SII-SWORD/CoKE huggingface dataset:
DNA replication factor Cdt1 (Cdt1)
Type: Family

Precise duplication of chromosomal DNA is required for genomic stability during replication. A process called replication licensing ensures that chromosomes are replicated only once per cell cycle. To form a pre-replicative complex on replication origins in the G phase, ORC first binds origin DNA and triggers the binding of Cdc6 and Cdt1. These two factors recruit a putative replicative helicase and the MCM2-7. The MCM2-7 complex promotes the unwinding of DNA origins, and the binding of additional factors to initiate the DNA replication in S-phase. Cdt1 is present during G1 and early S phase of the cell cycle and degraded during the late S, G2, and M phases .

This entry represents Cdt1, which can be divided into three regions based on sequence comparison and biochemical analyses: the N-terminal region (Cdt1_n) binds DNA in a sequence-, strand-, and conformation-independent manner; the middle winged helix fold (Cdt1_m) binds geminin to inhibit both binding of the MCM complex to origins of replication and DNA; and the C-terminal region (Cdt1_c) is essential for Cdt1 activity and directly interacts with the MCM2-7 helicase. The winged helix fold structure of Cdt1_m is similar to the structures of Cdt1_c and other archaeal homologues of the eukaryotic replication initiator, without apparent sequence similarity .
Dof zinc finger protein (Dof)
Type: Family

Dof domain is a zinc finger DNA-binding domain that shows resemblance to the Cys2 zinc finger, although it has a longer putative loop where an extra Cys residue is conserved . Dof domain containing proteins are transcription factors that play various roles in plants .
Peptidase M28 family (M28_fam)
Type: Family

This family includes metallopeptidases from the MEROPS subfamilies A, C, E and F, including aminopeptidase S and Y, IAP from E. coli, Bacterial leucyl aminopeptidase Ap1, Leucine aminopeptidase 1/2 and YwaD from Bacillus subtilis.

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .
Protein transport protein Got1 (Got1)
Type: Family

Got1 is required for the fusion of ER-derived transport vesicles with the Golgi complex .
Factor of DNA methylation 1-5/IDN2 (FDM1-5/IDN2)
Type: Family

RNA-directed DNA methylation (RdDM) is a biological process in which non-coding RNA molecules direct the addition of DNA methylation to specific DNA sequences. This entry represents a sub-group of SGS3-LIKE plant proteins that are components of RNA-directed DNA methylation pathway (RdDM), including FDM1-5 and IDN2 from Arabidopsis . RdDM has been implicated in a number of regulatory processes in plants, such as maintaining transposable element silencing and genome stability, affecting gamete formation and seed viability and protecting the plant from other biotic stresses .
Transcription regulator Fhl1/FHA1 (Fhl1/FHA1)
Type: Family

This entry represents a group of transcription regulators, including Fhl1 from Saccharomyces cerevisiae and FHA1 from plants. Most of the proteins in this entry contain the forkhead-associated (FHA) domain, which is a phosphopeptide recognition domain found in many regulatory proteins. Fhl1 is a ribosomal protein (RP) transcription regulator that recruits coactivator Ifh1 or corepressor Crf1 to RP gene promoters .

Tobacco NtFHA1 consists of an N-terminal FHA domain and a C-terminal acidic region, but lacks a known DNA-binding motif. Its function in plants may be analogous to Fhl1 function in yeast . There are two Arabidopsis homologues of FHA1, designated AtFHA1 (At3g07260) and AtFHA2 (At3g07220). Their function is not clear, however, they have differential expression patterns during plant development. AtFHA2 has been shown to regulate stamen development .
YgfZ/GcvT (YgfZ/GcvT)
Type: Family

This entry includes glycine cleavage system T proteins (GcvT) and the bacterial tRNA-modifying protein YgfZ. This entry also includes Iron-sulfur cluster assembly factor IBA57 homolog, mitochondrial (CAF17) proteins from eukaryotes.

YgfZ is a folate-binding protein involved in regulating the level of ATP-dnaA and in the modification of some tRNAs. It is probably a key factor in regulatory networks that act via tRNA modification, such as initiation of chromosomal replication .
La domain containing protein (La_dom_prot)
Type: Family

Human Ro ribonucleoproteins (RNPs) are composed of one of the four small Y RNAs and at least two proteins, Ro60 and La. The La protein is a 47kDa polypeptide that frequently acts as an autoantigen in systemic lupus erythematosus and Sjogren's syndrome . In the nucleus, La acts as a RNA polymerase III (RNAP III) transcription factor, while in the cytoplasm, La acts as a translation factor . In the nucleus, La binds to the 3'UTR of nascent RNAP III transcripts to assist in folding and maturation . In the cytoplasm, La recognises specific classes of mRNAs that contain a 5'-terminal oligopyrimidine (5'TOP) motif known to control protein synthesis . The specific recognition is mediated by the N-terminal domain of La, which comprises a La motif and a RNA recognition motif (RRM). The La motif adopts an α/β fold that comprises a winged-helix motif .

Homologous La domain-containing proteins have been identified in a wide range of organisms except Archaea, bacteria and viruses .
Protein JINGUBANG-like (JINGUBANG-like)
Type: Family

JINGUBANG (JGB) is a WD40 repeats containing protein highly conserved in flowering plants. It interacts with TCP4, a JA biosynthesis-related transcription factor, and negatively regulates pollen germination .
F-box-like/WD repeat-containing protein Ebi-like (Ebi-like)
Type: Family

This entry includes a group of F-box-like/WD repeat-containing proteins, including Hif2/Sif2 from yeasts, swd3 from fission yeast, Ebi from Drosophila melanogaster, TBL1X /TBL1XR1 from humans and HOS15 from Arabidopsis. Hif2/Sif2 is part of the set3 histone deacetylase complex involved in chromatin remodeling and transcription regulation . Ebi promotes the degradation of a repressor of neuronal differentiation (Ttk88) and also limits S phase entry .

TBL1X /TBL1XR1 act as a bridge between the corepressor protein and histones by interacting with both of them within the complex. The N terminus of TBL1X interacts with the N termini of both H2B and H4 histones, and the first three C-terminal WD40-repeats of TBL1X interact with the corepressor complex . TBL1X /TBL1XR1 serve as specific adaptors for the recruitment of the ubiquitin conjugating/19S proteasome complex and are important for both formation and dismantling of the NCOR complex, which is a corepressor complex. Mutations of the TBL1XR1 gene have been linked to several neurodevelopmental disorders, such as spanning from autism spectrum disorders (ASD), West syndrome, schizophrenia (SCZ), intellectual disability .

HOS15 represses genes associated with abiotic stress tolerance through histone deacetylation in Arabidopsis .
WD40 repeat-containing protein SMU1 (SMU1)
Type: Family

SMU1 is a component of the spliceosome involved in pre-mRNA splicing . In Arabidopsis SMU1 and SMU2 are required for low-Mg tolerance through regulating the pre-mRNA splicing of the Mg2+ transporter gene MRS2-7 . In Caenorhabditis elegans SMU1 and SMU2 function together to regulate splice site choice in the pre-mRNAs of unc-52 and other genes .
E3 ubiquitin-protein ligase PUB22/23/24-like (PUB22/23/24-like)
Type: Family

This entry represents a group of plant U-box domain-containing proteins, including PUB22/23/24 from Arabidopsis. PUB22/23/24 are E3 ubiquitin ligases that act as negative regulators of PAMP-triggered immunity (PTI) . PUB22/PUB23 also coordinately control a drought signaling pathway by ubiquitinating cytosolic RPN12a .
Indole-3-glycerol phosphate synthase (Indole-3-glycerol_P_synth)
Type: Family

Indole-3-glycerol phosphate synthase (

) (IGPS) catalyses the fourth step in the biosynthesis of tryptophan, the ring closure of 1-(2-carboxy-phenylamino)-1-deoxyribulose into indol-3-glycerol-phosphate. In some bacteria, IGPS is a single chain enzyme . In others, such as Escherichia coli, it is the N-terminal domain of a bifunctional enzyme that also catalyses N-(5'-phosphoribosyl)anthranilate isomerase (

) (PRAI) activity), the third step of tryptophan biosynthesis .
Cytochrome c/quinol oxidase subunit II (CcO_II)
Type: Family

Cytochrome c oxidase (

) is an oligomeric enzymatic complex which is a component of the respiratory chain and is involved in the transfer of electrons from cytochrome c to oxygen. In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane. The number of polypeptides in the complex ranges from 3-4 (prokaryotes), up to 13 (mammals). In Archaea, a cytochrome-c-type oxidase from Natronobacterium (cytochrome ba3) has been shown to consists of four subunits .

Subunit 2 (CO II) transfers the electrons from cytochrome c to the catalytic subunit 1. It contains two adjacent transmembrane regions in its N terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrial intermembrane space, respectively. CO II provides the substrate-binding site and contains a copper centre called Cu(A), probably the primary acceptor in cytochrome c oxidase. An exception is the corresponding subunit of the cbb3-type oxidase which lacks the copper A redox-centre. Several bacterial CO II have a C-terminal extension that contains a covalently bound haem c.
PH domain containing protein Boi1/Boi2-like (Boi1/Boi2-like)
Type: Family

This entry represents a group of PH domain containing proteins, including Boi1/2 from budding yeasts and PKHJ1/Sesquipedalian1-2/PKHA3 from humans. Budding yeast Boi1/2 are involved in polar growth and required for fusion of secretory vesicles with plasma membrane at sites of polarised growth . Sesquipedalian-1/2 are inositol polyphosphate phosphatase interacting proteins required for receptor recycling from endosomes, both to the trans-Golgi network and to the plasma membrane . PKHA3 plays a role in regulation of vesicular cargo transport from the trans-Golgi network to the plasma membrane . It regulates Golgi phosphatidylinositol 4-phosphate (PtdIns4P) levels and activates the PtdIns4P phosphatase activity of SACM1L when it binds PtdIns4P in 'trans' configuration .
E3 ubiquitin ligase UBR4-like (UBR4-like)
Type: Family

This entry includes E3 ubiquitin ligase UBR4 from animals, auxin transport protein BIG from plants and protein purity of essence from fruit flies.

UBR4, also known as p600, is a member of the N-recognin family, which contains proven and predicted E3 ligases that recognise and degrade proteins containing destabilising N termini . It is involved in anoikis, viral transformation and protein degradation . It also has roles in neurogenesis, neuronal migration, neuronal signaling and survival in mammalian brains .

BIG is required for auxin efflux and polar auxin transport (PAT) influencing auxin-mediated developmental responses (e.g. cell elongation, apical dominance, lateral root production, inflorescence architecture, general growth and development) . Auxin transport protein is also involved in the elongation of the pedicels and stem internodes through auxin action, the expression/modulation of light-regulated genes, repression of CAB1 and CAB3 genes in etiolated seedlings, etc .

Protein purity of essence, found in Drosophila melanogaster, has a role in growth of the perineurial glial layer of the larval peripheral nerve and it may have a role in male fertility and eye development or function .
Methylcrotonoyl-CoA carboxylase beta chain MCCB/AccD1-like (MCCB/AccD1-like)
Type: Family

This entry represents a subgroup of acetyl-coenzyme A carboxyltransferase, including mitochondrial MCCB and bacterial AccD1. MCCB is a carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyses the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism . AccD1 transfers the CO2 from carboxybiotin to the CoA ester substrate in the biotin-dependent acyl-CoA carboxylase complex . This entry also includes GCDA from Acidaminococcus fermentans. It is the decarboxylase subunit of the primary sodium pump glutaconyl-CoA decarboxylase (GCD) .

Acetyl-coenzyme A carboxylase (

) (ACC), a member of the biotin-dependent enzyme family, catalyses the formation of malonyl-coenzyme A (CoA) and regulates fatty acid biosynthesis and oxidation. Biotin-dependent carboxylase enzymes perform a two step reaction: enzyme-bound biotin is first carboxylated by bicarbonate and ATP and the carboxyl group temporarily bound to biotin is subsequently transferred to an acceptor substrate such as acetyl-CoA. The carboxyltransferase domain performs the second part of the reaction .
E3 ubiquitin-protein ligase MBR1/2-like (MBR1/2-like)
Type: Family

This entry represents a group of confirmed and predicted E3 ubiquitin-protein ligases, including RHG1A/MBR1-2 from Arabidopsis and ARK2C found in human and mouse. MBR1 and MBR2 are E3 ubiquitin-protein ligases that function as regulator of MED25 (a subunit of the Mediator complex) stability by targeting MED25 for degradation in a RING-H2-dependent way . The function of RHG1A is not known. In mouse, ARK2C acts as a regulator of motor axon elongation . It is required for efficient motor axon extension in the dorsal forelimb by enhancing the transcriptional responses of the SMAD1/SMAD5/SMAD8 effectors, which are activated downstream of BMP.
Clathrin coat assembly protein AP180-like (AP180-like)
Type: Family

Clathrin mediated endocytosis (CME) is a transmembrane cargo and ligand internalisation process that uses a clathrin coat to form vesicles . During this process, clathrin needs to be connected to the membrane through adapter proteins, such as the main adapter AP2 (adapter protein complex 2) and AP180. AP180 assembles clathrin faster than any other protein examined in vitro . Mammalian AP180 is only detectable in neurons, where it is strongly enriched within pre-synaptic boutons . It has been shown that synapses with mutated or disrupted AP180 fail to produce a sufficient number of synaptic vesicles .

This entry includes AP180 and related proteins.
E3 ubiquitin-protein ligase MGRN1/RNF157-like (MGRN1/RNF157-like)
Type: Family

This entry represents a group of confirmed and predicted E3 ubiquitin ligases, including MGRN1/RNF157 from humans and LOG2/LUL1-4 from Arabidopsis.

MGRN1 is a cytosolic E3 ubiquitin-protein ligase that inhibits signalling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes . It suppresses chaperone-associated misfolded protein aggregation and toxicity . MGRN1 interacts with cytosolic prion proteins (PrPs) that are linked with neurodegeneration
. It also interacts with expanded polyglutamine proteins, and suppresses misfolded polyglutamine aggregation and cytotoxicity. Moreover, MGRN1 inhibits melanocortin receptor signalling by competition with Galphas, suggesting a novel pathway for melanocortin signalling from the cell surface to the nucleus . Furthermore, MGRN1 interacts with and ubiquitylates TSG101, a key component of the endosomal sorting complex required for transport (ESCRT)-I, and regulates endosomal trafficking. A null mutation in the gene encoding MGRN1 causes spongiform neurodegeneration, suggesting a link between dysregulation of endosomal trafficking and spongiform neurodegeneration .

RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in brain. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localisation of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognised by T cells 3 or Tip110) is crucial to trigger apoptosis . Both MGRN1 and RNF157 contain a modified C3HC5-type RING-HC finger, and a functionally uncharacterised region, known as domain associated with RING2 (DAR2), N-terminal to the RING finger.

In Arabidopsis, LOG2 is a predicted E3 ubiquitin ligase that interact with GDU1 and is involved in the regulation of amino acid export from plant cells .
LOG2-like, modified RING finger, C3HC5-type (LOG2-like_mRING_C3HC5)
Type: Domain

This entry represent the C3HC5-type RING-HC finger found in the probable E3 ubiquitin-protein ligase LOG2 and LOG2-like Ubiquitin Ligases (LUL1-4) from Arabidopsis. LOG2 (also known as AtAIRP3) is a predicted E3 ubiquitin ligase that interact with GDU1 and is involved in the regulation of amino acid export from plant cells . It also functions in ABA-mediated drought stress responses . This domain is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.
Translation initiation factor IF2/IF5 (IF2/IF5)
Type: Family

The beta subunit of archaeal and eukaryotic translation initiation factor 2 (IF2beta) and the N-terminal domain of translation initiation factor 5 (IF5) show significant sequence homology . Archaeal IF2beta contains two independent structural domains: an N-terminal mixed α/β core domain (topological similarity to the common core of ribosomal proteins L23 and L15e), and a C-terminal domain consisting of a zinc-binding C4 finger . Archaeal IF2beta is a ribosome-dependent GTPase that stimulates the binding of initiator Met-tRNA(i)(Met) to the ribosomes, even in the absence of other factors . The C-terminal domain of eukaryotic IF5 is involved in the formation of the multi-factor complex (MFC), an important intermediate for the 43S pre-initiation complex assembly. IF5 interacts directly with IF1, IF2beta and IF3c, which together with IF2-bound Met-tRNA(i)(Met) form the MFC .
Nuclear pore membrane glycoprotein 210-like (NUP210-like)
Type: Family

This entry includes Nuclear pore membrane glycoprotein 210 (NUP210) and related proteins from eukaryotes. They are nucleoporins essential for nuclear pore assembly and fusion, nuclear pore spacing, as well as structural integrity . This entry also includes some uncharacterised proteins from bacteria and viruses.
Calcineurin B-like (CNBL1-10)
Type: Family

CBL proteins are calcium sensors that work with their interacting protein kinases (CIPKs) in the plant calcium signalling system . In Arabidopsis there are 10 CBL Ca2+ sensors and 26 CIPK-type kinases encoded in the genome. Different combinations of CBL-CIPK proteins contribute to the complex network that connects various extracellular signals to defined cellular responses .
ATPase family AAA domain-containing protein ATAD2-like (ATAD2-like)
Type: Family

This entry represents a group of AAA domain-containing protein, including ATAD2/ATD2B from humans, Tat-binding homolog 7 from Caenorhabditis elegans (Lex-1) and Saccharomyces cerevisiae (Yta7), and ATPase with bromodomain protein abo1/2 from S. pombe.

ATPase family AAA domain-containing protein 2, also known as ANCCA, is a transcriptional coactivator for estrogen-bound estrogen receptor (ER) alpha and androgen receptor . It is required for coregulator occupancy and chromatin modification . ANCCA is also required for recruiting specific E2Fs to their targets and for the assembly of the HCF-MLL hKMT complex, a complex that regulates cell cycle progression . Overexpression of ANCCA has been linked to various cancers .

In Caenorhabditis elegans, Lex-1 affects chromatin structure and promotes expression from repetitive sequences .

In Saccharomyces cerevisiae, Yta7 binds to histones and regulates transcription of histones and other gene .
CHIP , U-box domain (CHIP_RING-Ubox)
Type: Domain

This entry represents the RING-like U-box domain found in E3 ubiquitin-protein ligase CHIP.

CHIP is a multifunctional protein that functions both as a co-chaperone and an E3 ubiquitin-protein ligase. It couples protein folding and proteasome mediated degradation by interacting with heat shock proteins (e.g. HSC70) and ubiquitinating their misfolded client proteins thereby targeting them for proteasomal degradation . It is also important for cellular differentiation and survival (apoptosis), as well as susceptibility to stress. It targets a wide range of proteins, such as expanded ataxin-1, ataxin-3, huntingtin, and androgen receptor, which play roles in glucocorticoid response, tau degradation, and both p53 and cAMP signaling .
RAN GTPase-activating protein 1/2 (RanGAP1/2)
Type: Family

This entry includes RanGAP1/2 mostly from plants. They are GTPase activators for the nuclear Ras-related regulatory protein Ran, converting it to the putatively inactive GDP-bound state . RanGAP1 may have a role in spatial signaling during plant cell division .
Laforin-like, dual specificity phosphatase domain (DSP_laforin-like)
Type: Domain

Proteins containing this domain include vertebrate dual specificity protein phosphatase Laforin and plant starch excess4 (SEX4).

Laforin (encoded by the EPM2A gene) is a dual-specificity phosphatase that dephosphorylates complex carbohydrates. Mutations in the EPM2A gene cause Lafora disease (LD), a fatal autosomal recessive neurodegenerative disorder characterised by the presence of progressive neurological deterioration, myoclonus, and epilepsy . Pathologically, LD is characterised by distinctive polyglucosans, which are formations of abnormal glycogen . Laforin prevents LD by at least two mechanisms: by preventing hyperphosphorylation of glycogen by dephosphorylating it, allowing proper glycogen formation, and by promoting the ubiquitination of proteins involved in glycogen metabolism via its interaction with malin. Laforin contains an N-terminal CBM20 (carbohydrate-binding module, family 20) domain and a C-terminal catalytic dual specificity phosphatase (DSP) domain .

Plant SEX4 (also known as DSP4) regulates starch metabolism by selectively dephosphorylating glucose moieties within starch glucan chains. It contains an N-terminal catalytic DSP domain and a C-terminal Early (E) set domain .
Maestro heat-like repeat-containing protein (Maestro_heat-like_prot)
Type: Family

This entry represents a group of maestro heat-like repeat-containing proteins, including protein Maestro and SPIF from animals, and SGR6 from Arabidopsis. They contain HEAT repeats motif or regions that are highly similar to HEAT repeats.

Maestro (Male-specific Transcription in the developing Reproductive Organs (MRO)) is expressed in human granulosa cumulus cells and in testicular germ cells . SPIF may play a role in the process of sperm capacitation .

SGR6 (SHOOT GRAVITROPISM6) is a membrane-associated protein involved in the formation and/or maintenance of invaginated vacuolar membrane structures in gravity-sensing cells .