SII-SWORD/CoKE huggingface dataset:
Laminin-type EGF domain (LE_dom)
Type: Domain

This entry represents the laminin-type EGF-like domain (LE) found in Laminin subunit gamma-1 and Netrin-1 from Homo sapiens and Mus musculus.

Laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation . They are composed of distinct but related alpha, beta and gamma chains that form a cross-shaped molecule consisting of a long arm and three short globular arms. The long arm has a coiled coil structure contributed by all three chains and cross-linked by interchain disulphide bonds . Beside the different types of globular domains each subunit contains, in its first half, consecutive repeats of about 60 amino acids in length that include eight conserved cysteines . The tertiary structure of this domain is remotely similar in its N-terminal to that of the EGF-like module (see

). The number of copies of the LE domain in the different forms of laminins is highly variable; from 3 up to 22 copies have been found. A schematic representation of the topology of the four disulphide bonds in the LE domain is shown below.

+-------------------+
+-|-----------+ | +--------+ +-----------------+
| | | | | | | |
xxCxCxxxxxxxxxxxCxxxxxxxCxxCxxxxxGxxCxxCxxgaagxxxxxxxxxxxCxx
sssssssssssssssssssssssssssssssssss

'C': conserved cysteine involved in a disulphide bond
'a': conserved aromatic residue
'G': conserved glycine (lower case = less conserved)
's': region similar to the EGF-like domain

Long consecutive arrays of LE domains in laminins form rod-like elements of limited flexibility , which determine the spacing in the formation of laminin networks of basement membranes .

Netrins control guidance of the central nervous system commissural axons and peripheral motor axons . This protein also serves as a survival factor via its association with its receptors which prevent the initiation of apoptosis, thus being involved in tumorigenesis .
Haem oxygenase (Haem_Oase)
Type: Family

Haem oxygenase (

) (HO) is the microsomal enzyme that, in animals, carries out the oxidation of haem, it cleaves the haem ring at the alpha-methene bridge to form biliverdin and carbon monoxide . Biliverdin is subsequently converted to bilirubin by biliverdin reductase. In mammals there are three isozymes of haem oxygenase: HO-1 to HO-3. The first two isozymes differ in their tissue expression and their inducibility: HO-1 is highly inducible by its substrate haem and by various non-haem substances, while HO-2 is non-inducible. It has been suggested that HO-2 could be implicated in the production of carbon monoxide in the brain where it is said to act as a neurotransmitter. In the genome of the chloroplast of red algae as well as in cyanobacteria, there is a haem oxygenase (gene pbsA) that is the key enzyme in the synthesis of the chromophoric part of the photosynthetic antennae . A haem oxygenase is also present in the bacteria Corynebacterium diphtheriae (gene hmuO), where it is involved in the acquisition of iron from the host haem . There is, in the central section of these enzymes, a well-conserved region centred on a histidine residue.
DNA methylase, N-6 adenine-specific, conserved site (DNA_methylase_N6_adenine_CS)
Type: Conserved_site

In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. There are 2 major classes of DNA methyltransferase that differ in the nature of the modifications they effect. The members of one class (C-MTases) methylate a ring carbon and form C5-methylcytosine (see PRINTS signature C5METTRFRASE). Members of the second class (N-MTases) methylate exocyclic nitrogens and form either N4-methylcytosine (N4-MTases) or N6-methyladenine (N6-MTases). Both classes of MTase utilise the cofactor S-adenosyl-L-methionine (SAM) as the methyl donor and are active as monomeric enzymes .

N-6 adenine-specific DNA methylases (

) (A-Mtase) are enzymes that specifically methylate the amino group at the C-6 position of adenines in DNA. Such enzymes are found in the three existing types of bacterial` restriction-modification systems (in type I system the A-Mtase is the product of the hsdM gene, and in type III it is the product of the mod gene). All of these enzymes recognise a specific sequence in DNA and methylate an adenine in that sequence. It has been shown that A-Mtases contain a conserved motif Asp/Asn-Pro-Pro-Tyr/Phe in their N-terminal section, this conserved region could be involved in substrate binding or in the catalytic activity.
Glycoside hydrolase, family 25 (Glyco_hydro_25)
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.

Glycoside hydrolase family 25

comprises enzymes with only one known activity; lysozyme (

).

It has been shown that a number of cell-wall lytic enzymes are evolutionary related and can be classified into a single family. Two residues, an aspartate and a glutamate, have been shown to be important for the catalytic activity of the
Charalopsis
enzyme. These residues as well as some others in their vicinity are conserved in all proteins from this family.
DNA-directed DNA polymerase X (DNA-dir_DNA_pol_X)
Type: Domain

DNA carries the biological information that instructs cells how to exist in an ordered fashion: accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP) residues to the 5'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. Three motifs, A, B and C , are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-β secondary structure .

DNA polymerases (

) can be classified, on the basis of sequence similarity , into at least four different groups: A, B, C and X. X family polymerases fill in short gaps during DNA repair, and are small (about 40kDa) compared with other polymerases. They are relatively inaccurate enzymes and play roles in base excision repair, in non-homologous end joining (NHEJ) which acts mainly to repair damage due to ionizing radiation, and in V(D)J recombination . X family polymerases include eukaryotic Pol beta, Pol lambda, Pol mu and terminal deoxynucleotidyl-transferase (TdT) (

). Pol beta and Pol lambda are primarily DNA template-dependent polymerases, whereas TdT is a DNA template-independent polymerase . Pol mu has both template dependent and template independent activities . These enzymes catalyse addition of nucleotides in a distributive manner, i.e. they dissociate from the template-primer after addition of each nucleotide. DNA-polymerases show a degree of structural similarity with RNA-polymerases.

This domain is found either at the extreme N or C termini of DNA polymerase X proteins.
Protein import receptor MAS20 (MAS20)
Type: Family

Virtually all mitochondrial precursors are imported via the same mechanism : precursors first bind to receptors on the mitochondrial surface, then insert into the translocation channel in the outer membrane. Many outer-membrane proteins participate in the early stages of import, four of which (MAS20, MAS22, MAS37 and MAS70) are components of the receptor. MAS20, which forms a subcomplex with MAS22, seems to interact with most or all mitochondrial precursors, suggesting that the protein binds directly to mitochondrial targeting sequences. The MAS37 and MAS70 components also form a subcomplex, the two subcomplexes possibly binding via their trans- membrane (TM) regions - the TM region of MAS70 promotes oligomerisation of attached protein domains and shares sequence similarity with the TM region of MAS20 .

MAS20 is also known as TOM20.
Isopenicillin N synthase, conserved site (Isopenicillin-N_synth_CS)
Type: Conserved_site

Isopenicillin N synthase (IPNS) (

) is a nonhaem-Fe
2+
-dependent enzyme that belongs to a class of nonhaem Fe
2+
-containing enzymes, which includes 2-oxoglutarate-dependent dioxygenases, 2-oxoglutarate-dependent hydroxylases, and enzymes involved in ethylene formation and anthocyanin biosynthesis. IPNS catalyses the stereospecific formation of the beta-lactam and thiazolidine rings of IPN via a 4-electron oxidation of the tripeptide ACV. The enzyme uses, as the sole electron acceptor, one molecule of dioxygen, which is completely reduced to two molecules of water. The oxygen stoichiometry shown by IPNS is the same as that for cytochrome C oxidase, but is unusual for nonhaem-iron-containing enzymes, which typically catalyse the transfer of one or both atoms of dioxygen into their substrates. IPNS thus provides an interesting contrast to dioxygenase enzymes.

Two cysteines are conserved in fungal and bacterial IPNS sequences; these may be involved in iron-binding and/or substrate-binding.

Cephalosporium acremonium DAOCS/DACS is a bifunctional enzyme involved in cephalosporin biosynthesis. The DAOCS domain, which is structurally related to IPNS, catalyses the step from penicillin N to deacetoxy-cephalosporin C- used as a substrate by DACS to form deacetylcephalosporin C. Streptomyces clavuligerus possesses a monofunctional DAOCS enzyme (gene cefE) also related to IPNS.
PAP/25A-associated (PAP_assoc)
Type: Domain

This domain is found in eukaryotic poly(A) polymerases and terminal uridylyltransferases. It has been shown to have polynucleotide adenylyltransferase activity .
Cold-shock protein Csp, DNA-binding (CSP_DNA-bd)
Type: Domain

When Escherichia coli is exposed to a temperature drop from 37 to 10 degrees centigrade, a 4-5 hour lag phase occurs, after which growth is resumed at a reduced rate . During the lag phase, the expression of around 13 proteins, which contain specific DNA-binding regions , is increased 2-10 fold. These so-called 'cold shock' proteins (CSPs) are thought to help the cell to survive in temperatures lower than optimum growth temperature, by contrast with heat shock proteins, which help the cell to survive in temperatures greater than the optimum, possibly by condensation of the chromosome and organisation of the prokaryotic nucleoid . A conserved domain of about 70 amino acids has been found in prokaryotic and eukaryotic DNA-binding proteins . This domain is known as the 'cold-shock domain' (CSD), part of which is highly similar to the RNP-1 RNA-binding motif.

CSPs include the major cold-shock proteins CspA and CspB in bacteria and the eukaryotic gene regulatory factor Y-box protein. CSP expression is up-regulated by an abrupt drop in growth temperature. CSPs are also expressed under normal condition at lower level. The function of cold-shock proteins is not fully understood. They preferentially bind poly-pyrimidine region of single-stranded RNA and DNA . CSPs are thought to bind mRNA and regulate ribosomal translation, mRNA degradation, and the rate of transcription termination. The human Y-box protein, which contains a CSD , regulates transcription and translation of genes that contain the Y-box sequence in their promoters. This specific ssDNA-binding properties of CSD are required for the binding of Y-box protein to the promoter's Y-box sequence, thereby regulating transcription.
Squalene/phytoene synthase (Squ/phyt_synthse)
Type: Family

Squalene synthase

(farnesyl-diphosphate farnesyltransferase)(SQS) and phytoene synthase

(PSY) share a number of functional similarities. These similarities are also reflected at the level of their primary structure . In particular three well conserved regions are shared by SQS and PSY; they could be involved in substrate binding and/or the catalytic mechanism. SQS catalyses the conversion of two molecules of farnesyl diphosphate (FPP) into squalene. It is the first committed step in the cholesterol biosynthetic pathway. The reaction carried out by SQS is catalysed in two separate steps: the first is a head-to-head condensation of the two molecules of FPP to form presqualene diphosphate; this intermediate is then rearranged in a NADP-dependent reduction, to form squalene:

2 FPP ->presqualene diphosphate + NADP ->squalene

SQS is found in eukaryotes. In yeast it is encoded by the ERG9 gene, in mammals by the FDFT1 gene. SQS seems to be membrane-bound.

PSY catalyses the conversion of two molecules of geranylgeranyl diphosphate (GGPP)into phytoene. It is the second step in the biosynthesis of carotenoids from isopentenyl diphosphate. The reaction carried out by PSY is catalysed in two separate steps: the first is a head-to-head condensation of the two molecules of GGPP to form prephytoene diphosphate; this intermediate is then rearranged to form phytoene:

2 GGPP ->prephytoene diphosphate ->phytoene

PSY is found in all organisms that synthesise carotenoids: plants and photosynthetic bacteria as well as some non-photosynthetic bacteria and fungi. In bacteria PSY is encoded by the gene crtB. In plants PSY is localised in the chloroplast.
Scorpion long chain toxin/defensin (Scorpion_toxinL/defensin)
Type: Family

This family contains both neurotoxins and plant defensins. The mustard trypsin inhibitor, MTI-2, is a plant defensin. It is a potent inhibitor of trypsin with no activity towards chymotrypsin. MTI-2 is toxic for Lepidopteran insects, but has low activity against aphids . The scorpion toxin (a neurotoxin) binds to sodium channels and inhibits the activation mechanisms of the channels, thereby blocking neuronal transmission .
Oxytocin receptor (Oxytocn_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Vasopressin and oxytocin are members of the neurohypophyseal hormone family found in all mammalian species. They are present in high levels in the posterior pituitary. Oxytocin stimulates contraction of uterine smooth muscle, and stimulates milk secretion in response to suckling by inducing contraction of myoepithelial cells in the mammary gland. Clinically, it is used to induce labour and promote lactation.

Oxytocin receptors are found in uterine smooth muscle, myoepithelial cells in the mammary gland, and in the pituitary. Activation of phosphoinositide metabolism is effected via a pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
Haemerythrin (Haemerythrin)
Type: Family

The hemerythrin family is composed of hemerythrin proteins found in invertebrates, and a broader collection of bacterial and archaeal homologues. Hemerythrin is an oxygen-binding protein found in the vascular system and coelomic fluid, or in muscles (myohemerythrin) in invertebrates . Many of the homologous proteins found in prokaryotes are multi-domain proteins with signal-transducing domains such as the GGDEF diguanylate cyclase domain (

) and methyl-accepting chemotaxis protein (MCP) signalling domain (

). Most hemerythrins are oxygen-carriers with a bound non-haem iron, but at least one example is a cadmium-binding protein, apparently with a role in sequestering toxic metals rather than in binding oxygen. The prokaryote with the most instances of this domain is Magnetococcus sp. MC-1, a magnetotactic bacterium.

Hemerythrins and myohemerythrins are small proteins of about 110 to 129 amino acid residues that bind two iron atoms. They are left-twisted 4-α-helical bundles, which provide a hydrophobic pocket where dioxygen binds as a peroxo species, interacting with adjacent aliphatic side chains via van der Waals forces . In both hemerythrins and myohemerythrins, the active centre is a binuclear iron complex, bound directly to the protein via 7 amino acid side chains , 5 His, 1 Glu and 1 Asp . Ovohemerythrin , a yolk protein from the leech Theromyzon tessulatum seems to belong to this family of proteins, it may play a role in the detoxification of free iron after a blood meal .

This entry represents the haemerythrin family of proteins.
Thiol peroxidase Tpx (TPX)
Type: Family

Escherichia coli protein Tpx is a bacterial, periplasmic antioxidant protein with a thiol peroxidase activity. It is a small protein of 18kDa whose sequence is well conserved in other bacterial species. Tpx which differs from other peroxidases (PRXs) in that it shows substrate specificity toward alkyl hydroperoxides over hydrogen peroxide. As with all other PRXs, the peroxidatic cysteine (N-terminal) of Tpx is oxidized into a sulfenic acid intermediate upon reaction with peroxides. Tpx is able to resolve this intermediate by forming an intramolecular disulfide bond with a conserved C-terminal cysteine (the resolving cysteine), which can then be reduced by thioredoxin . This differs from the typical 2-cys PRX which resolves the oxidized cysteine by forming an intermolecular disulfide bond with the resolving cysteine from the other subunit of the homodimer. Atypical 2-cys PRX homodimers have a loop-based interface (A-type for alternate), in contrast with the B-type interface of typical 2-cys and 1-cys PRXs .
Mitochondrial carrier protein (MCP)
Type: Family

This family includes mitochondrial carrier proteins that transport a broad variety of substrates and, therefore, they are involved in different metabolic pathways such as the TCA cycle, lipid metabolism, nucleotides metabolism and energy transfer . Some examples of this group are the uncoupling proteins (UCPs). This family also includes peroxisomal proteins like PMP34 .

Mitochondrial brown fat uncoupling protein 1 from chordates (UCP1) is responsible for thermogenic respiration, a specialised capacity of brown adipose tissue to the regulation of energy balance. It regulates the production of reactive oxygen species/ROS by mitochondria .

A variety of substrate carrier proteins involved in energy transfer are found in the inner mitochondrial membrane or are integral to the membranes of other eukaryotic organelles such as the peroxisome . Such proteins include:

ADP/ATP carrier protein (ADP/ATP translocase)

2-oxoglutarate/malate carrier protein

Phosphate carrier protein

Tricarboxylate transport protein (or citrate transport protein)

Graves disease carrier protein

Yeast mitochondrial proteins MRS3 and MRS4

Yeast mitochondrial FAD carrier protein

And many others

These mitochondrial carrier proteins share a tripartite structure, consisting of up to three tandem repeats of a domain approximately 100 residues in length . Each domain contains two transmembrane (TM) regions, resulting in a total of six TM domains. Sequence analysis has shown that the TM regions and their adjacent hydrophilic loops are more highly conserved than other parts of the protein, with five of the six TM domains followed by the conserved motif (D/E)-Hy(K/R), where Hy denotes a hydrophobic residue . Structurally, these domains contain six α-helices that form a compact transmembrane unit. This structure exhibits a deep depression on the side facing the space between the inner and outer mitochondrial membranes, resembling a channel-like conformation . It is suggested that substrates bind at the bottom of this cavity, and translocation occurs through a conformational change from a 'pit' to a 'channel' structure.
Alpha crystallin/Hsp20 domain (A-crystallin/Hsp20_dom)
Type: Domain

Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of proteins collectively known as heat-shock proteins (hsp) . Amongst them is a family of proteins with an average molecular weight of 20 Kd, known as the hsp20 proteins . These seem to act as chaperones that can protect other proteins against heat-induced denaturation and aggregation. Hsp20 proteins seem to form large heterooligomeric aggregates.

These low-molecular-weight proteins are evolutionarily related to alpha-crystallin . Alpha-crystallin is an abundant constituent of the eye lens of most vertebrate species. Its main function appears to be to maintain the correct refractive index and transparency of the lens. It is also found in other tissues where it seems to act as a chaperone . Other related proteins include certain surface antigens .

This entry represents a conserved C-terminal domain of about 100 residues characteristic of this group of proteins .
Interferon gamma (Interferon_gamma)
Type: Family

Interferon gamma (IFN-gamma) is produced by lymphocytes activated by specific antigens or mitogens. IFN-gamma shows antiviral activity and has important immunoregulatory functions. It is a potent activator of microphages and had antiproliferative effects on transformed cells. It can potentiate the antiviral and antitumor effects of the type I interferons.

The crystal structures of a number IFN-gamma proteins have been solved, including bovine interferon-gamma at 2.0-A and human IFN-gamma at 2.9-A .