SII-SWORD/CoKE huggingface dataset:
Acyl-CoA binding protein superfamily (Acyl-CoA-binding_sf)
Type: Homologous_superfamily

Acyl-CoA-binding protein (ACBP) is a small (10 Kd) protein that binds medium-and long-chain acyl-CoA esters with very high affinity and may function as an intracellular carrier of acyl-CoA esters . ACBP is also known as diazepam binding inhibitor (DBI) or endozepine (EP) because of its ability to displace diazepam from the benzodiazepine (BZD) recognition site located on the GABA type A receptor. It is therefore possible that this protein also acts as a neuropeptide to modulate the action of the GABA receptor .

ACBP is a highly conserved protein of about 90 residues that is found in all four eukaryotic kingdoms, Animalia, Plantae, Fungi and Protista, and in some eubacterial species .

Although ACBP occurs as a completely independent protein, intact ACB domains have been identified in a number of large, multifunctional proteins in a variety of eukaryotic species. These include large membrane-associated proteins with N-terminal ACB domains, multifunctional enzymes with both ACB and peroxisomal enoyl-CoA Delta(3), Delta(2)-enoyl-CoA isomerase domains, and proteins with both an ACB domain and ankyrin repeats (

) .

The ACB domain consists of four α-helices arranged in a bowl shape with a highly exposed acyl-CoA-binding site. The ligand is bound through specific interactions with residues on the protein, most notably several conserved positive charges that interact with the phosphate group on the adenosine-3'phosphate moiety, and the acyl chain is sandwiched between the hydrophobic surfaces of CoA and the protein .

Other proteins containing an ACB domain include:

Endozepine-like peptide (ELP) (gene DBIL5) from mouse . ELP is a testis-specific ACBP homologue that may be involved in the energy metabolism of the mature sperm.

MA-DBI, a transmembrane protein of unknown function which has been found in mammals. MA-DBI contains a N-terminal ACB domain.

DRS-1 , a human protein of unknown function that contains a N-terminal ACB domain and a C-terminal enoyl-CoA isomerase/hydratase domain.
Ubiquitin-activating enzyme-like (Ubiquitin-activating_enz)
Type: Homologous_superfamily

This entry describes the ubiquitin-activating enzymes E1, ubiquitin-like modifier-activating enzymes, and related enzymes. It also includes adenylyltransferase and sulfurtransferase from the MOCS3 (humans) and UBA4 (yeast) complexes, which are enzymes involved in ubiquitin-like pathways. These enzymes play critical roles in activating ubiquitin-like proteins (UBLs) such as Urm1 .

The post-translational attachment of ubiquitin (

) to proteins (ubiquitinylation) alters the function, location or trafficking of a protein, or targets it to the 26S proteasome for degradation . Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2,

), and a ubiquitin ligase (E3,

,

), which work sequentially in a cascade . The E1 enzyme is responsible for activating ubiquitin, the first step in ubiquitinylation. The E1 enzyme hydrolyses ATP and adenylates the C-terminal glycine residue of ubiquitin, and then links this residue to the active site cysteine of E1, yielding a ubiquitin-thioester and free AMP. To be fully active, E1 must non-covalently bind to and adenylate a second ubiquitin molecule. The E1 enzyme can then transfer the thioester-linked ubiquitin molecule to a cysteine residue on the ubiquitin-conjugating enzyme, E2, in an ATP-dependent reaction.
PKD domain superfamily (PKD_dom_sf)
Type: Homologous_superfamily

The polycystic kidney disease (PKD) domain is an 80-90 amino acid module originally found in 16 copies in the extracellular segment of polycystin-1, a large cell surface glycoprotein. Polycystin-1 is encoded by the PKD1 gene, which is mutated in autosomal dominant polycystic kidney disease (ADPKD).
Although its function is unknown, it may be involved in protein-protein and protein-carbohydrate interactions based on its predicted domain structure. One or more copies of the PKD domain are also found in several other extracellular proteins from higher organisms, eubacteria, and archaebacteria. Singles copies of the PKD domain are found in the melanocytes heavily glycosylated cell-surface proteins Pmel 17, MMP and Nmp. Some bacterial collagenases and proteases also contain a single PKD domain adjacent to their catalytic domains, whereas four copies are present in the heavily glycosylated surface layer protein of archaebacteria . The PKD modules are often observed, within a same protein sequence, in association with FnIII domains .

The most conserved motif is the WDFGDGS sequence that is found in the central part of many PKD domains and could play a structural role . Determination of the solution structure of the first PKD domain from human polycystin-1 has shown that the module is built from two β-sheet, one of three strands and one of four strands, which are packed face-to-face .
Small ribosomal subunit protein uS8 superfamily (Ribosomal_uS8_sf)
Type: Homologous_superfamily

This entry includes small ribosomal subunit protein uS8 from bacteria, archaea and eukaryotes (in yeast, these proteins are also known as S22 and in vertebrates S15A) . In Escherichia coli, uS8 is known to bind directly to 16S ribosomal RNA.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
DBP-like superfamily (DBP_sf)
Type: Homologous_superfamily

This entry includes the major DNA-binding protein (DBP, UL57 or ICP8) from Herpesviruses. DBP binds single-stranded DNA, and the region encompassing residues 368-902 contains the DNA-binding site . UL5, UL8 and UL52 genes encode an essential heterotrimeric DNA helicase-primase that is responsible for concomitant DNA unwinding and primer synthesis at the viral DNA replication fork. DBP may stimulate DNA unwinding and enable bypass of cisplatin damaged DNA by recruiting the helicase-primase to the DNA . DBP helps initiate DNA replication by binding to the origin-binding protein (UL9) . It also reorganizes the host nucleus leading to the formation of prereplicative sites and replication compartments .
Triosephosphate isomerase superfamily (TIM_sf)
Type: Homologous_superfamily

Triosephosphate isomerase (

) (TIM) is the glycolytic enzyme that catalyses the reversible interconversion of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. TIM plays an important role in several metabolic pathways and is essential for efficient energy production, highly conserved in prokaryotes and eukaryotes. In pathogenic organisms, this enzyme plays a crucial role obtaining energy for infection and survival. TIM is a dimer of identical subunits, each of which is made up of about 250 amino-acid residues. A glutamic acid residue is involved in the catalytic mechanism .

The tertiary structure of TIM has eight β/α motifs folded into a barrel structure. The TIM barrel fold occurs ubiquitously and is found in numerous other enzymes that can be involved in energy metabolism, macromolecule metabolism, or small molecule metabolism .

The sequence around the active site residue is perfectly conserved in all known TIM's. Deficiencies in TIM are associated with haemolytic anaemia coupled with a progressive, severe neurological disorder .
Casein kinase II subunit beta-like (Casein_kinase_II_beta-like)
Type: Homologous_superfamily

Casein kinase, a ubiquitous well-conserved protein kinase involved in cell metabolism and differentiation, is characterised by its preference for Ser or Thr in acidic stretches of amino acids. The enzyme is a tetramer of 2 alpha-and 2 beta-subunits . However, some species (e.g., mammals) possess 2 related forms of the alpha-subunit (alpha and alpha'), while others (e.g., fungi) possess 2 related beta-subunits (beta and beta') .
Ricin B-like lectins (Ricin_B-like_lectins)
Type: Homologous_superfamily

Ricin is a legume lectin from the seeds of the castor bean plant, Ricinus communis. The seeds are poisonous to people, animals and insects and just one milligram of ricin can kill an adult.

Primary structure analysis has shown the presence of a similar domain in many carbohydrate-recognition proteins like plant and bacterial AB-toxins, glycosidases or proteases . This domain, known as the ricin B lectin domain, can be present in one or more copies and has been shown in some instance to bind simple sugars, such as galactose or lactose.

The ricin B lectin domain is composed of three homologous subdomains of 40 amino acids (alpha, beta and gamma) and a linker peptide of around 15 residues (lambda). It has been proposed that the ricin B lectin domain arose by gene triplication from a primitive 40 residue galactoside-binding peptide . The most characteristic, though not completely conserved, sequence feature is the presence of a Q-W pattern. Consequently, the ricin B lectin domain as also been refered as the (QxW)
3
domain and the three homologous regions as the QxW repeats . A disulphide bond is also conserved in some of the QxW repeats .

The 3D structure of the ricin B chain has shown that the three QxW repeats pack around a pseudo threefold axis that is stabilised by the lambda linker . The ricin B lectin domain has no major segments of a helix or β-sheet but each of the QxW repeats contains an ω-loop . An idealized ω-loop is a compact, contiguous segment of polypeptide that traces a 'loop-shaped' path in three-dimensional space; the main chain resembles a Greek omega.
Notch-like domain superfamily (Notch-like_dom_sf)
Type: Homologous_superfamily

The Notch domain is also called the 'DSL' domain or the Lin-12/Notch repeat (LNR). The LNR region is present only in Notch related proteins C-terminal to EGF repeats. The lin-12/Notch proteins act as transmembrane receptors for intercellular signals that specify cell fates during animal development. In response to a ligand, proteolytic cleavages release the intracellular domain of Notch, which then gains access to the nucleus and acts as a transcriptional co-activator . The LNR region is supposed to negatively regulate the Lin-12/Notch proteins activity. It is a triplication of an around 35-40 amino acids module present on the extracellular part of the protein . Each module contains six cysteine residues engaged in three disulphide bonds and three conserved aspartate and asparagine residues . The biochemical characterisation of a recombinantly expressed LIN-12.1 module from the human Notch1 receptor indicate that the disulphide bonds are formed between the first and fifth, second and fourth, and third and sixth cysteines. The formation of this particular disulphide isomer is favored by the presence of Ca
2+
, which is also required to maintain the structural integrity of the rLIN-12.1 module. The conserved aspartate and asparagine residues are likely to be important for Ca
2+
binding, and thereby contribute to the native fold.
Nucleoside phosphorylase superfamily (Nucleoside_phosphorylase_sf)
Type: Homologous_superfamily

Phosphorylases with this domain include:

Purine nucleoside phosphorylase (

) (PNP) from most bacteria (gene deoD), which catalyses the cleavage of guanosine or inosine to respective bases and sugar-1-phosphate molecules .

Uridine phosphorylase (

) (UdRPase) from bacteria (gene udp) and mammals, which catalyses the cleavage of uridine into uracil and ribose-1-phosphate, the products of the reaction are used either as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis .

5'-methylthioadenosine phosphorylase (

) (MTA phosphorylase) from Sulfolobus solfataricus .

Purine nucleoside phosphorylase (

) (PNP) from mammals as well as from some bacteria (gene deoD). This enzyme catalyzes the cleavage of guanosine or inosine to respective bases and sugar-1-phosphate molecules .

5'-methylthioadenosine phosphorylase (

) (MTA phosphorylase) from eukaryotes .
Bowman-Birk type proteinase inhibitor (Bowman-Birk_prot_inh)
Type: Homologous_superfamily

This family of eukaryotic proteinase inhibitors, belongs to MEROPS inhibitor family I12, clan IF. They predominantly inhibit serine peptidases of the S1 family (

) . They play a role in defense response against pathogens and insects, but they also have been studied as therapeutic treatment in cancer and inflammatory disorders . Exceptionally, cowpea trypsin inhibitor inhibits a cathepsin L-like cysteine proteinase CPL-1 from the nematode Heterodera glycines .

The Bowman-Birk inhibitor family is one of the numerous families of serine proteinase inhibitors. They have a duplicated structure and generally possess two distinct inhibitory sites. These inhibitors are primarily found in plants and in particular in the seeds of legumes as well as in cereal grains. In cereals they exist in two forms, one of which is a duplication of the basic structure .
Proteins of the Bowman-Birk inhibitor family of serine proteinase inhibitors interact with the enzymes they inhibit via an exposed surface loop that adopts the canonical proteinase inhibitory conformation. The resulting non-covalent complex renders the proteinase inactive. This inhibition mechanism is common for the majority of serine proteinase inhibitor proteins and many analogous examples are known. A particular feature of the Bowman-Birk inhibitor protein, however, is that the interacting loop is a particularly well-defined disulphide-linked short β-sheet region .
Tetrapyrrole methylase superfamily (4pyrrol_Methylase_sf)
Type: Homologous_superfamily

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway . The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including cobalamin (vitamin B12), haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin .

These enzymes catalyse the methylation of their substrates using S-adenosyl-L-methionine as a methyl source. Enzymes in this family include:

Uroporphyrinogen III methyltransferase (

) (SUMT), which catalyses the conversion of uroporphyrinogen III to precorrin-2 at the first branch-point of the tetrapyrrole synthesis pathway, directing the pathway towards cobalamin or sirohaem synthesis .

Precorrin-2 C20-methyltransferase CobI/CbiL (

), which introduces a methyl group at C-20 on precorrin-2 to produce precorrin-3A during cobalamin biosynthesis. This reaction is key to the conversion of a porphyrin-type tetrapyrrole ring to a corrin ring . In some species, this enzyme is part of a bifunctional protein.

Precorrin-4 C11-methyltransferase CobM/CbiF (

), which introduces a methyl group at C-11 on precorrin-4 to produce precorrin-5 during cobalamin biosynthesis .

Sirohaem synthase CysG (

), domains 4 and 5, which synthesizes sirohaem from uroporphyrinogen III, at the first branch-point in the tetrapyrrole biosynthetic pathway, directing the pathway towards sirohaem synthesis .

Diphthine synthase (

), which carries out the methylation step during the modification of a specific histidine residue of elongation factor 2 (EF-2) during diphthine synthesis.

This entry represents a tetrapyrrole methylase domain, which consist of two non-similar subdomains . The first domain has parallel sheet of five strands,
while the second domain has mixed sheet of five strands, with strands 4 and 5 antiparallel to the rest.
MTMR4, PH-GRAM domain (MTMR4_PH-GRAM)
Type: Domain

Myotubularin-related protein 4 (MTMR4) is a member of the myotubularin (MTM) family. It is the only family member that possesses a FYVE domain (a zinc finger domain) at its C terminus . MTMR4 has dual-specificity phosphatase activity that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate . MTMR4 has a unique distribution to endosomes and has been shown to function in early and recycling endosomes ; through phosphatidylinositol 3-phosphate turnover in phagosome membranes regulates phagocytosis and phagosome maturation . MTMR4 attenuates TGF-beta signalling by dephosphorylating intracellular signalling mediator R-Smads . Similarly, it acts as a negative modulator for the homeostasis of bone morphogenetic proteins (BMPs) signalling .

Both MTMR3 and MTMR4 contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an active PTP domain, a SET-interaction domain, a coiled-coil region, and a C-terminal lipid-binding FYVE domain which binds phosphotidylinositol-3-phosphate. Myotubularin-related proteins are a subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in this family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome . Six of the 13 MTMRs (MTMRs 5, 9-13) contain naturally occurring substitutions of residues required for catalysis by PTP family enzymes. Although these proteins are predicted to be enzymatically inactive, they are thought to function as antagonists of endogenous phosphatase activity or interaction modules .
MTMR6, PH-GRAM domain (MTMR6_PH-GRAM)
Type: Domain

Myotubularin-related protein 6 (MTMR6) is a catalytically active member of the myotubularin (MTM) family, which possess 3-phosphatase activity dephosphorylating phosphatidylinositol-3-phoshate and phosphatidylinositol-3,5-bisphosphate . MTMR6 forms a heteromer with enzymatically inactive MTMR9. MTMR9 increases MTMR6 binding to phospholipids and increases the 3-phosphatase activity of MTMR6 and it plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3-phosphate in membrane ruffles . MTMR6 is reported to be involved in the regulation of the Ca2+-activated K+ channel KCa3.1 and apoptosis . The cellular localisation of MTMR6 is regulated by Rab1B in the early secretory and autophagic pathways .

MTMR6 contains an N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an active PTP domain, a SET-interaction domain, and a C-terminal coiled-coil region. The GRAM domain, found in myotubularins, glucosyltransferases, and other putative membrane-associated proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold. This entry represents the PH-GRAM domain of MTMR6.

The myotubularin family constitutes a large group of conserved proteins, with 14 members in humans consisting of myotubularin (MTM1) and 13 myotubularin-related proteins (MTMR1-MTMR13). Orthologues have been found throughout the eukaryotic kingdom, but not in bacteria. MTM1 dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) to phosphatidylinositol and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] to phosphatidylinositol 5-monophosphate (PI5P) [

,

, . The substrate phosphoinositides (PIs) are known to regulate traffic within the endosomal-lysosomal pathway . MTMR1, MTMR2, MTMR3, MTMR4, and MTMR6 have also been shown to utilise PI(3)P as a substrate, suggesting that this activity is intrinsic to all active family members. On the other hand, six of the MTM family members encode for catalytically inactive phosphatases. Inactive myotubularin phosphatases contain substitutions in the Cys and Arg residues of the Cys-X5-Arg motif. MTM pseudophosphatases have been found to interact with MTM catalytic phosphatases . The myotubularin family includes several members mutated in neuromuscular diseases or associated with metabolic syndrome, obesity, and cancer .
Sec7 domain superfamily (Sec7_dom_sf)
Type: Homologous_superfamily

Protein containing this domain are highly divergent in their overall sequence, however, they share a common region of roughly 200 amino acids known as the SEC7 domain . The 3D structure of the domain displays several α-helices . It was found to be associated with other domains involved in guanine nucleotide exchange (e.g., CDC25, Dbl) in mammalian guanine-nucleotide-exchange factors .

SEC7 domain containing proteins are guanine nucleotide exchange factors (GEFs) specific for the ADP-rybosylation factors (ARF), a Ras-like GTPases which is important for vesicular protein trafficking. These proteins can be divided into five families, based on domain organisation and conservation of primary amino acid sequence: GBF/BIG, cytohesins,eFA6, BRAGs, and F-box . They are found in all eukaryotes, and are involved in membrane remodelling processes throughout the cell .
Class II myosin, Myh3, motor domain (MYSc_Myh3)
Type: Domain

Developing skeletal muscles express unique myosin isoforms, including embryonic myosin heavy chain 3 (MYH3) . This entry represents the myosin motor domain of MYH3 (MYHC-EMB, MYHSE1, HEMHC, SMHCE) in tetrapods including mammals, lizards, and frogs. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome .

Class II myosins, also called conventional myosins, are the myosin type responsible for producing actomyosin contraction in metazoan muscle and non-muscle cells. Myosin II contains two heavy chains made up of the head (N-terminal) and tail (C-terminal) domains with a coiled-coil morphology that holds the two heavy chains together. The intermediate neck domain is the region creating the angle between the head and tail. It also contains 4 light chains which bind the heavy chains in the 'neck' region between the head and tail. The head domain is a molecular motor, which utilizes ATP hydrolysis to generate directed movement toward the plus end along actin filaments .