SII-SWORD/CoKE huggingface dataset:
Proteinase inhibitor I25C, fetuin, conserved site (Prot_inh_fetuin_CS)
Type: Conserved_site

The cystatins are a superfamily of similar proteins present in mammals, birds, fish, insects, plants and protozoa. In general they are potent peptidase inhibitors belonging to MEROPS inhibitor family I25, clan IH.

This family of proteinase inhibitors are cystatins belonging to MEROPS inhibitor family I25 (clan IH), subfamily I25C. They are primarily metalloprotease inhibitors, which include snake venom anti-hemorrhagic factors and the mammalian fetuins, for example:

Anti-hemorrhagic factor BJ46a, which is a potent inhibitor of atrolysin and jararhagin (MEROPS peptidase family M12) from the venomous snake Bothrops jararaca .

Anti-hemorrhagic factor, HSF, from the Japanese Habu snake (Trimeresurus flavoviridis). HSF contains two N-terminal cystatin domains which show a remarkable sequence homology (about 50%) to those of plasma glycoproteins such as alpha 2-HS (human) and fetuin (bovine) and to a lesser extent to that of HRG (human). In spite of the presence of cystatin domains, HSF does not inhibit cysteine proteinases such as papain and cathepsin B but does inhibit several metalloproteases in Habu venom .

Mammalian fetuins have been demonstrated to bind to matrix metalloproteinase (MMPs, MEROPS peptidase family M10). This binding protects the MMPs from autolytic degradation without interfering with their enzymatic activity .

Fetuins are known to consist of three domains: two tandemly arranged N-terminal cystatin domains (D1 and D2) and an unrelated domain (D3) located in the C-terminal region . When compared with the other members of this family, D3, especially its N-terminal half, varies greatly due to deletions, insertions or substitutions. Sequence comparisons suggest that the conformation of the human alpha2HS glycoprotein differs greatly from that of other members of this family. Human fetuin is a heterodimer of chains A and B, which are derived by cleavage of a connecting peptide from a common precursor. It is synthesised in the liver and selectively concentrated in bone matrix. It has a wide functional diversity having been shown to be involved in immune response, bone formation and resorption.
Haemagglutinin, influenzavirus A/B (Hemagglutn_influenz_A/B)
Type: Family

Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics . The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.

The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets . Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two α helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.

This entry represents the entire haemagglutinin protein (HA0) consisting of both the HA1 and HA2 regions, as found in influenza A and B viruses.
Adenosine deaminase domain (A_deaminase_dom)
Type: Domain

This entry represents the main structural domain of adenosine deaminase proteins.

Adenosine deaminases (

) are monomeric zinc dependent enzymes involved in purine metabolism. They are required for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. Adenosine deaminases convert adenosine to the related nucleoside inosine by the substitution of the amino group for a hydroxyl group. These enzymes are distantly related to AMP deaminases as they share three regions of sequence similarities; these regions are centred on residues which are proposed to play an important role in the catalytic mechanism of these two enzymes.

This entry also includes a group of adenine deaminases more related to the bacterial and eukaryotic adenosine deaminases than to Bacillus subtilis adenine deaminase and its bacterial homologues . Adenine deaminase catalyses the hydrolytic deamination of adenine to hypoxanthine.
Iron dependent repressor, metal binding and dimerisation domain (Fe_dep_repressor)
Type: Domain

The diphtheria toxin repressor protein (DTXR) is a member of this group . In Corynebacterium diphtheriae where it has been studied in some detail this protein acts as an iron-binding repressor of diphtheria toxin gene expression and may serve as a global regulator of gene expression. DTXR comprises an N-terminal DNA-binding domain, an interface domain (which contains two metal-binding sites) and a third, very flexible C-terminal domain. The second domain is responsible for dimerization and metal binding. The N terminus may be involved in iron binding and may associate with the Tox operator. Binding of DTXR to Tox operator requires a divalent metal ion such as cobalt, ferric, manganese and nickel whereas zinc shows weak activation .
TNFR/NGFR cysteine-rich region (TNFR/NGFR_Cys_rich_reg)
Type: Domain

A number of proteins, some of which are known to be receptors for growth factors, have been found to contain a cysteine-rich domain of about 110 to 160 amino acids in their N-terminal part, that can be subdivided into four (or in some cases, three) modules of about 40 residues containing 6 conserved cysteines. Some of the proteins containing this domain are listed below :

Tumor Necrosis Factor type I and type II receptors (TNFR). Both receptors bind TNF-alpha and TNF-beta, but are only similar in the cysteine-rich region. TNFR contains four cysteine-rich domain modules (CRDs), termed CRD1 through CRD4. CRD2 and CRD3 are known as TNF-binding domains .

Shope fibroma virus soluble TNF receptor (protein T2)

Lymphotoxin alpha/beta receptor

Low-affinity nerve growth factor receptor (LA-NGFR) (p75)

CD40 (Bp50), the receptor for the CD40L (or TRAP) cytokine

CD27, the receptor for the CD27L cytokine

CD30, the receptor for the CD30L cytokine

T-cell protein 4-1BB, the receptor for the 4-1BBL putative cytokine

FAS antigen (or APO-1), the receptor for FASL, a protein involved in apoptosis (programmed cell death)

T-cell antigen OX40, the receptor for the OX40L cytokine

Wsl-1, a receptor (for a yet undefined ligand) that mediates apoptosis

Vaccinia virus protein A53 (SalF19R)

It has been shown that the six cysteines all involved in intrachain disulphide bonds. A schematic representation of the structure of the 40 residue module of these receptors is shown below:

+-------------+ +--------------+
| | | |
xCxxxxxxxxxxxxxCxCxxCxxxxxxxxxCxxxxCxx
| |
+------------+

'C': conserved cysteine involved in a disulphide bond.
BIR repeat (BIR_rpt)
Type: Repeat

The BIR domain has a fold that is stabilised by zinc tetrahedrally coordinated by one histidine and three cysteine residues. The structure consists of three short α-helices and turns with the zinc packed in an unusually hydrophobic environment created by residues that are highly conserved among all BIRs. A subclass of repeats, comprising those at the C terminus of a series of BIR repeats from IAP proteins bearing RING finger domains, are likely to contain a C-terminal region that form an α-helix .

Proteins that are known to contain this domain include:

Baculoviruses apoptosis inhibitors (IAPs).

Mammalian apoptosis inhibitors 1 and 2 (IAP1 and IAP2; BIRC-2 and BIRC-3; MEROPS identifiers I32.002 and I32.003, respectively).

Mammalian X-linked inhibitor of apoptosis protein (X-linked IAP; MEROPS identifier I32.004).

Chicken IAP (ITA).

Human neuronal apoptosis inhibitory protein (NAIP, BIRC-1; MEROPS identifier I32.001).

Drosophila apoptosis inhibitors 1 and 2 (Iap1 and Iap2; MEROPS identifiers I32.009 and I32.011, respectively)).

African Swine Fever Virus (ASFV) protein p27.

The 'baculovirus inhibitior of apoptosis protein repeat' (BIR) is a domain of about 70 residues arranged in tandem repeats separated by a variable length linker, that seems to confer cell death-preventing activity. It is found in proteins belonging to the IAP (inhibitor of apoptosis proteins) family. The critical motifs required for anti-apoptotic activity of IAP proteins are the BIRs. All IAP proteins contain from one to three BIRs, and all known interactions between IAPs and other proteins are mediated by one or more BIRs . In higher eukaryotes, BIR domains inhibit apoptosis by acting as direct inhibitors of the caspase family of protease enzymes. Proteins with BIR domains are considered peptidase inhibitors in family I32. In yeast, BIR domains are involved in regulating cytokinesis. This novel fold is stabilized by zinc tetrahedrally coordinated by one histidine and three cysteine residues and resembles a classical zinc finger .
Glycoside hydrolase, family 14B, plant (Glyco_hydro_14B_pln)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Family 14 (

,

) encompasses the beta-amylase enzymes. Beta-amylases, which are found in plants and bacteria, hydrolyse 1,4-alpha-glucosidic linkages in starch-type polysaccharide substrates, removing successive maltose units from the non-reducing ends of the chains. In Solanum tuberosum (potato), the enzyme has been found to work optimally at 40 degrees C, becoming unstable above this temperature. On the basis of sequence comparisons, plant and bacterial beta-amylases can be readily distinguished from each other.

The 3D structure of a complex of soybean beta-amylase with an inhibitor (alpha-cyclodextrin) has been determined to 3.0A resolution by X-ray diffraction . The enzyme folds into large and small domains: the large domain has a (β α)8 super-secondary structural core, while the smaller is formed from two long loops extending from the β3 and β4 strands of the (β α)8 fold . The interface of the two domains, together with shorter loops from the (β α)8 core, form a deep cleft, in which the inhibitor binds . Two maltose molecules also bind in the cleft, one sharing a binding site with alpha-cyclodextrin, and the other sitting more deeply in the cleft .
Dynein light chain, type 1/2 (Dynein_light_chain_typ-1/2)
Type: Family

Dynein is a multisubunit microtubule-dependent motor enzyme that acts as the force generating protein of eukaryotic cilia and flagella. The cytoplasmic isoform of dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.

Dynein is composed of a number of ATP-binding large subunits (see

), intermediate size subunits and small subunits. Among the small subunits, there is a family of highly conserved proteins which make up this family . Proteins in this family act as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function and may play a role in changing or maintaining the spatial distribution of cytoskeletal structures. In yeast, it was identified as a component of the nuclear pore complex where it may contribute to the stable association of the Nup82 subcomplex with the nuclear pore complex .

Both type 1 (DLC1) and 2 (DLC2) dynein light chains have a similar two-layer α-β core structure consisting of β-α(2)-β-X-β(2) .
Cullin, N-terminal (Cullin_N)
Type: Domain

Cullins are a family of hydrophobic proteins that act as scaffolds for ubiquitin ligases (E3). Cullins are found throughout eukaryotes. Humans express several cullins (Cul1, 2, 3, 4A, 4B, 5, 7 and 9), each forming part of a multi-subunit ubiquitin complex . Cullin-RING ubiquitin ligases (CRLs), such as Cul1 (SCF) , play an essential role in targeting proteins for ubiquitin-mediated destruction; as such, they are diverse in terms of composition and function, regulating many different processes from glucose sensing and DNA replication to limb patterning and circadian rhythms. The catalytic core of CRLs consists of a RING protein and a cullin family member. For Cul1, the C-terminal cullin-homology domain binds the RING protein. The RING protein appears to function as a docking site for ubiquitin-conjugating enzymes (E2s). Other proteins contain a cullin-homology domain, such as the APC2 subunit of the anaphase-promoting complex/cyclosome and the p53 cytoplasmic anchor PARC; both APC2 and PARC have ubiquitin ligase activity. The N-terminal region of cullins is more variable, and is used to interact with specific adaptor proteins .

This entry represents the N-terminal region of cullin proteins, which consists of several domains, including cullin repeat domain, a 4-helical bundle domain, an α+β domain, and a winged helix-like domain.
R3H domain (R3H_dom)
Type: Domain

The R3H domain is a conserved sequence motif found in proteins from a diverse range of organisms including eubacteria, green plants, fungi and various groups of metazoans, but not in archaea and Escherichia coli. The domain is named R3H because it contains an invariant arginine and a highly conserved histidine, that are separated by three residues. It also displays a conserved pattern of hydrophobic residues, prolines and glycines. It can be found alone, in association with AAA domain or with various DNA/RNA binding domains like DSRM, KH, G-patch, PHD, DEAD box, or RRM. The functions of these domains indicate that the R3H domain might be involved in polynucleotide-binding, including DNA, RNA and single-stranded DNA .

The 3D structure of the R3H domain has been solved. The fold presents a small motif, consisting of a three-stranded antiparallel β-sheet, against which two α-helices pack from one side. This fold is related to the structures of the YhhP protein and the C-terminal domain of the translational initiation factor IF3. Three conserved basic residues cluster on the same face of the R3H domain and could play a role in nucleic acid recognition. An extended hydrophobic area at a different site of the molecular surface could act as a protein-binding site .
Peptidase S9, prolyl oligopeptidase, catalytic domain (Peptidase_S9_cat)
Type: Domain

This domain covers the active site serine of the serine peptidases belonging to MEROPS peptidase family S9 (prolyl oligopeptidase family, clan SC). The protein fold of the peptidase domain for members of this family resembles that of serine carboxypeptidase D, the type example of clan SC. Examples of protein families containing this domain are:

Prolyl endopeptidase (

) (PE) (also called post-proline cleaving enzyme). PE is an enzyme that cleaves peptide bonds on the C-terminal side of prolyl residues. The sequence of PE has been obtained from a mammalian species (pig) and from bacteria (Flavobacterium meningosepticum and Aeromonas hydrophila); there is a high degree of sequence conservation between these sequences.

Escherichia coli protease II (

) (oligopeptidase B) (gene prtB) which cleaves peptide bonds on the C-terminal side of lysyl and argininyl residues.

Dipeptidyl peptidase IV (

) (DPP IV). DPP IV is an enzyme that removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.

Saccharomyces cerevisiae (Baker's yeast) vacuolar dipeptidyl aminopeptidases A and B (DPAP A and DPAP B), encoded by the STE13 and DAP2 genes respectively. DPAP A is responsible for the proteolytic maturation of the alpha-factor precursor.

Acylamino-acid-releasing enzyme (

) (acyl-peptide hydrolase). This enzyme catalyses the hydrolysis of the amino-terminal peptide bond of an N-acetylated protein to generate a N-acetylated amino acid and a protein with a free amino-terminus.

These proteins belong to MEROPS peptidase families S9A, S9B and S9C.

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence . Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases .

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base . The geometric orientations of the catalytic residues are similar between families, despite different protein folds . The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .
Small ribosomal subunit protein eS6 (Ribosomal_eS6)
Type: Family

A number of eukaryotic and archaeal ribosomal proteins have been grouped on the basis of sequence similarities. Small ribosomal subunit protein eS6, previously known as Ribosomal protein S6 is the major substrate of protein kinases in eukaryotic ribosomes and may play an important role in controlling cell growth and proliferation through the selective translation of particular classes of mRNA.

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 .
Egg lysin (Sperm-lysin) (Egg_lysin)
Type: Family

This entry represents Egg-lysin from Haliotis rufescens and similar proteins from molluscs. This protein, also known as Sperm-lysin, binds to the egg vitelline envelope (VE) via the VE receptor for lysin (VERL) following its release from sperm. It then dissolves the VE non-enzymatically to create a hole, thereby allowing the sperm to pass through the envelope and fuse with the egg . Structurally, this protein consists of a bundle of helices and show species-specific binding to their egg receptor, possibly through differences in charged surface residues .
Large ribosomal subunit protein eL13 (Ribosomal_eL13)
Type: Family

This entry represents the ribosomal protein eL13 found in vertebrates , fruit fly, plants, yeast, amongst other eukaryotes and archaea.

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 .