SII-SWORD/CoKE huggingface dataset:
Ephrin, conserved site (Ephrin_CS)
Type: Conserved_site

Ephrins are a family of proteins that are ligands of class V (EPH-related) receptor protein-tyrosine kinases. These receptors and their ligands have been implicated in regulating neuronal axon guidance and in patterning of the developing nervous system and may also serve a patterning and compartmentalisation role outside of the nervous system as well.

Ephrins are membrane-attached proteins of 205 to 340 residues. Attachment appears to be crucial for their normal function. Type-A ephrins are linked to the membrane via a glycosylphosphatidylinositol (GPI)-linkage, while type-B ephrins are type-I membrane proteins.
Signal peptidase I, all-beta subdomain (Sign_pep_all-beta_subdom)
Type: Homologous_superfamily

The S26 family includes Escherichia coli signal peptidase, SPase, which is a membrane-bound endopeptidase with two N-terminal transmembrane segments and a C-terminal catalytic region . SPase functions to release proteins that have been translocated into the inner membrane from the cell interior, by cleaving off their signal peptides. In SPase proteins, this domain is inserted into a domain with a complex fold made of several coiled β-sheets that form a β-ribbon structure and contains an SH3-like β-barrel.

This superfamily represents an all-β-sheet subdomain (but not the β-ribbon domain it is inserted into) found in members of the peptidase S26A family of type 1 signal peptidase .
Erythropoietin/thrombopoeitin, conserved site (EPO/TPO_CS)
Type: Conserved_site

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 .

Thrombopoeitin (TPO), a glycoprotein, is the mammalian0 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.

EPO and TPO are evolutionary related. As a signature pattern, this entry represents a conserved region located at the N-terminal extremity of mature EPO and TPO and that includes two cysteines which have been shown, in human EPO, to be implicated in disulphide bonds.
Translation elongation factor, IF5A, hypusine site (Trans_elong_IF5A_hypusine_site)
Type: PTM

Translation initiation factor 5A (IF-5A) was previously reported to be involved in the first step of peptide bond formation in translation; however more recent work implicates it as a universally conserved translation elongation factor .

eIF5A is a cofactor for the Rev and Rex transactivator proteins of human immunodeficiency virus-1 and T-cell leukaemia virus I, respectively . IF-5A is the sole protein in eukaryotes and archaea to contain the unusual amino acid hypusine (Ne-(4- amino-2-hydroxybutyl)lysine) that is an absolute functional requirement. The first step in the post-translational modification of lysine to hypusine is catalyzed by the enzyme deoxyhypusine synthase, the structure of which has been reported.
Eukaryotic translation initiation factor 4E (eIF-4E), conserved site (TIF_eIF_4E_CS)
Type: Conserved_site

Eukaryotic translation initiation factor 4E (eIF-4E) is a protein that binds to the cap structure of eukaryotic cellular mRNAs. eIF-4E recognises and binds the 7-methylguanosine-containing (m7Gppp) cap during an early step in the initiation of protein synthesis and facilitates ribosome binding to a mRNA by inducing the unwinding of its secondary structures.
F-actin capping protein, beta subunit, conserved site (F-actin_capping_bsu_CS)
Type: Conserved_site

The actin filament system, a prominent part of the cytoskeleton in eukaryotic cells, is both a static structure and a dynamic network that can undergo rearrangements: it is thought to be involved in processes such as cell movement and phagocytosis , as well as muscle contraction.

The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike gelsolin (see

) and severin this protein does not sever actin filaments. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha and beta. Neither of the subunits shows sequence similarity to other filament-capping proteins .

The beta-subunit is a protein of about 280 amino acid residues whose sequence is well conserved in eukaryotic species . The signature pattern in this entry is a conserved hexapeptide in the N-terminal region of the beta-subunit.
Tyrosine 3-monooxygenase-like (Tyrosine_3-monooxygenase-like)
Type: Family

Phenylalanine, tyrosine and tryptophan hydroxylases constitute a family of tetrahydrobiopterin-dependent aromatic amino acid hydroxylases, all of which are rate-limiting catalysts for important metabolic pathways . The proteins are structurally and functionally related, each containing iron, and catalysing ring hydroxylation of aromatic amino acids, using tetra-hydrobiopterin (BH4) as a substrate. All are regulated by phosphorylation at serines in their N-termini. It has been suggested that the proteins each contain a conserved C-terminal catalytic (C) domain and an unrelated N-terminal regulatory (R) domain. It is possible that the R domains arose from genes that were recruited from different sources to combine with the common gene for the catalytic core. Thus, by combining with the same C domain, the proteins acquired the unique regulatory properties of the separate R domains.

A variety of enzymes belong to this family that includes, phenylalanine-4-hydroxylase from Chromobacterium violaceum where it is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa, phenylalanine-4-hydroxylase catalyzes the conversion of phenylalanine to tyrosine. In humans, deficiencies are the cause of phenylketonuria, the most common inborn error of amino acid metabolism , tryptophan 5-hydroxylase catalyzes the rate-limiting step in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy-anthranilate and tyrosine 3-hydroxylase catalyzes the rate limiting step in catecholamine biosynthesis: the conversion of tyrosine to 3,4-dihydroxy-L-phenylalanine.
Aromatic amino acid hydroxylase, C-terminal (Aromatic-AA_hydroxylase_C)
Type: Domain

Hydroxylation of the aromatic amino acids phenylalanine, tyrosine and tryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin (BH4) dependent enzymes: the aromatic amino acid hydroxylase . Theseenzymes are structurally and functionally similar. The eukaryotic forms include a regulatory N-terminal domain, a catalytic domain and a C-terminal oligomerization motif. The eukaryotic enzymes are all homotetramers .

Three-dimensional structures have been determined for the three types of enzymes. The iron atom is bound to three amino acid residues, two close histidine and a more distant acidic residue. This arrangement of ligands has been observed in a number of metalloproteins with divergent function .

Enzymes that belong to the aromatic amino acid hydroxylase family are listed below:

Phenylalanine-4-hydroxylase (

) (PAH). Catalyzes the conversion of phenylalanine to tyrosine. In humans, deficiencies of PAH are the cause of phenylketonuria, the most common inborn error of amino acid metabolism. In the bacteria Chromobacterium violaceum , PAH is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa .

Tyrosine 3-hydroxylase (

) (TYH). Catalyzes the rate limiting step in catecholamine biosynthesis: the conversion of tyrosine to 3,4- dihydroxy-L-phenylalanine.

Tryptophan 5-hydroxylase (

) (TRH). Catalyzes the rate-limiting step in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy- anthranilate.

This entry represents a domain containing the catalytic domain and the coiled-coil C-terminal oligomerization motif.
WD40 repeat, conserved site (WD40_repeat_CS)
Type: Conserved_site

This entry represents a conserved site found in the WD40 repeat.

WD-40 repeats (also known as WD or beta-transducin repeats) are short ~40 amino acid motifs, often terminating in a Trp-Asp (W-D) dipeptide. WD40 repeats usually assume a 7-8 bladed β-propeller fold, but proteins have been found with 4 to 16 repeated units, which also form a circularised β-propeller structure. WD-repeat proteins are a large family found in all eukaryotes and are implicated in a variety of functions ranging from signal transduction and transcription regulation to cell cycle control and apoptosis. Repeated WD40 motifs act as a site for protein-protein or protein-DNA interaction, and proteins containing WD40 repeats are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins . The specificity of the proteins is determined by the sequences outside the repeats themselves. Examples of such complexes are G proteins (beta subunit is a β-propeller), TAFII transcription factor, and E3 ubiquitin ligase . In Arabidopsis spp., several WD40-containing proteins act as key regulators of plant-specific developmental events.
Flagellar basal body rod protein, conserved site (Flagellar_basal_body_rod_CS)
Type: Conserved_site

Many bacterial species swim actively by means of flagella. The flagella organelle is made of three parts: the basal body, the hook and the filament. The basal body consists of four rings (L,P,S, and M) mounted on a central rod .

In Salmonella typhimurium and related organisms the rod has been shown to consist of four different, yet evolutionary related proteins: in the distal portion of the rod there are about 26 subunits of protein flgG and in the proximal portion there are about six subunits each of proteins flgB, flgC, and flgF. These four proteins contain a highly conserved asparagine-rich domain at their N terminus.
Formate C-acetyltransferase glycine radical, conserved site (Form_AcTrfase_GR_CS)
Type: Conserved_site

This entry represents a conserved site found in Formate acetyltransferase.

Protein radicals are components of several biologically important reactions. Glycyl radical enzymes are involved in a great variety of functions, for example, nucleotide, pyruvate and toluene metabolism . These enzymes are post-translationally interconverted, under anaerobic conditions, from an inactive to an active form that carries a stable radical localised to a specific glycine at the C-terminal region of the polypeptidic chain. Extreme sensitivity towards destruction by oxygen, leading to polypeptide cleavage between the N-C alpha-bond of the Gly residue, is a conspicuous property of all protein-based glycyl radicals, thus confining their existence to strictly anaerobic conditions.
Class I Hydrophobin, conserved site (Class_I_Hydrophobin_CS)
Type: Conserved_site

This entry represents a cysteine-rich conserved site found at the C-terminal end of class I hydrophobin sequences.

Hydrophobins are small, moderately hydrophobic extracellular proteins characterised by eight cysteine residues arranged in a strictly conserved motif. They are typically found on the outer surface of conidia and the hyphal wall, where they are thought to mediate contact and communication between the fungus and its environment . The hydrophobin family includes proteins such as cryparin, a cell surface-associated hydrophobin secreted by filamentous fungi ; cerato-ulmin, a secreted toxin implicated in Dutch elm disease ; and trihydrophobin from Claviceps fusiformis, which self-assembles at hydrophilic-hydrophobic interfaces on the hyphal surface . Hydrophobins are broadly categorised into two classes based on their solubility and assembly properties. Class I hydrophobins form rodlet bundles that coat aerial cell surfaces and contribute to cellular hydrophobicity, supporting fungal growth, development, and dispersal. In contrast, Class II hydrophobins form highly ordered films at water-air interfaces via intermolecular interactions but do not form rodlet structures. Hyd1 is a class II hydrophobin that not only fulfils structural roles but also functions as an elicitor of induced systemic resistance (ISR) in plants. During interaction with maize, Hyd1 binds the host target protein UBL and recruits additional UBL proteins in the roots, triggering defence responses such as cell death and activation of brassinosteroid, jasmonate (JA), and ethylene (ET) signalling pathways .
Galactose-1-phosphate uridyl transferase, class I His-active site (GalP_UDPtransf1_His-AS)
Type: Active_site

Galactose-1-phosphate uridyl transferase

(galT) catalyses the transfer of an uridyldiphosphate group on galactose (or glucose) 1-phosphate. During the reaction, the uridyl moiety links to a histidine residue. In the Escherichia coli enzyme, it has been shown that two histidine residues separated by a single proline residue are essential for enzyme activity. The first one is a ligand to a zinc ion and the second act as a nucleophile (and an active site).

On the basis of sequence similarities, two apparently unrelated families seem to exist. Class-I enzymes are found in eukaryotes as well as some bacteria such as E. coli or Streptomyces lividans, while class-II enzymes have been found so far only in bacteria such as Bacillus subtilis or Lactobacillus helveticus .

This entry represents the active site residues of the class-I enzymes.
Germin, manganese binding site (Germin_Mn-BS)
Type: Binding_site

Germins and germin-like proteins are a family of hexameric ubiquitous plant glycoproteins. They are not restricted to germinating grains as initially thought and therefore called 'germins', but they exist in all organs and developmental stages. They are all partly associated with the extracellular matrix.

A wide range of functions have been uncovered for germins and germin-like proteins: some act as oxalate oxidases (

) or as superoxide dismutases (

), while others seem to be structural proteins or receptors for auxins or other proteins.

Germins and germin-like proteins are highly similar to slime mold spherulins 1a and 1b which are proteins that accumulate specifically during spherulation, a process induced by various forms of environmental stress which leads to encystment and dormancy.
Ribosome maturation protein SDO1/SBDS, N-terminal (SDO1/SBDS_N)
Type: Domain

This entry represents the N-terminal domain of proteins that are highly conserved in species ranging from archaea to vertebrates and plants , including several Shwachman-Bodian-Diamond syndrome (SBDS, OMIM 260400) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. It is characterised by bone marrow failure and leukemia predisposition.

Members of this entry play a role in RNA metabolism . In yeast, SBDS orthologue SDO1 is involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with the EF-2-like GTPase RIA1 (EfI1), it triggers the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating TIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. This data links defective late 60S subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition .

The SBDS protein is composed of three domains. The N-terminal domain (FYSH, represented in this entry) is the most frequent target for disease mutations and contains a novel mixed α/β-fold, the central domain (

) consists of a three-helical bundle and the C-terminal domain (

) has a ferredoxin-like fold .
Zinc finger, PHD-type, conserved site (Zinc_finger_PHD-type_CS)
Type: Conserved_site

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

This entry represents the PHD (homeodomain) zinc finger domain , which is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in chromatin-mediated transcriptional regulation. The PHD finger motif is reminiscent of, but distinct from the C3HC4 type RING finger.

The function of this domain is not yet known but in analogy with the LIM domain it could be involved in protein-protein interaction and be important for the assembly or activity of multicomponent complexes involved in transcriptional activation or repression. Alternatively, the interactions could be intra-molecular and be important in maintaining the structural integrity of the protein. In similarity to the RING finger and the LIM domain, the PHD finger is thought to bind two zinc ions.

The signature of this entry starts at the first cysteine of the zinc finger region and ends at the last one. The spacing between cysteines in the PHD finger is closely related to that in the RING finger. Discrimination between these two domains with either a pattern or a profile is therefore difficult, and some rare domains are recognised by both the RING and PHD patterns and profiles.
Zinc finger, PHD-finger (Znf_PHD-finger)
Type: Domain

This entry represents the PHD (homeodomain) zinc finger domain , which is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in chromatin-mediated transcriptional regulation. The PHD finger motif is reminiscent of, but distinct from the C3HC4 type RING finger.

The function of this domain is not yet known but in analogy with the LIM domain it could be involved in protein-protein interaction and be important for the assembly or activity of multicomponent complexes involved in transcriptional activation or repression. Alternatively, the interactions could be intra-molecular and be important in maintaining the structural integrity of the protein. In similarity to the RING finger and the LIM domain, the PHD finger is thought to bind two zinc ions.

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
Xylulose 5-phosphate/Fructose 6-phosphate phosphoketolase, thiamine diphosphate binding site (Xul5P/Fru6P_PKetolase_ThDP_BS)
Type: Binding_site

Phosphoketolases (PK) are key enzymes of the pentose phosphate pathway of heterofermentative and facultative homofermentative lactic acid bacteria and of the D-fructose 6-phosphate shunt of bifidobacteria. PK activity has been sporadically reported in other microorganisms including eukaryotic yeasts. Xylulose-5-phosphate/fructose-6-phosphate phosphoketolase is a thiamine diphosphate (ThdP)-dependent enzyme found in bacteria such as Bifidobacterium sp . This enzyme has dual-specificity with the following catalytic activities:

: xylose 5-P + Pi = acetyl-P + glyeraldehyde-3-P

: fructose-6-P + Pi = acetyl-P + erythrose-4-P

Phosphoketolases are distantly related to transketolases, e.g.

.

A multiple alignment of PK sequences shows several highly conserved regions. The signature in this entry corresponds to the ThDP binding site .
Xylulose 5-phosphate/Fructose 6-phosphate phosphoketolase, conserved site (Xul5P/Fru6P_PKetolase_CS)
Type: Conserved_site

Phosphoketolases (PK) are key enzymes of the pentose phosphate pathway of heterofermentative and facultative homofermentative lactic acid bacteria and of the D-fructose 6-phosphate shunt of bifidobacteria. PK activity has been sporadically reported in other microorganisms including eukaryotic yeasts. Xylulose-5-phosphate/fructose-6-phosphate phosphoketolase is a thiamine diphosphate (ThdP)-dependent enzyme found in bacteria such as Bifidobacterium sp . This enzyme has dual-specificity with the following catalytic activities:

: xylose 5-P + Pi = acetyl-P + glyeraldehyde-3-P

: fructose-6-P + Pi = acetyl-P + erythrose-4-P

Phosphoketolases are distantly related to transketolases, e.g.

.

A multiple alignment of PK sequences shows several highly conserved regions. The function of the conserved site represented by the signature in this entry is unknown.