SII-SWORD/CoKE huggingface dataset:
Non-structural protein NSP15, N-terminal domain superfamily, coronavirus (NSP15_N_CoV)
Type: Homologous_superfamily

The unique coronavirus transcription/replication machinery comprised of multiple virus-encoded non structural proteins (NSP) plays a vital role during initial and intermediate phases of the viral life cycle. NSP15 forms a hexamer made of dimers of trimers which is suggested to be a functional unit, responsible for the endoribonuclease activity. The NSP15 monomer consists of three domains: N-terminal, middle and C-terminal . The catalytic function of NSP15 resides in the C-terminal NendoU domain. The active site carries six key residues conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, suggesting that its activity is important for sustained replication in the host .

This superfamily represents the N-terminal oligomerization domain of NSP15, which is an uridine-specific endonuclease . This domain stabilises the hexamer and is critical for its formation . Structurally, this domain consists of 2 small α-helices and 3 β-strands.
Pre-mRNA-processing-splicing factor 8, U5-snRNA-binding domain superfamily (Prp8_U5-snRNA-bd_sf)
Type: Homologous_superfamily

The essential spliceosomal protein Prp8 interacts with U5 and U6 snRNAs and with specific pre-mRNA sequences that participate in catalysis . This close association with crucial RNA sequences, together with extensive genetic evidence, suggests that Prp8 could directly affect the function of the catalytic core, perhaps acting as a splicing cofactor .

This superfamily represents the U5-snRNA-binding domain of the pre-mRNA-processing-splicing factor 8 (Prp8). Structurally, this domain consists of 4 anti-parallel β sheets and 3 α helices.
Beta-1,3-glucanase, N-terminal, subdomain 2 (Glyco_hydro_64_N_2)
Type: Homologous_superfamily

This superfamily represents the subdomain 2 found in the N-terminal domain of glucan endo-1,3-beta-glucosidase, which constitutes the glycoside hydrolase family 64 and has beta-1,3-glucanase activity . Structurally, this subdomain consists of 3 α helices and 5 β sheets.
Precorrin-2 dehydrogenase, C-terminal helical domain (SirC_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal helical domain of precorrin-2 dehydrogenase SirC. Its function is unknown.

Precorrin-2 dehydrogenase (sirC) catalyzes the dehydrogenation of precorrin-2 to form sirohydrochlorin, a precursor in siroheme biosynthesis and in anaerobic adenosylcobalamin biosynthesis . SirC is composed of three structural domains: an NAD -binding domain, a central dimerization domain and a C-terminal helical domain .
Non-structural protein NSP3, N-terminal, rotavirus (NSP3_N_rotavirus)
Type: Homologous_superfamily

The NSP3 protein has been shown to bind viral RNA. It consists of 3 conserved functional domains; a basic region which binds ssRNA, a region containing heptapeptide repeats mediating oligomerisation and a leucine zipper motif . NSP3 may play a central role in replication and assembly of genomic RNA structures . Rotaviruses have a dsRNA genome and are a major cause of acute gastroenteritis in the young of many species .

The NPS3 homodimer fold has two domains, one all-alpha and the other alpha beta. It is asymmetric with each domain intertwining with its counterpart.

This entry represents the N-terminal domain of NSP3 from rotavirus. It consists of 5 α helices.
Glutamate--cysteine ligase GshA, N-terminal (GshA_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain found in a rare family of glutamate--cysteine ligases, demonstrated first in Thiobacillus ferrooxidans and present in a few other Proteobacteria . It is the first of two enzymes for glutathione biosynthesis. It is also called gamma-glutamylcysteine synthetase.

Structurally, this domain consists of 3 α helices and 9 β strands.
Dual specificity tyrosine-phosphorylation-regulated kinase (DYRK)
Type: Homologous_superfamily

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key roles in brain development, regulation of splicing, and apoptosis, and are potential drug targets for neurodegenerative diseases and cancer . All DYRKs contain a conserved catalytic kinase domain preceded by the DYRK-characteristic DYRK homology (DH) box .
Ubiquitin-like modifier-activating enzyme Atg7, N-terminal, subdomain 1 (Atg7_N_1)
Type: Homologous_superfamily

This superfamily represents the first subdomain found in the N-terminal domain of ubiquitin-like modifier-activating enzyme Atg7. In Arabidopsis, the N-terminal domain binds the E2 enzymes Atg10 and Atg3 .
Ubiquitin-like modifier-activating enzyme Atg7, N-terminal, subdomain 2 (Atg7_N_2)
Type: Homologous_superfamily

This superfamily represents the second subdomain found in the N-terminal domain of ubiquitin-like modifier-activating enzyme Atg7. In Arabidopsis, the N-terminal domain binds the E2 enzymes Atg10 and Atg3 .
Presenilin, C-terminal (Presenilin_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal region of aspartic peptidases belonging to the MEROPS peptidase family A22 (presenilin family), subfamily A22A, the type example being presenilin 1 from Homo sapiens (Human).

Presenilins are polytopic transmembrane (TM) proteins, mutations in which
are associated with the occurrence of early-onset familial Alzheimer's
disease, a rare form of the disease that results from a single-gene
mutation . Alzheimer's disease is associated with the formation of extracellular deposits of amyloid, which contain aggregates of the amyloid-beta peptide. The β-peptides are released from the Alzheimer's amyloid precursor protein (APP) by the action of two peptidase activities: "beta-secretase" cleaves at the N terminus of the peptide, and "gamma-secretase" cleaves at the C terminus. The gamma-secretase cleavage occurs in a transmembrane segment of APP. Presenilin, which exists in a complex with nicastrin, APH-1 and PEN-2, has been identified as gamma-secretase from its deficiency and mutation of its active site residues , but proteolytic activity has only been directly demonstrated on a peptide derived from APP .

Presenilin-1 is also known to process notch proteins and syndecan-3 .

Presenilin has nine transmembrane regions with the active site aspartic acid residues located on TM6, within a Tyr-Asp motif, and TM7, within a Gly-Xaa-Gly-Asp motif . The protein autoprocesses to form an amino-terminal fragment (TMs 1-6) and a C-terminal fragment (TMs 7-9) . The tertiary structure of the human gamma-sectretase complex has been solved . Nicastrin is extracellular, whereas presenilin-1, APH-1 and PEN-2 are all transmembrane proteins. The transmembrane regions of all three proteins form a horseshoe shape.
DNA repair protein Rad52/59/22 superfamily (Rad52_Rad59_Rad22_sf)
Type: Homologous_superfamily

The DNA single-strand annealing proteins (SSAPs), such as RecT, Red-beta, ERF and Rad52, function in RecA-dependent and RecA-independent DNA recombination pathways. This superfamily includes proteins related to Rad52. These proteins contain two helix-hairpin-helix motifs .

Rad52 was identified in Saccharomyces cerevisiae (Baker's yeast) as a component of the homologous recombination repair pathway and to play an important role in both meiotic and mitotic recombination. The human protein is highly homologous in both structure and function. In the presence of absence of DNA, Rad52 forms ring-shaped oligomers which bind both single and double stranded DNA, stimulating annealing of complimentary DNA strands and promoting ligation of both cohesive and blunt-end fragments. Rad52 may act as a recombination mediator, optimising catalysis of strand exchange by the Rad51 protein.

A C-terminal self-association domain has been identified that mediates formation of higher order oligomers of Rad52 rings. Formation of these oligomers may be important for interaction with more than one DNA molecule .
Autophagy protein Atg5, helix rich domain (Atg5_HR)
Type: Homologous_superfamily

Macroautophagy is a bulk degradation process induced by starvation in eukaryotic cells. In yeast, 15 Atg proteins coordinate the formation of autophagosomes. The pre-autophagosomal structure contains at least five Atg proteins: Atg1p, Atg2p, Atg5p, Aut7p/Atg8p and Atg16p, found in the vacuole . The C-terminal glycine of Atg12p is conjugated to a lysine residue of Atg5p via an isopeptide bond. During autophagy, cytoplasmic components are enclosed in autophagosomes and delivered to lysosomes/vacuoles. Autophagy protein 16 (Atg16) has been shown to bind to Atg5 and is required for the function of the Atg12p-Atg5p conjugate . Autophagy protein 5 (Atg5) is directly required for the import of aminopeptidase I via the cytoplasm-to-vacuole targeting pathway .

Atg5 comprises two ubiquitin-like domains that flank a helix-rich domain. The N- and C-terminal ubiquitin-like domains are called UblA and UblB, respectively, and the helix-rich domain between UblA and UblB, is called HR. Both UblA and UblB comprise a five-stranded -sheet and two-helices, which is a conserved feature in all ubiquitin superfamily proteins. The HR domain consists of three α helices .

This superfamily represents the helix rich domain (HR) found in Atg5.
Autophagy protein Atg5, UblA domain superfamily (Atg5_UblA_dom_sf)
Type: Homologous_superfamily

Macroautophagy is a bulk degradation process induced by starvation in eukaryotic cells. In yeast, 15 Atg proteins coordinate the formation of autophagosomes. The pre-autophagosomal structure contains at least five Atg proteins: Atg1p, Atg2p, Atg5p, Aut7p/Atg8p and Atg16p, found in the vacuole . The C-terminal glycine of Atg12p is conjugated to a lysine residue of Atg5p via an isopeptide bond. During autophagy, cytoplasmic components are enclosed in autophagosomes and delivered to lysosomes/vacuoles. Autophagy protein 16 (Atg16) has been shown to bind to Atg5 and is required for the function of the Atg12p-Atg5p conjugate . Autophagy protein 5 (Atg5) is directly required for the import of aminopeptidase I via the cytoplasm-to-vacuole targeting pathway .

Atg5 comprises two ubiquitin-like domains that flank a helix-rich domain. The N- and C-terminal ubiquitin-like domains are called UblA and UblB, respectively, and the helix-rich domain between UblA and UblB, is called HR. Both UblA and UblB comprise a five-stranded -sheet and two-helices, which is a conserved feature in all ubiquitin superfamily proteins. The HR domain consists of three α helices .

This superfamily represents the UblA domain.
Translation initiation factor eIF-2B subunit alpha, N-terminal (elF-2B_alpha_N)
Type: Homologous_superfamily

Translation initiation factor 2 binds to Met-tRNA, GTP and the small ribosomal subunit. The eukaryotic translation initiation factor eIF-2B is a complex which comprises five different subunits, alpha, beta, gamma, delta and epsilon, and catalyses the exchange of eIF-2-bound GDP for GTP .

This superfamily represents the N-terminal α helical domain of the translation initiation factor (eIF-2B) alpha subunit from eukaryotes.
Initiation factor 2B-like, C-terminal (IF_2B-like_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain of the eukaryotic translation initiation factor (eIF-2B) and are found in initiation factor 2B alpha, beta and delta subunits from eukaryotes; related proteins from archaebacteria and IF-2 from prokaryotes in addition to a subfamily of proteins in eukaryotes, archaea, or eubacteria.

Initiation factor 2 binds to Met-tRNA, GTP and the small ribosomal subunit. The eukaryotic translation initiation factor EIF-2B is a complex made up of five different subunits, alpha, beta, gamma, delta and epsilon, and catalyses the exchange of EIF-2-bound GDP for GTP. This family includes initiation factor 2B alpha, beta and delta subunits from eukaryotes; related proteins from archaebacteria and IF-2 from prokaryotes and also contains a subfamily of proteins in eukaryotes, archaeae (e.g. Pyrococcus furiosus), or eubacteria such as Bacillus subtilis and Thermotoga maritima. Many of these proteins were initially annotated as putative translation initiation factors despite the fact that there is no evidence for the requirement of an IF2 recycling factor in prokaryotic translation initiation. Recently, one of these proteins from B. subtilis has been functionally characterised as a 5-methylthioribose-1-phosphate isomerase (MTNA) . This enzyme participates in the methionine salvage pathway catalysing the isomerisation of 5-methylthioribose-1-phosphate to 5-methylthioribulose-1-phosphate . The methionine salvage pathway leads to the synthesis of methionine from methylthioadenosine, the end product of the spermidine and spermine anabolism in many species.
EME1/EME2, C-terminal domain (EME1/EME2_C)
Type: Homologous_superfamily

This superfamily includes the C-terminal domain found in Eme1 from fission yeasts, and EME1/EME2 from animals. They interact with Mus81 to from a complex, which acts as a structure-specific endonuclease that targets branched DNA structures with a 5'-end at the branch nick . The typical substrates of this complex include 3'-flap structures, replication forks and nicked Holliday junctions .

Similar to MUS81-EME1, human MUS81-EME2 cleaves 3'-flaps, replication forks and nicked Holliday junctions, and exhibits limited endonuclease activity with intact Holliday junctions. However, MUS81-EME2 can also cleave a variety of DNA structures including D-loop recombination intermediates and nicked duplex .

Both Mus81 and Eme1 consist of a central nuclease domain, two repeats of the helix-hairpin-helix (HhH) motif at their C-terminal region, and a linker helix .
Phospholipase C-beta, C-terminal domain superfamily (PLC-beta_C_sf)
Type: Homologous_superfamily

The distal α helical C-terminal domain (CTD) of phospholipase C beta (PLC-beta) has key roles in membrane targeting and in optimising the orientation of the catalytic core at the membrane for maximal rates of lipid hydrolysis. Structurally, it consists of a helical bundle with three antiparallel segments .
Exocyst complex component EXOC3/Sec6, C-terminal domain (EXOC3/Sec6_C)
Type: Homologous_superfamily

Sec6 is a component of the multiprotein exocyst complex. Sec6 interacts with Sec8, Sec10 and Exo70. These exocyst proteins localise to regions of active exocytosis-at the growing ends of interphase cells and in the medial region of cells undergoing cytokinesis-in an F-actin-dependent and exocytosis-independent manner .

This superfamily represents the C-terminal domain found in EXOC3/Sec6. Structurally, this domain consists of multiple helical bundles .
Nucleoporin, Nup155-like, C-terminal, subdomain 1 (Nucleoporin_Nup155_C_1)
Type: Homologous_superfamily

Nucleoporins are the main components of the nuclear pore complex (NPC) in eukaryotic cells, and mediate bidirectional nucleocytoplasmic transport, especially of mRNA and proteins. RNA undergoing nuclear export first encounters the basket of the nuclear pore and many nucleoporins are accessible on the basket side of the pore .

The S. Cerevisiae Nup-170, equivalent to the human Nup-155, contains two structural domains: an N-terminal β-propeller and a C-terminal α-helical domain .

This superfamily represents the subdomain 1 of the C-terminal region found in nucleoporins Nup-155.
Sin3 associated polypeptide p18 superfamily (SAP18_sf)
Type: Homologous_superfamily

This superfamily includes several eukaryotic Sin3 associated polypeptide p18 (SAP18) sequences. SAP18 is known to be a component of the Sin3-containing complex which is responsible for the repression of transcription via the modification of histone polypeptides . SAP18 (UBL domain) is one of the three three ASAP subunits (along with Acinus (β-hairpin motif) and RNPS1 (RRM domain)) that play a role in programmed cell death, transcriptional regulation, pre-mRNA splicing and mRNA quality control . The ASAP complex interacts with the exon-junction complex (EJC), a messenger ribonucleoprotein complex involved in post-transcriptional regulation .

The high degree of evolutionary conservation and the fortuitous crystal contacts at the α-β groove suggest that this surface of SAP18 is a hot spot for interactions. Possible binding partners targeting this surface of SAP18 are transcription factors (such as Bicoid and Kruppel) and/or Sin3a-HDAC subunits.
TFIIIC, subcomplex tauA subunit Sfc1, triple barrel domain superfamily (TFIIIC_tauA_Sfc1)
Type: Homologous_superfamily

TFIIIC (transcription factor III C) is a multisubunit complex, divided in 2 subcomplexes, tauA and tauB, that recognise and bind to A-box and B-box gene promoters . This superfamily represents the N-terminal domain of Sfc1 (also known as Tfc1 in budding yeasts and GTF3C5 in humans), a subunit of the subcomplex tauA. The N-terminal Sfc1/Sfc7 dimerization module consists of a triple β-barrel, whereas the C-terminal Sfc1 DNA-binding domain contains a winged-helix domain .
Nucleoporin, Nup155-like, C-terminal, subdomain 2 (Nucleoporin_Nup155_C_2)
Type: Homologous_superfamily

Nucleoporins are the main components of the nuclear pore complex (NPC) in eukaryotic cells, and mediate bidirectional nucleocytoplasmic transport, especially of mRNA and proteins. RNA undergoing nuclear export first encounters the basket of the nuclear pore and many nucleoporins are accessible on the basket side of the pore .

The S. Cerevisiae Nup-170, equivalent to the human Nup-155, contains two structural domains: an N-terminal β-propeller and a C-terminal α-helical domain .

This superfamily represents the subdomain 2 of the C-terminal region found in nucleoporins Nup-155.
Nucleoporin, Nup155-like, C-terminal, subdomain 3 (Nucleoporin_Nup155_C_3)
Type: Homologous_superfamily

Nucleoporins are the main components of the nuclear pore complex (NPC) in eukaryotic cells, and mediate bidirectional nucleocytoplasmic transport, especially of mRNA and proteins. RNA undergoing nuclear export first encounters the basket of the nuclear pore and many nucleoporins are accessible on the basket side of the pore .

The S. Cerevisiae Nup-170, equivalent to the human Nup-155, contains two structural domains: an N-terminal β-propeller and a C-terminal α-helical domain .

This superfamily represents the subdomain 3 of the C-terminal region found in nucleoporins Nup-155.
Viral matrix protein, C-terminal domain (Matrix_C)
Type: Homologous_superfamily

The matrix protein plays a crucial role in virus assembly, and interacts with the RNP complex as well as with the viral membrane. It is found in Morbillivirus, Paramyxovirus, Pneumovirus.

Viral matrix proteins are built of two domains that have similar β-sandwich folds, N-terminal and C-terminal respectively, suggesting a gene duplication during evolution .

This superfamily represents the C-terminal domain of the viral matrix protein.
Viral matrix protein, N-terminal domain (Matrix_N)
Type: Homologous_superfamily

The matrix protein plays a crucial role in virus assembly, and interacts with the RNP complex as well as with the viral membrane. It is found in Morbillivirus, Paramyxovirus, Pneumovirus.

Viral matrix proteins are built of two domains that have similar β-sandwich folds, N-terminal and C-terminal respectively, suggesting a gene duplication during evolution .

This superfamily represents the N-terminal domain of the viral matrix protein.
BART domain superfamily (BART_sf)
Type: Homologous_superfamily

This domain superfamily is found in ADP-ribosylation factor-like 2 (ARF2) binding protein, also known as BART. BART binds specifically to ARF2.GTP with a high affinity. However, it does not bind to ARF2.GDP. It is thought that this specific interaction is due to BART being the first identified ARF2-specific effector. The function is not completely characterised . BART is predominantly cytosolic but can also be found to be associated with mitochondria. BART is also involved in binding to the adenine nucleotide transporter ANT1 .

The interactions between ARL2 and BART involve a conserved N-terminal LLxIL motif of ARL2 . This domain is also found in CFAP36/CCDC104, a protein renamed as BARTL1. The BART-like domain of CCDC104/BARTL1 recognizes an LLxILxxL motif at the N-terminal amphipathic helix of ARL3 .
S-adenosylmethionine synthetase, domain 2 (AdoMet_synthase_2)
Type: Homologous_superfamily

S-adenosylmethionine synthetase (MAT,

) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP . AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.

In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.

The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance .

This superfamily represents the second domain found in S-adenosylmethionine synthase. Structurally, this domain consists of 5 β strands and 3 α helices.
S-adenosylmethionine synthetase, domain 3 (AdoMet_synthase_3)
Type: Homologous_superfamily

S-adenosylmethionine synthetase (MAT,

) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP . AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.

In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.

The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance .

This superfamily represents the C-terminal domain found in S-adenosylmethionine synthase. Structurally, this domain consists of 6 β strands and 3 α helices. Within S-adenosylmethionine synthetase, the domain is not made up a contiguous polypeptide chain, and has some residues contributed from regions away from the C-terminal.