SII-SWORD/CoKE huggingface dataset:
Glycerate/sugar phosphate transporter, conserved site (Sugar-P_transporter_CS)
Type: Conserved_site

Proteins in this group are involved in the transport system that mediates the uptake of a number of sugar phosphates as well as the regulatory components that are responsible for induction of this transport system by external glucose 6-phosphate. In Escherichia coli its role in transmembrane signalling may involve sugar-phosphate-binding sites and transmembrane orientations similar to those of the transport protein . The following proteins in this entry, involved in the uptake of phosphorylated metabolites, are evolutionary related :

E. coli, Bacillus subtilis and Haemophilus influenzae glycerol-3- phosphate transporter (gene glpT).

Salmonella typhimurium phosphoglycerate transporter (gene pgtP).

E. coli and S. typhimurium hexose-6-phosphate transporter (gene uhpT).

E. coli and S. typhimurium protein uhpC. UhpC is necessary for the expression of uhpT and seems to act jointly with the uhpB sensor/kinase protein.

Human glucose 6-phosphate translocase .

These proteins of about 50kDa apparently contain 12 transmembrane regions.

This entry represents a conserved region in the central section of these transporters.
Mitogen-activated protein (MAP) kinase kinase kinase kinase (MAPKKKK)
Type: Family

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .

Eukaryotic serine-threonine mitogen-activated protein (MAP) kinases are key regulators of cellular signal transduction systems and are conserved from Saccharomyces cerevisiae (Baker's yeast) to human beings. MAPK pathways are signalling cascades differentially regulated by growth factors, mitogens, hormones and stress which mediate cell growth, differentiation and survival. MAPK activity is regulated through a (usually) three-tiered cascade composed of a MAPK, a MAPK kinase (MAPKK, MEK) and a MAPK kinase kinase (MAPKK, MEKK). Substrates for the MAPKs include other kinases and transcription factors .

This group represents a mitogen-activated protein kinase kinase kinase kinase, which may play a role in the response to environmental stress. It appears to act upstream of the JUN N-terminal pathway .
Histone H3-K79 methyltransferase, fungi (Dot1)
Type: Family

This entry represents a group of fungal histone H3-K79 methyltransferase, including Dot1 from Saccharomyces cerevisiae. Dot1 specifically methylates histone H3 to form H3K79me. This methylation is required for telomere silencing and for the pachytene checkpoint during the meiotic cell cycle by allowing the recruitment of Rad9 (yeast 53BP1 ortholog) to double strand breaks .
Ferredoxin-NADP+ reductase, adrenodoxin-type (Ferredox_Rdtase_adrenod)
Type: Family

This family represents a group of adrenodoxin-type ferredoxin reductases, including human Fdxr (NADPH:adrenodoxin oxidoreductase, mitochondrial) and Mycobacterium FprA .
Tyrosine hydroxylase, conserved site (Tyrosine_hydroxylase_CS)
Type: Conserved_site

This domain family is found in eukaryotes, and is approximately 30 amino acids in length. There is a single completely conserved residue G that may be functionally important. Tyrosine hydroxylase converts L-tyrosine to L-DOPA in the catecholamine synthesis pathway.
Saposin, chordata (Saposin_chordata)
Type: Family

Sphingolipids are bioactive compounds found in lower and higher eukaryotes. They are involved in the regulation of various cellular functions, such as growth, differentiation and apoptosis, and are believed to be essential in a healthy diet. Sphigolipids are degraded in the lysosome, and the products from their hydrolysis are used in other biosynthetic and regulatory pathways in the host.

There are a number of lysosomal enzymes involved in the breakdown of sphinogolipids, and these act in sequence to degrade the moieties . These enzymes require co-proteins called sphingolipid activator proteins, (SAPs or saposins), to stabilise and activate them as necessary. SAPs are non-enzymatic and usually have a low molecular weight. They are conserved across a wide range of eukaryotes and contain specific saposin domains that aid in the activation of hydrolase enzymes. There have been four human saposins described so far, sharing significant similarity with each other and with other eukaryotic SAP proteins.

Mutations in SAP genes have been linked to a number of conditions. A defect in the saposin B region leads to metachromatic leucodystrophy (MLD), while a single nucleotide polymorphism in the SAP-C region may give rise to Gaucher disease . More recently, an opportunistic protozoan parasite protein has shown similarity both to the higher and lower eukaryotic saposins. The pore-forming protein isolated from virulent Naegleria fowleri (Brain eating amoeba) has been dubbed Naegleriapore A. It also shares structural similarity with cytolytic bacterial peptides, although this similarity does not extend to the sequence level.

This entry represents a group of saposins found specifically in chordates.
Uncharacterised conserved protein, UCP027887, phosphatidlglycerophosphatase-related (UCP027887_Ptd-glyceroPase-rel)
Type: Family

This group represents an uncharacterised protein with a phosphatidlglycerophosphatase domain.
Bifunctional polymyxin resistance protein, ArnA (Bifun_polymyxin_resist_ArnA)
Type: Family

Bifunctional enzyme that catalyzes the oxidative decarboxylation of UDP-glucuronic acid (UDP-GlcUA) to UDP-4-keto-arabinose (UDP-Ara4O) and the addition of a formyl group to UDP-4-amino-4-deoxy-L-arabinose (UDP-L-Ara4N) to form UDP-L-4-formamido-arabinose (UDP-L-Ara4FN). The modified arabinose is attached to lipid A and is required for resistance to polymyxin and cationic antimicrobial peptides.
Histone H3-K79 methyltransferase, metazoa (DOT1L/grappa)
Type: Family

This entry represents a group of histone H3-K79 methyltransferases from insects and vertebrates. They are yeast Dot1 homologues that possess intrinsic H3-K79-specific histone methyltransferase (HMTase) activity . In Drosophila, it is also known as protein grappa (gpp), which is required for Polycomb Group (PcG) and trithorax Group (trxG) maintenance of expression. It is also involved in telomeric silencing, but do not affect centric heterochromatin .
DnaJ homologue subfamily C member 10 (ERdj5)
Type: Family

This group represents ER-resident disulfide reductase protein ERdj5, also known as DnaJ homologue subfamily C member 10. It is a endoplasmic reticulum co-chaperone, involved both in the correct folding of proteins that form obligatory non-native disulfides and degradation of misfolded proteins .
Core histone macro-H2A (Core_histone_macro-H2A)
Type: Family

This group represents a core histone macro-H2A.

MacroH2A is a variant of the major-type core histone H2A which contains an N-terminal H2A domain and a C-terminal nonhistone macro domain. Histone macroH2A is enriched on the inactive X chromosome of mammalian female cells . It does not bind poly ADP-ribose, but does bind the monomeric SirT1 metabolite O-acetyl-ADP-ribose (OAADPR) with high affinity through its macro domain . In addition, the macro domain of macroH2A associates with histone deacetylases and affects the acetylation status of nucleosomes. MacroH2A-containing nucleosomes are repressive toward transcription .
Uncharacterised conserved protein, RNA methylase-related (UCP006607_RNA_methylase-rel)
Type: Family

Members of this group are related to ribosomal protein L11 methyltransferase (

) and, therefore, are predicted to be RNA methylases.
Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (Algn-8)
Type: Family

This entry represents a group of proteins from Caenorhabditis, including Dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase from Caenorhabditis elegans (Algn-8), which operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
Uncharacterised conserved protein UCP037139 (UCP037139)
Type: Family

There are currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function.
Bifunctional inorganic polyphosphate/ATP-NAD kinase, predicted (Bifunctional_PpnK_predicted)
Type: Family

This group represents a bifunctional inorganic polyphosphate/ATP-NAD kinase from archaea. The enzyme from Methanocaldococcus jannaschii has been characterised and is involved in the NAD(H)/NADP(H) intracellular balance, producing the physiologically, required amount of NADP but not an excess. The enzyme has two domains, one phosphorylating NAD and the other dephosphorylating NADP .
Competence-induced protein CoiA (Competence-induced_CoiA)
Type: Family

This group represents competence protein CoiA found in bacteria belonging to the Bacilli class. It is required for optimal transformation . CoiA is a transient protein expressed specifically during competence and required for genetic transformation, but not for DNA uptake .
Serum albumin/Alpha-fetoprotein/Afamin (Serum_albumin/AFP/Afamin)
Type: Family

A number of serum transport proteins are known to be evolutionarily related, including albumin, alpha-fetoprotein, vitamin D-binding protein and afamin . Albumin is the main protein of plasma; it binds water, cations (such as Ca
2+
, Na
+
and K
+
), fatty acids, hormones, bilirubin and drugs - its main function is to regulate the colloidal osmotic pressure of blood. Alphafeto- protein (alpha-fetoglobulin) is a foetal plasma protein that binds various cations, fatty acids and bilirubin. Vitamin D-binding protein binds to vitamin D and its metabolites, as well as to fatty acids. The biological role of afamin (alpha-albumin) has not yet been characterised. The 3D structure of human serum albumin has been determined by X-ray crystallography to a resolution of 2.8A . It comprises three homologous domains that assemble to form a heart-shaped molecule . Each domain is a product of two subdomains that possess common structural motifs . The principal regions of ligand binding to human serum albumin are located in hydrophobic cavities in subdomains IIA and IIIA, which exhibit similar chemistry. Structurally, the serum albumins are similar, each domain containing five or six internal disulphide bonds, as shown schematically below:

+---+ +----+ +-----+
| | | | | |
xxCxxxxxxxxxxxxxxxxCCxxCxxxxCxxxxxCCxxxCxxxxxxxxxCxxxxxxxxxxxxxxCCxxxxCxxxx
| | | | | |
+-----------------+ +-----+ +---------------+

This entry includes serum albumin, alpha-fetoprotein and afamin.
Mercury(II) reductase (Mercury_reductase_MerA)
Type: Family

This entry represents the mercuric reductase found in the mer operon for the detoxification of mercury compounds. MerA is a FAD-containing flavoprotein which reduces Hg(II) to Hg(0) utilizing NADPH .
Protein lysine methyltranseferase, predicted (Protein_Lys_MeTrfase_predicted)
Type: Family

This entry represents a group of uncharacterised bacterial proteins, predicted to be lysine methyltranseferases.
Mitochondrial Rho GTPase (Miro)
Type: Family

Mitochondrial Rho (Miro) proteins are aberrant members of the small GTPase superfamily found in most eukaryotes. Miro contains a transmembrane region located at the C terminus anchors the protein to the outer membrane of mitochondria, the GTPase domains and EF-hands located in the cytoplasm. Miro and its cytoplasmic binding partner Milton/TRAK link mitochondria to kinesin and dynein molecular motors in various cell types . Mammals have two Miro orthologs , Miro1 and Miro2. They mediate mitochondrial trafficking in neurons by linking mitochondria to kinesin and dynein motor proteins for their transport in axons and dendrites . Yeasts have one Miro homologue, known as Gem1, which is part of the ERMES complex that links the ER to mitochondria . Interestingly, ERMES is absent in metazoa .
Protein SOSEKI, magnoliopsida (SOK_magnoliopsida)
Type: Family

This entry represents proteins SOSEKI 1-5 (SOK1-5) from Arabidopsis thaliana. SOSEKI proteins (SOK1-5) integrate apical-basal and radial organismal axes to localize to polar cell edges and contain a DIX oligomerization domain that resembles that in the animal Dishevelled polarity regulator . SOK2 is also known as Protein UPSTREAM OF FLC (UFC, At5g10150) and is part of a three-gene cluster containing FLC, UFC and DFC, which is coordinately regulated in response to vernalization .
N-terminal acetyltransferase A, auxiliary subunit (NatA_aux_su)
Type: Family

This entry represents N-terminal acetyltransferase A (NatA) auxiliary subunit, which is a non-catalytic component of the NatA N-terminal acetyltransferase that catalyses acetylation of proteins beginning with Met-Ser, Met-Gly and Met-Ala. N-terminal acetylation plays a role in normal eukaryotic translation and processing, protecting against proteolytic degradation and protein turnover. NAT1 anchors ARD1 and NAT5 to the ribosome, and may present the N terminus of nascent polypeptides for acetylation .
Tumour necrosis factor, conserved site (TNF_CS)
Type: Conserved_site

This entry represents α conserved site located in a β-strand in the central section of the protein which is conserved across all members of the Tumor Necrosis Factor family.

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities . Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia . The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine . A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers . Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide .

There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.

The following cytokines can be grouped into a family on the basis of sequence, functional, and structural similarities :

Tumor Necrosis Factor (TNF) (also known as cachectin or TNF-alpha) is a cytokine which has a wide variety of functions. It can cause cytolysis of certain tumor cell lines; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; finally, it can stimulate cell proliferation and induce cell differentiation under certain conditions.

Lymphotoxin-alpha (LT-alpha) and lymphotoxin-beta (LT-beta), two related cytokines produced by lymphocytes and which are cytotoxic for a wide range of tumor cells in vitro and in vivo .

T cell antigen gp39 (CD40L), a cytokine which seems to be important in B-cell development and activation.

CD27L, a cytokine which plays a role in T-cell activation. It induces the proliferation of costimulated T cells and enhances the generation of cytolytic T cells.

CD30L, a cytokine which induces proliferation of T cells.

FASL, a cytokine involved in cell death .

4-1BBL, a inducible T cell surface molecule that contributes to T-cell stimulation.

OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production .

TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis .

TNF-alpha is synthesised as a type II membrane protein which then undergoes post-translational cleavage liberating the extracellular domain. CD27L, CD30L, CD40L, FASL, LT-beta, 4-1BBL and TRAIL also appear to be type II membrane proteins. LT-alpha is a secreted protein.

All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.
Tumour necrosis factor family protein, CD30 ligand type (TNF_CD30_ligand_type)
Type: Family

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities . Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia . The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine . A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers . Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide .

There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.

The following cytokines can be grouped into a family on the basis of sequence, functional, and structural similarities :

Tumor Necrosis Factor (TNF) (also known as cachectin or TNF-alpha) is a cytokine which has a wide variety of functions. It can cause cytolysis of certain tumor cell lines; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; finally, it can stimulate cell proliferation and induce cell differentiation under certain conditions.

Lymphotoxin-alpha (LT-alpha) and lymphotoxin-beta (LT-beta), two related cytokines produced by lymphocytes and which are cytotoxic for a wide range of tumor cells in vitro and in vivo .

T cell antigen gp39 (CD40L), a cytokine which seems to be important in B-cell development and activation.

CD27L, a cytokine which plays a role in T-cell activation. It induces the proliferation of costimulated T cells and enhances the generation of cytolytic T cells.

CD30L, a cytokine which induces proliferation of T cells.

FASL, a cytokine involved in cell death .

4-1BBL, a inducible T cell surface molecule that contributes to T-cell stimulation.

OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production .

TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis .

TNF-alpha is synthesised as a type II membrane protein which then undergoes post-translational cleavage liberating the extracellular domain. CD27L, CD30L, CD40L, FASL, LT-beta, 4-1BBL and TRAIL also appear to be type II membrane proteins. LT-alpha is a secreted protein.

All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.

This group represents a tumour necrosis factor family protein, CD30 ligand type, also known as Tumor necrosis factor ligand superfamily member 8. It is a cytokine that binds to TNFRSF8/CD30, inducing proliferation of T-cell .
Band 4.1 protein, FERM domain, F1 sub-domain (EPB4.1_FERM_F1)
Type: Domain

Protein 4.1 (EPB4.1) is a major structural element of the erythrocyte membrane skeleton. It plays a key role in regulating physical properties of the membrane, such as mechanical stability and de-formability, by stabilising spectrin-actin interactions . It is required for dynein-dynactin complex and NUMA1 recruitment at the mitotic cell cortex during anaphase . The protein has been shown to associate with the nuclear mitotic apparatus, the contractile apparatus and tight junctions. Defects in this protein can cause elliptocytosis type 1 and hereditary pyropoikilocytosis.

Note: Band 4.1 and Band 7 (

) proteins refer to human erythrocyte membrane proteins separated by SDS polyacrylamide gels and stained with coomassie blue .

This entry represents the N-terminal F1 sub-domain of the FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain found in EPB4.1. This domain is also known as the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).
N6 adenine-specific DNA methyltransferase, TaqI class (N6_DNA_MeTrfase_TaqI)
Type: Family

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.

N6-MTase TaqI recognises the double-stranded sequence TCGA, causing specific methylation on A-4 on both strands which protects the DNA from cleavage by the TaqI endonuclease .
Peptidase M10A (Pept_M10A)
Type: Family

The MEROPS peptidase family M10, subfamily M10A, consists of extracellular metalloproteases, such as collagenase and stromelysin, that degrade the extracellular matrix and are known as matrixins or matrix metalloproteinases (MMPs). They are zinc-dependent, calcium-activated proteases synthesised as inactive precursors(zymogens), which are proteolytically cleaved to yield the active enzyme .

All matrixins and related proteins possess two domains: an N-terminal domain, and a zinc-binding active site domain. The N-terminal domain peptide, cleaved during the activation step, includes a conserved PRCGVPDV octapeptide, known as the cysteine switch, whose Cys residue chelates the active site zinc atom, rendering the enzyme inactive . The active enzyme degrades components of the extracellular matrix, playing a role in the initial steps of tissue remodelling during morphogenesis, wound healing, angiogenesis and tumour invasion . Although it was initially thought that the primary function of these enzymes is to degrade proteins of the extracellular matrix, MMPs have a much broader spectrum of activity that includes the proteolytic processing of cytokines, growth factors, growth factor receptors, and cell adhesion molecules .