PI31 FP domain contains a novel α/β-fold and two intermolecular contact surfaces .
E3 ubiquitin-protein ligase RNF123/RKP/RSPRY1 (RNF123/RKP/RSPRY1)
Type: Family

This entry represents a group of RING finger-containing proteins, including RNF123/RSPRY1 from humans and RKP from Arabidopsis. The role of RSPRY1, while not fully understood, may involve bone development, as mutations in this protein are associated with skeletal dysplasia .

RNF123 is the catalytic subunit of the KPC complex and functions as an E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasome-mediated degradation of CDKN1B, a cyclin-dependent kinase inhibitor involved in the G0-G1 transition of the cell cycle . In addition to its E3 ligase activity, RNF123 also acts as an inhibitor of innate antiviral signalling mediated by DDX58 and IFIH1, functioning independently of its ligase activity .

RKP is an E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of KRP1 and KRP2 .
GDP-fucose protein O-fucosyltransferase 2-like (OFUT2-like)
Type: Family

Protein O-fucosylation is a post-translational modification found on serine/threonine residues of thrombospondin type 1 repeats (TSR). The fucose transfer is catalysed by the protein O-fucosyltransferase 2 (POFUT2) . POFUT2 is required for the proper secretion of ADAMTS (a disintegrin and metalloproteinase with thrombospondin type 1 repeats) family members such as ADAMSL1 and ADAMST13 .
CDGSH iron-sulfur domain-containing protein 1/2 (CISD1/2)
Type: Family

Proteins in this family contain the CDGSH-type zinc finger. Interestingly, they do not contain any zinc ions, but rather iron contained in a 2Fe-2S (iron-sulfur) cluster. The conserved sequence C-X-C-X(2)-(S/T)-X(3)-P-X-C-D-G-(S/A/T)-H is a defining feature of this unique family of proteins and is likely involved in iron binding . They play an important part in the proliferation of breast cancer cells and tumour formation . CISD1 (also known as mitoNEET) is a mitochondrial protein that plays an important part in mitochondrial bioenergetics. It also plays a part in insulin regulation, inflammation and autophagy . CISD2 (also known as NAF-1) can be found in endoplasmic reticulum (ER) and mitochondrial outer membrane . It regulates autophagy .

Mutations of the CISD2 gene cause Wolfram syndrome 2 (WFS2), a rare disorder characterised by juvenile-onset insulin-dependent diabetes mellitus with optic atrophy .
Ubiquitin conjugation factor E4 (UBE4)
Type: Family

E4 is an ubiquitin chain-elongation enzyme specifically involved in polyubiquitin chain assembly. It is involved in N-terminal ubiquitin fusion degradation proteolytic pathway (UFD pathway). E4 binds to the ubiquitin moieties of preformed conjugates and catalyses ubiquitin chain assembly in conjunction with E1, E2, and E3. E4 appears to influence the formation and topology of the multi-Ub chain as it enhances ubiquitination at 'Lys-48' but not at 'Lys-29' of the N-terminal Ub moiety .
Serine/threonine-protein kinase/endoribonuclease IRE1/2-like (IRE1/2-like)
Type: Family

This entry includes IRE1/2 and related proteins. Human IRE1 is a transmembrane protein kinase essential for the endoplasmic reticulum (ER) unfolded protein response (UPR) . IRE1 is activated by autophosphorylation through its cytoplasmic kinase domain, and this leads to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator .

Human IRE2 induces translational repression through 28S ribosomal RNA cleavage in response to ER stress . However, mouse IRE2 does not have this function, instead, it plays a role in expression of the DDIT3 transcription factor, required for the unfolded-protein response, growth arrest and apoptosis .
UHRF1/2-like (UHRF1/2-like)
Type: Family

This entry includes UHRF1/2 from animals and ORTHRUS 1-5 from Arabidopsis. They are ubiquitin-like proteins with PHD and RING finger domains. UHRF1, also known as ICBP90, is a transcription and cell cycle regulator and a methyl K9 H3-specific binding protein . UHRF2 is a ubiquitin E3 ligase for cell cycle proteins, such as CCND1 and CCNE1 . It can also act as a SUMO E3 ligase for ZNF131 . This family also includes UHRF1-like protein from Cryptococcus neoformans, which binds hemimethylated DNA and is involved in DNA methylation maintenance. Unlike the human orthologue, UHRF1-like lacks the Tudor H3K9me reader and RING E3 ligase domains found in its human ortholog .

In plants, ORTHRUS family members are E3 ligases mediating DNA methylation status in vivo. ORTH1-ORTH5 are predicted to encode proteins that contain one plant homeodomain (PHD), two really interesting new gene (RING) domains, and one set ring associated (SRA) domain .
26S proteasome regulatory subunit Rpn7, N-terminal (Rpn7_N)
Type: Domain

This entry represents the N-terminal domain found in Rpn7 and Csn1.

The 26S proteasome plays a major role in ATP-dependent degradation of ubiquitinated proteins. Substrate specificity is conferred by the regulatory particle (RP), which can dissociate into stable lid and base subcomplexes. The regulatory subunit RPN7 is one of the lid subunits of the 26S proteasome and has been shown in Saccharomyces cerevisiae to be required for structural integrity .

The COP9 signalosome is a conserved protein complex composed of eight subunits, where individual subunits of the complex have been linked to various signal transduction pathways leading to gene expression and cell cycle control . The overall organisation and the amino acid sequences of the COP9 signalosome subunits resemble the lid subcomplex of the 19 S regulatory particle for the 26 S proteasome . COP9 subunit 1 (CSN1 or GPS1) of the COP9 complex is an essential subunit of the complex with regard to both structural integrity and functionality. The N-terminal region of subunit 1 (CSN1-N) can inhibit c-fos expression from either a transfected template or a chromosomal transgene (fos-lacZ), and may contain the activity domain that confers most of the repression functions of CSN1. The C-terminal region of subunit 1 (CSN1-C) allows integration of the protein into the COP9 signalosome.
Isoamyl acetate-hydrolyzing esterase Iah1-like (Iah1-like)
Type: Family

This entry includes isoamyl acetate-hydrolyzing esterase Iah1 and related proteins. Iah1 hydrolyses short chain esters from acetate (C2) to hexanoate (C6), showing more specificity for shorter chain esters. There is no activity for decanoate (C10) esters .
RNA-binding protein 26/27 (RBM26/27)
Type: Family

This entry includes a group of RNA recognition motif domain containing proteins, including RBM27 and RBM26. The function of RBM27 is not clear.

RBM26, also known as cutaneous T-cell lymphoma (CTCL) tumor antigen se70-2, was identified as a cutaneous lymphoma (CL)-associated antigen . It contains two RNA recognition motifs (RRMs). The RRMs may play some functional roles in RNA-binding or protein-protein interactions.
Methyl-CpG binding protein MeCP2/MBD4 (MeCP2/MBD4)
Type: Family

Methyl-CpG-binding protein 2 (Mecp2) binds specifically to methylated DNA and represses transcription through the recruitment of chromatin remodeling complexes containing histone deacetylase activities . It is a multi-functional protein whose function depends on its protein partners and post-translational modifications . Mecp2 is required for proper mitotic spindle organisation and affects proliferation and apoptosis . Mutations in MeCP2 gene cause an X-linked neurodevelopmental disease known as Rett syndrome .

Methyl-CpG-binding domain protein 4 (MBD4) is a mismatch-specific DNA N-glycosylase involved in DNA repair. It has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites .
Aladin (Aladin)
Type: Family

Aladin (adracalin) is a nuclear envelope WD-repeat protein. It is encoded by the AAAS gene in humans. Aladin is a component of the nuclear pore complex, where it forms a heterodimer with nucleoporin NDC1 . It regulates Aurora A localisation to ensure robust mitotic spindle formation . There are two ALADIN-NDC1 dimers in each inner ring subunit, one on the cytoplasmic side and the other on the nuclear side . The ALADIN β-propellers are located in close proximity to the nuclear envelope. One side of the ALADIN β-propeller is targeted by 15 achalasia-addisonianism-alacrima syndrome (AAAS)-derived mutations. These mutations either alter the structure or damage the interaction of ALADIN with other proteins.