SII-SWORD/CoKE huggingface dataset:
Class II aldolase/adducin N-terminal (Aldolase_II/adducin_N)
Type: Domain

This entry represents the α/β/α domain found in class II aldolases and in adducin (usually at the N terminus of adducin). Proteins containing this domain include: rhamnulose-1-phosphate aldolase (

), L-fuculose phosphate aldolase (

) that is involved in the third step in fucose metabolism, L-ribulose- 5-phosphate 4-epimerase (

) involved in the third step of L-arabinose catabolism, a probable sugar isomerase SgbE and the metazoan adducins, which have not been ascribed any enzymatic function but which play a role in cell membrane cytoskeleton organisation . It also includes ribulose-1-phosphate aldolase that catalyses the cleavage of ribulose 1-phosphate to dihydroxyacetone phosphate and glycolaldehyde .
C-type lectin-like (C-type_lectin-like)
Type: Domain

A number of different families of proteins share a conserved domain which was first characterised in some animal lectins and which seem to function as a calcium-dependent carbohydrate-recognition domain . This domain, which is known as the C-type lectin domain (CTL) or as the carbohydrate-recognition domain (CRD), consists of about 110 to 130 residues. There are four cysteines which are perfectly conserved and involved in two disulphide bonds.

There are proteins with modules similar in overall structure to CRDs that serve functions other than sugar binding. Therefore, a more general term C-type lectin-like domain was introduced to refer to such domains, although both terms C-type lectin and C-type lectin-like are sometimes used interchangeably .

C-type lectins can be further divided into seven subgroups based on additional non-lectin domains and gene structure: (I) hyalectans, (II) asialoglycoprotein receptors, (III) collectins, (IV) selectins, (V) NK group transmembrane receptors, (VI) macrophage mannose receptors, and (VII) simple (single domain) lectins . Lectins are a diverse group of proteins, both in terms of structure and activity. Carbohydrate binding ability may have evolved independently and sporadically in numerous unrelated families, where each evolved a structure that was conserved to fulfil some other activity and function. In general, animal lectins act as recognition molecules within the immune system, their functions involving defence against pathogens, cell trafficking, immune regulation and the prevention of autoimmunity .

This entry also includes alpha-type phospholipase A2 inhibitors (PLI-alpha), a group of proteins that have been found in a number of Viperidae snakes . Most PLI-alpha proteins are homomultimers composed of 3-5 subunits, except in Trimeresurus flavoviridis (Habu), where PLI-alpha consists of a trimer of two homologous subunits (PLI-alpha-A and PLI-alpha-B), each of which contains one C-type lectin-like domain and exhibiting significant homology to serum mannose-binding protein and lung-surfactant apoprotein . A PLI-alpha homologue that lacks inhibitory activity was found in the non-venomous snake Elaphe quadrivirgata (Japanese four-lined ratsnake) .
Heat shock protein DnaJ, cysteine-rich domain (HSP_DnaJ_Cys-rich_dom)
Type: Domain

The hsp70 chaperone machine performs many diverse roles in the cell, including folding of nascent proteins, translocation of polypeptides across organelle membranes, coordinating responses to stress, and targeting selected proteins for degradation. DnaJ is a member of the hsp40 family of molecular chaperones, which is also called the J-protein family, the members of which regulate the activity of hsp70s. DnaJ (hsp40) binds to DnaK (hsp70) and stimulates its ATPase activity, generating the ADP-bound state of DnaK, which interacts stably with the polypeptide substrate . Besides stimulating the ATPase activity of DnaK through its J-domain, DnaJ also associates with unfolded polypeptide chains and prevents their aggregation .

DnaJ consists of an N-terminal conserved domain (called 'J' domain) of about 70 amino acid residues, a glycine and phenylalanine-rich domain ('G/F' domain), a central cysteine rich domain (CR-type zinc finger) containing four repeats of a CXXCXGXG motif which can coordinate two zinc atom and a C-terminal domain (CTD) .

This entry represents the central cysteine-rich (CR) domain of DnaJ proteins. This central cysteine rich domain (CR-type zinc finger) has an overall V-shaped extended β-hairpin topology and contains four repeats of the motif CXXCXGXG where X is any amino acid. The isolated cysteine rich domain folds in zinc dependent fashion. Each set of two repeats binds one unit of zinc. Although this domain has been implicated in substrate binding, no evidence of specific interaction between the isolated DnaJ cysteine rich domain and various hydrophobic peptides has been found .
Thiosulphate sulfurtransferase, conserved site (Thiosulphate_STrfase_CS)
Type: Conserved_site

Synonym(s): Rhodanese

Thiosulphate sulphurtransferase (

) is an enzyme which catalyses the transfer of the sulphane atom of thiosulphate to cyanide, to form sulphite and thiocyanate. In vertebrates, rhodanese is a mitochondrial enzyme that is involved in forming iron-sulphur complexes and cyanide detoxification. A cysteine residue takes part in the catalytic mechanism . Some bacterial proteins may also express sulphotransferase activity. These include, SseA from Mycobacterium leprae and Escherichia coli, Azotobacter vinelandii rhdA, Saccharopolyspora erythraea cysA and Synechococcus sp. (strain PCC 7942) rhdA .
Electron transfer flavoprotein alpha subunit/FixB (ETF_a/FixB)
Type: Family

This entry includes electron transfer flavoprotein alpha subunit and the FixB protein.

Electron transfer flavoproteins (ETFs) serve as specific electron acceptors for primary dehydrogenases, transferring the electrons to terminal respiratory systems. They can be functionally classified into constitutive, "housekeeping" ETFs, mainly involved in the oxidation of fatty acids (Group I), and ETFs produced by some prokaryotes under specific growth conditions, receiving electrons only from the oxidation of specific substrates (Group II) .

ETFs are heterodimeric proteins composed of an alpha and beta subunit, and contain an FAD cofactor and AMP . ETF consists of three domains: domains I and II are formed by the N- and C-terminal portions of the alpha subunit, respectively, while domain III is formed by the beta subunit. Domains I and III share an almost identical α-β-α sandwich fold, while domain II forms an α-β-α sandwich similar to that of bacterial flavodoxins. FAD is bound in a cleft between domains II and III, while domain III binds the AMP molecule. Interactions between domains I and III stabilise the protein, forming a shallow bowl where domain II resides. The alpha subunit of both Group I and Group II ETFs is composed of domains I and II.

Many enterobacteria are able to convert carnitine, via crotonobetaine, to gamma-butyrobetaine in the presence of carbon and nitrogen sources under anaerobic conditions . In Escherichia coli the enzymes involved in this pathway are encoded by the caiTABCDE operon . The adjacent but divergent fixABCD operon also appears to be necessary for carnintine meatbolism . The Fix proteins are homologous to proteins found in known electron transport pathways.
Peptidase C14, p20 domain (Pept_C14_p20)
Type: Domain

This group of sequences represent the p20 subunit found in caspases. Caspases are composed of an N-terminal pro-domain that is cleaved during activation, and C-terminal catalytic and interaction domains . All caspases contain two essential caspase catalytic domains: the p20 subunit (20kDa) and the p10 subunit (10kDa) (

), which are derived from the p45 (45kDa) precursor. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases are cysteine proteases (MEROPS clan CD, family C14) that use the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The key catalytic residues, a cysteine and a histidine, are on the p20 subunit.

Caspases are mainly involved in mediating cell death (apoptosis), either as initiators that trigger the cell death process, or as effectors of the process itself . At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (

), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation .
Histidine triad (HIT) protein (Histidine_triad_HIT)
Type: Family

The Histidine Triad (HIT) motif, His-x-His-x-His-x-x (x, a
hydrophobic amino acid) was identified as being highly conserved in a variety of organisms . On the basis of sequence, substrate specificity, structure, evolution and mechanism, HIT proteins are classified into three branches: the Hint branch, which consists of adenosine 5' -monophosphoramide hydrolases, the FHIT branch, that consists of diadenosine polyphosphate hydrolases, and the GalT branch consisting of specific nucloside monophosphate transferases .

In budding yeast Hnt1 has been shown to have adenosine monophosphoramidase activity and function as positive regulators of Cdk7/Kin28 in vivo . FHIT plays a very important role in the development of tumours. In fact, FHIT deletions are among the earliest and most frequent genetic alterations in the development of tumours . The third branch of the HIT superfamily, which includes GalT homologues, contains a related His-X-His-X-Gln motif and transfers nucleoside monophosphate moieties to phosphorylated second substrates rather
than hydrolysing them .
Hexokinase (Hexokinase)
Type: Family

Hexokinase (

) is an important glycolytic enzyme that catalyses
the phosphorylation of keto- and aldohexoses (e.g. glucose, mannose and
fructose) using MgATP as the phosphoryl donor.

In vertebrates there are four major isoenzymes, commonly referred as types I,
II, III and IV. Type IV hexokinase, which is often incorrectly designated
glucokinase , is only expressed in liver and pancreatic beta-cells and
plays an important role in modulating insulin secretion; it is a protein of a
molecular mass of about 50 Kd. Hexokinases of types I to III, which have low
Km values for glucose, have a molecular mass of about 100 Kd. Structurally
they consist of a very small N-terminal hydrophobic membrane-binding domain
followed by two highly similar domains of 450 residues. The first domain has
lost its catalytic activity and has evolved into a regulatory domain.

In yeast there are three different isoenzymes: hexokinase PI (gene HXK1), PII
(gene HXKB), and glucokinase (gene GLK1). All three proteins have a molecular
mass of about 50 Kd.

The hexokinase domain has an α/β fold and is distinctly folded in two
subdomains of unequal size: the large and small subdomains.
The large subdomain comprises a six-stranded mixed β-sheet and a number of
additional α-helices. On one side, the sheet packs against the small
subdomain, and on the other side it is shielded by several α-helices. The
dominant feature of the small subdomain is a five stranded mixed β-sheet.
The sheet is flanked by two helices on one side and by one helix on the other.
The subdomain also has an additional β-sheet formed by two antiparallel
strands .

All these enzymes contain one (or two in the case of types I to III isozymes)
strongly conserved region which has been shown to be involved in substrate binding.
Pumilio RNA-binding repeat (Pumilio_RNA-bd_rpt)
Type: Repeat

Members of the Pumilio family of proteins (Puf) regulate translation and mRNA stability in a wide variety of eukaryotic organisms including mammals, flies, worms, slime mold, and yeast . Pumilio family members are characterised by the presence of eight tandem copies of an imperfectly repeated 36 amino acids sequence motif, the Pumilio repeat, surrounded by a short N- and C-terminal conserved region. The eight repeats and the N- and C-terminal regions form the Pumilio homology domain (PUM-HD). The PUM-HD domain is a sequence-specific RNA binding domain. The Puf family of proteins are mainly post-transcriptional regulators. Several Puf members have been shown to bind specific RNA sequences mainly found in the 3' UTR of mRNA and repress their translation . Frequently, Puf proteins function asymmetrically to create protein gradients, thus causing asymmetric cell division and regulating cell fate specification .

Crystal structure of Pumilio repeats has been solved . The PUM repeat with the N- and C-terminal regions pack together to form a right-handed superhelix that approximates a half doughnut structurally similar to the Armadillo (ARM) repeat proteins, beta-catenin and
karyopherin alpha. The RNA binds the concave surface of the molecule, where
each of the protein's eight repeats makes contacts with a different RNA base
via three amino acid side chains at conserved positions .

This entry represents the Pumilio repeat.
Peptidase S1A, chymotrypsin family (Peptidase_S1A)
Type: Family

This group of serine peptidases and non-peptidase homologues belong to the MEROPS peptidase family S1, subfamily S1A (chymotrypsin subfamily, clan PA(S)). These peptidases contain the catalytic triad histidine, aspartate and serine found in all members of subfamily S1A. Testes-specific protein TSP50 is also included in this family which has the serine replaced by threonine, although the serine is conserved in many vertebrates . The type example being chymotrypsin A from Bos taurus (Bovine).

Members of the chymotrypsin family may occasionally function intracellularly (for example, the intracellular digestion of bacteria in neutrophils), but
most function extracellularly, for example in roles such as food digestion, fibrinolysis and complement activation . The essential catalytic unit of the chymotrypsin family is around 220 amino acids in length, although the protein may be extended at the N terminus with unrelated sequences, often containing modules. They are rarely extended at the C terminus: exceptions include acrosin, complement component C2, and coagulation factor X, which has a 16 residue extension that is removed upon activation .
CARD domain (CARD)
Type: Domain

The caspase recruitment domain (CARD domain) is a homotypic protein interaction module composed of a bundle of six α-helices. CARD is related in sequence and structure to the death domain (DD, see

) and the death effector domain (DED, see

), which work in similar pathways and show similar interaction properties . The CARD domain typically associates with other CARD-containing proteins, forming either dimers or trimers. CARD domains can be found in isolation, or in combination with other domains. Domains associated with CARD include: NACHT (

) (in Nal1 and Bir1), NB-ARC (

) (in Apaf-1), pyrin/dapin domains (

) (in Nal1), leucine-rich repeats (

) (in Nal1), WD repeats (

) (in Apaf1), Src homology domains (

), PDZ (

), RING, kinase and DD domains .

CARD-containing proteins are involved in apoptosis through their regulation of caspases that contain CARDs in their N-terminal pro-domains, including human caspases 1, 2, 9, 11 and 12 . CARD-containing proteins are also involved in inflammation through their regulation of NF-kappaB . The mechanisms by which CARDs activate caspases and NF-kappaB involve the assembly of multi-protein complexes, which can facilitate dimerisation or serve as scaffolds on which proteases and kinases are assembled and activated.
Peptidase S1A, streptogrisin (Pept_S1A_streptogrisin)
Type: Family

This group of serine peptidases belong to the MEROPS peptidase family S1, subfamily S1E (streptogrisin A subfamily, clan PA(S)). A type example is streptogrisin A from Streptomyces griseus .
Inhibin, beta C subunit (Inhibin_betaC)
Type: Family

Inhibins and activins are glycoproteins, secreted by the gonads, that belong to the transforming growth factor beta family . They participate in differentiation and growth of diverse cell types. Inhibin inhibits secretion of follicle-stimulating hormone by the pituitary .

Inhibin has two isoforms, A and B, with the same alpha subunit but different beta subunits. Inhibin A is a dimer of alpha and beta A subunits, inhibin B is a dimer of alpha and beta B subunits.

Activin A is a dimer of beta A subunits, activin AB is a dimer of beta A and beta B chains.
Nuclear transition protein 1 (Nuclear_transition_prot1)
Type: Family

Nuclear transition protein 1 (TP1) is one of the spermatid-specific proteins . TP1 is a basic protein well conserved in mammalian species. In mammals, the second stage of spermatogenesis is characterised by the conversion of nucleosomal chromatin to the compact, non-nucleosomal and transcriptionally inactive form found in the sperm nucleus. This condensation is associated with a double-protein transition. The first transition corresponds to the replacement of histones by several spermatid-specific proteins (also called transition proteins) which are themselves replaced by protamines during the second transition.
Ionotropic glutamate receptor, C-terminal (Iontro_rcpt_C)
Type: Domain

There are three classes of ionotropic glutamate receptors (iGluRs), namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors. They are believed to play critical roles in synaptic plasticity. At many synapses in the brain, transient activation of NMDA receptors leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors and kainate receptors can act as the induction trigger for long-term changes in synaptic transmission .

Ionotropic glutamate receptors (iGluRs) are a highly conserved family of ligand-gated ion channels present in animals, plants, and bacteria, which are best characterised for their roles in synaptic communication in vertebrate nervous systems . A variant subfamily of iGluRs, the Ionotropic Receptors (IRs), consist of non-glutamate-binding chemosensory receptors first identified in Drosophila melanogaster. They function in detecting odors and tastants .
Hypoxia-inducible factor-1 alpha (HIF-1_alpha)
Type: Family

Hypoxia-inducible factors (HIFs) are transcription factors that respond to changes in available oxygen in the cellular environment. Specifically, they respond to decreases in oxygen, mediating the effects of hypoxia . HIFs are heterodimers, composed of an alpha and a beta subunit. At least 3 different alpha subunits are known to exist, termed HIF-1, -2 and -3 alpha. Beta subunits, meanwhile, are constitutively-expressed aryl hydrocarbon receptor nuclear translocators (ARNTs).

In addition to their role in hypoxia, HIFs have been shown to be involved in a range of processes, including angiogenesis, metal transport, mitochondrial function and cell growth .

This entry represents the HIF-1 alpha subunit.
Lamin tail domain (Lamin_tail_dom)
Type: Domain

Intermediate filaments (IFs) constitute a major structural element of metazoan cells. They build two distinct systems: one inside the nucleus attached to the inner membrane, and one that is cytoplasmic, which connects intercellular junctional complexes situated at the plasma membrane with the outer nuclear membrane. In both cases, their major function is assumed to be that of a mechanical stress absorber and an integrating device for the entire cytoskeleton. In the nucleus, the IF system is assembled from lamins, which together with an ever increasing number of associated transmembrane and chromatin-binding proteins constitute the nuclear lamina. Despite the large diversity among IF proteins, they all share a similar structural building plan, with a long central α-helical 'rod' domain that is flanked by non-α-helical N- and C-terminal end domains called 'head' and 'tail', respectively .

Lamins exhibit a highly conserved globular C-terminal lamin-tail domain (LTD) which has the immunoglobulin (Ig) fold. Invertebrate cytoplasmic IFs share sequence similarity with nuclear lamins and also contain a C-terminal tail domain with homology to the LTD .

Domains homologous to the LTD have been detected in several uncharacterised proteins from phylogenetically diverse bacteria and two archaea, Methanosarcina and Halobacterium. In several bacterial proteins, the LTD cooccurs with membrane-associated hydrolases of the metallo-beta-lactamase, synaptojanin, and calcineurin-like phosphoesterase superfamilies. In other secreted or periplasmic bacterial proteins, the LTDs are associated with oligosaccharide-binding domains or are present as multiple tandem repeats in a single protein. These associations suggest a potential role for the prokaryotic LTDs in tethering proteins to the membrane or membrane-associated structures. In contrast to the bacterial homologs, all animal LTDs are closely related and are contained in proteins with a stereotypic architecture. The precursor of the animal LTD might have been acquired via horizontal gene transfer from bacteria relatively late in the evolution of the eukaryotic crown group. Subsequent to this acquisition, a coiled-coil domain, derived from preexisting intermediate filament coil-coils, might have been fused to the N-terminal of the LTD .

The LTD domain could be involved both in protein and DNA binding . The LTD domain adopts an Ig-like fold of type s. It consists of a 2-layered sandwich of 9 anti-parallel β-strands arranged in two β-sheets with a Greek key topology. One of the sheets has five β-strands while the other has four. Seven of the 9 strands are present in the classical Ig fold topology .
Erythropoietin/thrombopoietin (EPO_TPO)
Type: Family

Erythropoietin, a plasma glycoprotein, is the primary physiological mediator of erythropoiesis . It is involved in the regulation of the level of peripheral erythrocytes by stimulating the differentiation of erythroid progenitor cells, found in the spleen and bone marrow, into mature erythrocytes . It is primarily produced in adult kidneys and foetal liver, acting by attachment to specific binding sites on erythroid progenitor cells, stimulating their differentiation . Severe kidney dysfunction causes reduction in the plasma levels of erythropoietin, resulting in chronic anaemia - injection of purified erythropoietin into the blood stream can help to relieve this type of anaemia. Levels of erythropoietin in plasma fluctuate with varying oxygen tension of the blood, but androgens and prostaglandins also modulate the levels to some extent . Erythropoietin glycoprotein sequences are well conserved, a consequence of which is that the hormones are cross-reactive among mammals, i.e. that from one species, say human, can stimulate erythropoiesis in other species, say mouse or rat .

Thrombopoietin (TPO), a glycoprotein, is the mammalian hormone which functions as a megakaryocytic lineage specific growth and differentiation factor affecting the proliferation and maturation from their committed progenitor cells acting at a late stage of megakaryocyte development. It acts as a circulating regulator of platelet numbers.