SII-SWORD/CoKE huggingface dataset:
Aspartokinase/Bifunctional aspartokinase/homoserine dehydrogenase, catalytic domain (AsparK_Bifunc_asparK/hSer_DH)
Type: Homologous_superfamily

Aspartokinase is the first enzyme in the aspartate metabolic pathway and catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP. In Bacillus subtilis, YclM is reported to be a single polypeptide of 50 kD. The B. subtilis 168 AKIII is induced by lysine and repressed by threonine, and it is synergistically inhibited by lysine and threonine .

The bifunctional enzyme aspartokinase/homoserine dehydrogenase (AK-HSDH), found in bacteria and plant chloroplasts, catalyses the first and third steps of the aspartate pathway. Homoserine dehydrogenase (

) catalyses the conversion of L-homoserine to L-aspartate-4-semialdehyde using NAD(P), while aspartate kinase (

) catalyses the phosphorylation of L-aspartate to 4-phospho-L-aspartate. There are two genes encoding different isoforms of this bifunctional enzymes; one isoform is threonine-sensitive, while the other is methionine-sensitive .

This superfamily represents the N-terminal catalytic domain found in aspartokinase and in the bifunctional enzyme aspartokinase/homoserine dehydrogenase. It has a key role in amino acid binding.
Formin, FH2 domain superfamily (FH2_Formin_sf)
Type: Homologous_superfamily

Formin homology (FH) proteins play a crucial role in the reorganisation of the actin cytoskeleton, which mediates various functions of the cell cortex including motility, adhesion, and cytokinesis . Formins are multidomain proteins that interact with diverse signalling molecules and cytoskeletal proteins, although some formins have been assigned functions within the nucleus. Formins are characterised by the presence of three FH domains (FH1, FH2 and FH3), although members of the formin family do not necessarily contain all three domains . The proline-rich FH1 domain mediates interactions with a variety of proteins, including the actin-binding protein profilin, SH3 (Src homology 3) domain proteins, and WW domain proteins. The FH2 domain is required for the self-association of formin proteins through the ability of FH2 domains to directly bind each other , and may also act to inhibit actin polymerisation . The FH3 domain (

) is less well conserved and may be important for determining intracellular localisation of formin family proteins. In addition, some formins can contain a GTPase-binding domain (GBD) (

) required for binding to Rho small GTPases, and a C-terminal conserved Dia-autoregulatory domain (DAD).

This superfamily represents the FH2 domain, which was shown by X-ray crystallography to have an elongated, crescent shape containing three helical subdomains .
Duffy-antigen binding superfamily (Duffy-ag-bd_sf)
Type: Homologous_superfamily

This superfamily represents the duffy-antigen binding domain, found on Plasmodium parasite proteins and which mediate the molecular processes that govern pathogenic features of erythrocyte invasion and cytoadherence in malaria. These are cysteine-rich modules that recognize diverse host cell-surface receptors during pathogenesis. Duffy binding-like (DBL) domain containing proteins constitute potential vaccine candidates .

However, a main problem is the variable nature of DBL domain as they present low sequence identity but a conserved molecular architecture. This enables them to maintain ligand binding while evading the immune response and will guide future drug and vaccine development. This is achieved through the presence of polymorphic loops that immediately surround regions of functional importance as these surfaces are accessible to both ligand and immune system. Structural studies on chondroitin sulfate-binding DBL3X domain show the way this is achieved. The sulfate-binding loop is polymorphic and is flexible in the absence of ligand and it cover the partial putative CSA-binding surface underneath, protecting its conserved features from the immune detection. In the presence of a sulfate ion, alone or as part of a polysaccharide, the loop folds completing a positively charged patch that can form electrostatic interactions with other parts of the CSA molecule, generating the binding site .
Leucyl/phenylalanyl-tRNA-protein transferase, C-terminal (Leu/Phe-tRNA_Trfase_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain of leucyl/phenylalanyl-tRNA-protein transferases (L/F-transferases).

L/F-transferase is an N-end rule pathway enzyme, involved in the transfer of Leu and Phe from aminoacyl-tRNAs to exposed N-terminal Arg or Lys residues of acceptor proteins . This C-terminal domain has a highly conserved fold, observed in the GCN5-related N-acetyltransferase (GNAT) family.
The interface of the N-terminal and C-terminal domains forms a large central cavity, with the characteristic positive charge contributed by the corner of the cleft on the C-terminal domain surface, suggesting that they probably complement the negatively charged phosphate backbone of the substrate aminoacyl-tRNA .
2Fe-2S iron-sulfur cluster binding domain, N-terminal (2Fe-2S-bd_N)
Type: Homologous_superfamily

This superfamily includes proteins from the 2Fe-2S ferredoxin family, that have a general core structure consisting of β(2)-α-β(2) with a β-grasp type fold. The domain is around one hundred amino acids with four conserved cysteine residues to which the 2Fe-2S cluster is ligated. This superfamily represents the N-terminal domain found in sarcosine oxidase proteins, alpha subunit.
Hepatitis C virus non-structural protein NS2, C-terminal domain (HCV_NS2_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain of hepatitis C virus non-structural protein NS2.

The viral genome is translated into a single polyprotein of about 3000 amino acids. Generation of the mature non-structural proteins relies on the activity of viral proteases. Non-structural protein 2 (NS2) is an zinc-dependent autocatalytic endopeptidase which cleaves at the NS2/NS3 junction . The action of NS3 proteinase, which resides in the N-terminal one-third of the NS3 protein, then yields all remaining non-structural proteins.

NS2 belongs to MEROPS peptidase family C18 (hepatitis C virus endopeptidase 2, clan CM). The fold consists of two subdomains connected by an extended linker: an N-terminal helical domain and a C-terminal β sheet. Peptidases are active as a homodimer and the two active sites are formed at the dimer interface by His and Glu from one monomer and Cys from the other. The dimer resembles a 'butterfly' with two-fold symmetry along the vertical axis. The N-terminal subdomain of one molecule interacts with the C-terminal subdomain of the other molecule and vice versa .
CRISPR-associated endonuclease Cas1, C-terminal domain (CRISPR-assoc_Cas1_C)
Type: Homologous_superfamily

The CRISPR-Cas system is a prokaryotic defence mechanism against foreign genetic elements. The key elements of this defence system are the Cas proteins and the CRISPR RNA.

This superfamily corresponds to the C-terminal domain found in Cas1, a CRISPR-associated protein. Cas1 is common to all CRISPR-containing prokaryotes and it may be involved in linking DNA segments to CRISPR.
Glycoprotein VP7, domain 1 (VP7_1)
Type: Homologous_superfamily

Glycoprotein VP7, also known as outer shell glycoprotein, is a serotype-specific antigen, and is the major neutralisation antigen. It is found in the dsRNA rotaviruses.

This superfamily represents the domain 1 found in glycoprotein VP7, it consists of 6 α helices and 5 β strands arranged into a Rossmann fold. Within VP7, this superfamily makes up the first of 2 domains, the other being a jelly-roll β sandwich domain. A single disulfide bond is present within the domain.
D-serine dehydratase-like domain superfamily (D-ser_dehydrat-like_sf)
Type: Homologous_superfamily

This superfamily represents a domain found in D-serine dehydratase, a zinc dependent enzyme involved in the degradation of D-serine, a physiological co-agonist of the NMDA receptor which is thus involved in the regulation of excitatory neurotransmission, important for higher brain functions in vertebrates. The primary structure of the enzyme shows significant similarities to that of metal-activated D-threonine aldolases, fold-type III pyridoxal 5'-phosphate (PLP)-dependent enzymes .
Hepatitis C virus non-structural protein NS2, N-terminal domain (HCV_NS2_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of hepatitis C virus non-structural protein NS2.

The viral genome is translated into a single polyprotein of about 3000 amino acids. Generation of the mature non-structural proteins relies on the activity of viral proteases. Non-structural protein 2 (NS2) is an zinc-dependent autocatalytic endopeptidase which cleaves at the NS2/NS3 junction . The action of NS3 proteinase, which resides in the N-terminal one-third of the NS3 protein, then yields all remaining non-structural proteins.

NS2 belongs to MEROPS peptidase family C18 (hepatitis C virus endopeptidase 2, clan CM). The fold consists of two subdomains connected by an extended linker: an N-terminal helical domain and a C-terminal β sheet. Peptidases are active as a homodimer and the two active sites are formed at the dimer interface by His and Glu from one monomer and Cys from the other. The dimer resembles a 'butterfly' with two-fold symmetry along the vertical axis. The N-terminal subdomain of one molecule interacts with the C-terminal subdomain of the other molecule and vice versa .
Glycoprotein VP7, domain 2 (VP7_2)
Type: Homologous_superfamily

Glycoprotein VP7, also known as outer shell glycoprotein, is a serotype-specific antigen, and is the major neutralisation antigen. It is found in the dsRNA rotaviruses.

This superfamily represents the domain 2 found in glycoprotein VP7, it consists of 8 β strands arranged into a jelly-roll β sandwich.
CRISPR-associated endonuclease Cas1, N-terminal domain (CRISPR-assoc_Cas1_N)
Type: Homologous_superfamily

The CRISPR-Cas system is a prokaryotic defence mechanism against foreign genetic elements. The key elements of this defence system are the Cas proteins and the CRISPR RNA.

This superfamily represents the CRISPR-associated endonuclease Cas1, N-terminal β-sandwich-like domain. Cas1 may play a role in the recognition, cleavage, and/or integration of foreign nucleic acids into CRISPRs.
Four-carbon acid sugar kinase, nucleotide binding domain superfamily (NBD_C_sf)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain found in proteins in a range of Proteobacteria as well as the Gram-positive Oceanobacillus iheyensis. Structural analysis of the whole protein indicates the N- and C-termini act together to produce a surface into which a threonate-ADP complex is bound, demonstrating that a sugar binding site is on the N-terminal domain, and a nucleotide binding site is in the C-terminal domain . There is a critical motif, DDXTG, at approximately residues 22-25. Proteins containing this domain have been predicted as kinases. Some members are associated with PdxA2 by physical clustering and gene fusion with PdxA2. Some members that are fused with PdxA2 have been shown to be involved in L-4-hydroxythreonine (4HT) phosphorylation, part of the alternative pathway to make PLP (pyridoxal 5'-phosphate) out of a toxic metabolite, 4HT. However, 4HT phosphorylation might not be the main function of this group of proteins. Moreover, some members that are not associated with pdxA2, and even one that is associated with pdxA2, have lost 4HT kinase activity . Functional analysis demonstrate that family members include D-Threonate kinases (DtnK), D-Erythronate kinases (DenK) and 3-Oxo-tetronate kinases (OtnK) .
Pseudouridine synthase, TruD, catalytic domain (TruD_catalytic)
Type: Homologous_superfamily

Pseudouridine synthase TruD modifies uracil-13 in tRNA . TruD belongs to a large family of pseudouridine synthases present in all kingdoms of life . It folds into a V-shaped molecule with an RNA-binding cleft formed between its two domains: a catalytic domain and an insertion domain. The catalytic domain differs in sequence but is structurally very similar to the catalytic domain of other pseudouridine synthases. The insertion (or TRUD) domain displays an α/β structure that forms a compact fold titled away from the catalytic domain to create a deep cleft in TruD which is lined with basic residues from each domain. The insertion domain is characterised by two conserved sequence motifs that form a part of the hydrophobic core, as well as by large insertions at several specific sites that are seen in many archaeal and eukaryotic homologues. The insertion domain is likely to be involved in substrate recognition and may represent a RNA binding module .

This superfamily represents the catalytic domain of TruD.
CarD-like, C-terminal domain (CarD-like_C)
Type: Homologous_superfamily

This superfamily represents the all α-helical C-terminal domain of CarD from Mycobacterium tuberculosis (Mtb), an essential protein thought to be involved in stringent response through down-regulation of rRNA and ribosomal protein genes . CarD is DNA binding protein but the N-terminal domain is not involved in this process. Mutation studies have revealed that the C-terminal domain is the DNA interaction domain. The N-terminal domain of CarD is responsible for interaction with the beta-subunit of RNAP. This interaction is vital for Mtb's survival during the persistent infection state .
MitoNEET, CDGSH iron-sulfur domain (MitoNEET_CISD)
Type: Homologous_superfamily

CDGSH iron-sulfur domains (CISDs) are classified into seven major types and are widely distributed throughout the three domains of life . This superfamily represents the C-terminal domain found in the human CISD protein mitoNEET, also designated CSD1, an iron-containing integral protein of the outer mitochondrial membrane (OMM). MitoNEET contains two domains: a β-cap region and a cluster-binding domain, containing the CDGSH motif, that coordinates two acid-labile 2Fe-2S clusters (one bound to each protomer) . The CDGSH iron-sulphur domain is oriented towards the cytoplasm and is tethered to the mitochondrial membrane by a more N-terminal domain found in higher vertebrates . The whole protein regulates oxidative capacity and might be involved in electron transfer.
Type IV secretion system, VirB10/TrbI (T4SS_VirB10/TrbI)
Type: Homologous_superfamily

This superfamily represents the type IV secretion system proteins VirB10 and TrbI. They are part of the different DNA transfer systems the tumour-inducing (Ti) plasmid of Agrobacterium tumefaciens encodes where the virB operon is required for DNA transfer to the plant host .
The trbI gene encodes an intrinsic inner-membrane protein that is 128-amino-acids long. Although it is not essential for conjugational transfer, the TrbI protein greatly increases conjugational efficiency as it is believed to influence the kinetics of pilus outgrowth and/or retraction .
Dynein heavy chain AAA lid domain superfamily (AAA_lid_11_sf)
Type: Homologous_superfamily

Dyneins can be divided into two groups: cytoplasmic dyneins and axonemal dyneins, which are also called ciliary or flagellar dyneins.

Dyneins power the beating of cilia and flagella, transport various intracellular cargos and are necessary for mitosis. All dyneins have a 300kDa motor domain consisting of a ring of six AAA domains. ATP hydrolysis in the AAA ring drives the cyclic relocation of a motile element, the linker domain, to generate the force necessary for movement .

The cytoplasmic dynein is composed of two identical heavy chains (each >500kDa) and a number of smaller chains. The dynein heavy chain, which belongs to the AAA superfamily of mechanochemical enzymes, is responsible for the motor activities of dynein . The heavy-chain folds into a ring-like head composed of six AAA domains, a stem, and a stalk emerging from the head. The stalk is the microtubule-binding domain with a long coiled-coil structure . The 380kDa recombinant fragment of the C-terminal two-thirds of the Dictyostelium dynein heavy chain maintains microtubule (MT)-activated ATPase activity and drives robust MT sliding, showing that this fragment is the motor domain of the Dictyostelium dynein .

This superfamily represents the AAA lid domain found near the C-terminal region of dynein heavy chain.
NLR family CARD domain-containing protein 4 (NLRC4)
Type: Family

NLRC4 is a nucleotide binding/leucine-rich Repeat (NLR) protein and a inflammasome activator. It contains an N-terminal homotypic interaction domain, a central nucleotide binding domain, and a series of C-terminal LRRs. NLRC4 activates CASP1, the primary protease responsible for converting pro-IL-1beta to active, secreted IL-1beta. NLRC4 has been linked to autoinflammation diseases .
Leucyl/phenylalanyl-tRNA-protein transferase, N-terminal (Leu/Phe-tRNA_Trfase_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of leucyl/phenylalanyl-tRNA-protein transferases (L/F-transferases).

L/F-transferase is an N-end rule pathway enzyme, involved in the transfer of Leu and Phe from aminoacyl-tRNAs to exposed N-terminal Arg or Lys residues of acceptor proteins . This C-terminal domain has a highly conserved fold, observed in the GCN5-related N-acetyltransferase (GNAT) family.
The interface of the N-terminal and C-terminal domains forms a large central cavity, with the characteristic positive charge contributed by the corner of the cleft on the C-terminal domain surface, suggesting that they probably complement the negatively charged phosphate backbone of the substrate aminoacyl-tRNA .
Dynein heavy chain, domain 2, N-terminal (Dynein_2_N)
Type: Homologous_superfamily

Dyneins are described as motor proteins of eukaryotic cells, as they can convert energy derived from the hydrolysis of ATP to force and movement along cytoskeletal polymers, such as microtubules. Dyneins generally contain one to three heavy chains, which belong to the AAA+ superfamily of mechanochemical enzymes . Each heavy chain consists of a flexible N-terminal tail known as the cargo-binding domain and a motor domain which consists of an ATP-hydrolysing AAA+ ring, a flexible microtubule-binding stalk, a linker and a C-sequence . The stalk has an ATP-sensitive microtubule-binding site (MTBD) at its tip , whereas the linker has been suggested to function as a mechanical element for generating dynein's power stroke .

The two categories of dyneins are the axonemal dyneins, which produce the bending motions that propagate along cilia and flagella, and the cytosolic dyneins, which drive a variety of fundamental cellular processes including nuclear migration, organisation of the mitotic spindle, chromosome separation during mitosis, and the positioning and function of many intracellular organelles. Cytoplasmic dyneins contain several accessory subunits ranging from light to intermediate chains.

This superfamily represents the N-terminal part of the second domain of dynein heavy chain. No function seems to have been attributed specifically to this region.
Homeobox protein SEBOX (SEBOX)
Type: Family

SEBOX is a probable transcription factor involved in preparing oocytes for embryonic development in mice . It is required for early embryonic development in pigs and appears to regulate the degradation of maternal transcripts and the expression of pluripotency genes .
General transcription factor II-I repeat domain-containing protein 2 (GTF2IRD2)
Type: Family

This eukaryotic family includes general transcription factor II-I repeat domain-containing protein 2 (GTF2IRD2). The function of GTF2IRD2 is not clear.
Negative cofactor 2 complex subunit beta (Ncb2)
Type: Family

This entry includes budding yeast Ncb2 and its homologues. Ncb2 is a component of the NC2 complex which represses RNA polymerase II transcription through binding to Spt15/TBP and thereby inhibiting the assembly of the preinitiation complex . Its human homologue, DR1, associates with DRAP1 through histone fold motifs to form the NC2 complex, which negatively regulates transcription initiation .

This entry also includes proteins from fungi, such as NctB from Neosartorya fumigata and Ncb2 from Candida albicans. NctB forms a complex with NctA, and this complex acts as a general transcriptional cofactor . In Candida albicans, conditional Ncb2 null mutants have been shown to display decreased susceptibility toward azole and an enhanced transcription of CDR1 .
eRF1, domain 2 superfamily (eFR1_2_sf)
Type: Homologous_superfamily

This superfamily represents the conserved region in the release factor eRF1, designated domain 2. eRF1 is involved in termination of protein biosynthesis through stop codon recognition at the A site of the ribosome and stimulation of peptidyl-tRNA bond hydrolysis at the peptidyl transferase centre . The overall shape and dimensions of eRF1 resemble a tRNA molecule with domains 1, 2, and 3 of eRF1 corresponding to the anticodon loop, aminoacyl acceptor stem, and T stem of a tRNA molecule, respectively. The presence of the essential GGQ motif at an exposed tip of domain 2 suggests that this motif plays a direct role at the catalytic site of the peptidyl transferase centre .
NF-kappa-B inhibitor-interacting Ras-like protein (KBRS)
Type: Family

This entry represents a group of NF-kappa-B inhibitor-interacting Ras-like proteins, known as kappaB-Ras proteins, including KBRS1 and KBRS2 from humans. They are Ras-like proteins that inhibit NF-kappaB transcriptional activity. Despite their high sequence similarity to Ras GTPases, kappaB-Ras proteins contain two Ras oncogenic mutations that drastically reduce GTP hydrolysis . KBRAS1 has been shown to bind IkappaBbeta and regulates cytoplasmic retention of IkappaBbeta/NF-kappaB complexes .
Dynein heavy chain, linker, subdomain 3 (Dynein_linker_3)
Type: Homologous_superfamily

Dyneins are described as motor proteins of eukaryotic cells, as they can convert energy derived from the hydrolysis of ATP to force and movement along cytoskeletal polymers, such as microtubules. Dyneins generally contain one to three heavy chains, which belong to the AAA+ superfamily of mechanochemical enzymes . Each heavy chain consists of a flexible N-terminal tail known as the cargo-binding domain and a motor domain which consists of an ATP-hydrolysing AAA+ ring, a flexible microtubule-binding stalk, a linker and a C-sequence . The stalk has an ATP-sensitive microtubule-binding site (MTBD) at its tip , whereas the linker has been suggested to function as a mechanical element for generating dynein's power stroke .

The two categories of dyneins are the axonemal dyneins, which produce the bending motions that propagate along cilia and flagella, and the cytosolic dyneins, which drive a variety of fundamental cellular processes including nuclear migration, organisation of the mitotic spindle, chromosome separation during mitosis, and the positioning and function of many intracellular organelles. Cytoplasmic dyneins contain several accessory subunits ranging from light to intermediate chains.

This superfamily represents the subdomain 3 found in the linker domain of dynein heavy chain. The linker exists as a rod-like structure that comprises nineteen α-helices and eight β-strands and can be divided into five subdomains from 0 to 4. This subdomain interacts with subdomain 2 and 4 and has been suggested to play a role in the interactions between the linker base and the ring .
Listeria-Bacteroides repeat domain superfamily (Listeria/Bacterioides_rpt_sf)
Type: Homologous_superfamily

This superfamily represents a conserved core region of about 43 residues, which occurs in at least two families of tandem repeats. These include 78-residue repeats which occur from 2 to 15 times in some proteins of Tannerella forsythensis ATCC 43037, and 70-residue repeats found in families of internalins of Listeria species. Single copies are found in proteins of Fibrobacter succinogenes, Geobacter sulfurreducens, and a few other bacteria.