SII-SWORD/CoKE huggingface dataset:
Mitogen-activated protein (MAP) kinase, conserved site (MAP_kinase_CS)
Type: Conserved_site

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 .

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 .
Long hematopoietin receptor, single chain, conserved site (Long_hematopoietin_rcpt_CS)
Type: Conserved_site

A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.

Several receptor chains for large hematopoietins are structurally related such that their extracellular parts strictly contain the 200 amino-acids hematopoietin domain, duplicated in the thrombopoietin receptor and in avian prolactin receptors. This subgroup of receptor chains contains: Growth hormone receptor (GHR), Prolactin receptor (PRLR), Erythropoietin receptor (EPOR), Thrombopoietin receptor (TPOR).

A schematic representation of the structure of these receptors is shown below:

+----------------------------------------xxxxxxx-------------------------+
| C C C C Extracellular XXXXXXX Cytoplasmic |
+-|-|-------|--|-------------------------xxxxxxx-------------------------+
| | | | Transmembrane
+-+ +--+

These receptor chains are single components of receptors that homodimerize upon binding of the cognate cytokine, following the structural model described for the growth hormone-receptor complex .
Long hematopoietin receptor, Gp130 family 2, conserved site (Hematopoietin_rcpt_Gp130_CS)
Type: Conserved_site

A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.

One subset of individual receptor chains that are part of receptor complexes for large hematopoietins contain common structural elements in their extracellular parts: an immunoglobulin-like domain, an hematopoietin-receptor domain, and 3 fibronectin type-III domains (2 in the leptin receptor). This subgroup was designated as "Gp130 family of receptors" and contains the following chains: Leptin receptor (LPTR), Granulocyte colony stimulating factor receptor (GCSFR), Interleukin-6/-11/LIF/OSM/CNTF common beta chain (Gp130), Leukemia inhibiting factor receptor (LIFR), Oncostatin-M receptor beta chain (OSMR), Interleukin-12 receptor beta-1 chain (IL12RB1), Interleukin-12 receptor beta-2 chain (IL12RB2).

A schematic representation of the structure of these receptors is shown below:

+-------+-------------------------+-----------------xxxxxxx-----------------+
|Ig-like| C C C C Extracellular | FnIII (x3) XXXXXXX Cytoplasmic |
+-------+-|-|--|--|---------------+-----------------xxxxxxx-----------------+
| | | | Transmembrane
+-+ +--+

These receptor chains homodimerize (GCSFR, Gp130, LPTR) or heterodimerize (Gp130 with LIFR or OSMR, IL12RB1 with IL12RB2) upon binding of the cognate cytokine: G-CSF, LIF, OSM, LPT, or the cytokine/alpha chain complex: IL-6/IL6RA, IL-11/IL11RA, CNTF/CNTFRA, IL-12 (p35/p40) .
Long hematopoietin receptor, soluble alpha chain, conserved site (Hematopoietin_rcpt_L_F3_CS)
Type: Conserved_site

A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.

One subset of individual receptor chains that are part of receptor complexes for large hematopoietins contain common structural elements in their extracellular parts: an immunoglobulin-like domain at the N-terminal end of the hematopoietin receptor domain (except for the EBCV-induced interleukin-12 beta chain) and a short (or no) cytoplasmic domain. They define a structural subgroup containing the following chains: Interleukin-6 receptor alpha chain (IL6RA). Interleukin-11 receptor alpha chain (IL11RA), Ciliary neurotrophic factor receptor alpha chain (CNTFRA), Interleukin-12 beta chain p40 (IL12BC), Interleukin-12 beta chain induced by Epstein-Barr virus (strain GD1) (HHV-4) (Human herpesvirus 4).

Members of this subgroup bind to their cognate cytokines with low affinity and possess transmembrane and short cytoplasmic domains (IL6RA and IL11RA), or are GPi-linked membrane proteins (CNTFRA). Truncated soluble forms of IL-6 and CNTF receptors alpha chains are physiologically active . IL-12 is an heterodimeric cytokine made of an alpha chain (p35) and a beta chain (p40). p40 (IL12BC) can be regarded as an alpha chain receptor devoid of cytoplasmic domain . Members of this family have the ability to bind corresponding cytokines with no signalling function.
Short hematopoietin receptor, family 1, conserved site (Hempt_rcpt_S_F1_CS)
Type: Conserved_site

A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins.

One subset of individual receptor chains that are part of receptor complexes for small hematopoietins are structurally related such that their extracellular parts strictly contain the 200 amino-acids hematopoietin domain (duplicated in IL-3/-5/GM-CSF beta chain receptors KH97/AIC2B and AIC2A). They define a structural subgroup containing the following chains: Interleukin-2 receptor beta chain (IL2RB), Interleukin-2 receptor common gamma chain (IL2RG), Interleukin-3 receptor beta chain (AIC2A), Interleukin-3/-5/GM-CSF receptor common beta chain (KH97/AIC2B), Interleukin-4 receptor alpha chain (IL4RA), Interleukin-7 receptor alpha chain (IL7RA), Interleukin-9 receptor alpha chain (IL9RA).
Short hematopoietin receptor, family 2, conserved site (Short_hematopoietin_rcpt_2_CS)
Type: Conserved_site

A number of receptors for lymphokines, hematopoietic growth factors and growth hormone-related molecules have been found to share a common binding domain. These receptors are designated as hematopoietin receptors and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: large (long) and small (short) hematopoietins.

One subset of individual receptor chains that are part of receptor complexes for small hematopoietins contain common structural elements: an extracellular receptor domain that contains an immunoglobulin-like region at the N-terminal end; a transmembrane domain; and a short cytoplasmic domain. They define a structural subgroup containing the following chains:

Granulocyte/macrophage colony stimulating factor receptor alpha (GMCSFRA)

Interleukin-3 receptor alpha chain (IL3RA)

Interleukin-5 receptor alpha chain (IL5RA)

Interleukin-13 receptor alpha-1 chain (IL13RA1)

Interleukin-13 receptor alpha-2 chain (IL13RA2)

GMCSFRA, IL3RA or IL5RA chains of this subgroup bind to their cognate cytokines: GM-CSF, IL-3 and IL-5, with a common beta chain, KH97/AIC2B . Either IL13RA1 chain or IL13RA2 chain form the IL13R complex together with IL4RA chain. IL-4 can compete with IL-13 to bind to either IL13R form .
Doublecortin domain (Doublecortin_dom)
Type: Domain

X-linked lissencephaly is a severe brain malformation affecting males. Recently it has been demonstrated that the doublecortin gene is implicated in this disorder . Doublecortin was found to bind to the microtubule cytoskeleton. In vivo and in vitro assays show that Doublecortin stabilises microtubules and causes bundling . Doublecortin is a basic protein with an iso-electric point of 10, typical of microtubule-binding proteins. However, its sequence contains no known microtubule-binding domain(s).

The detailed sequence analysis of Doublecortin and Doublecortin-like proteins allowed the identification of an evolutionarily conserved Doublecortin (DC) domain, which is ubiquitin-like. This domain is found in the N terminus of proteins and consists of one or two tandemly repeated copies of an around 80 amino acids region. It has been suggested that the first DC domain of Doublecortin binds tubulin and enhances microtubule polymerisation .

Some proteins known to contain a DC domain are listed below:

Doublecortin. It is required for neuronal migration . A large number of point mutations in the human DCX gene leading to lissencephaly are located within the DC domains .

Human serine/threonine-protein kinase DCAMKL1. It is a probable kinase that may be involved in a calcium-signaling pathway controlling neuronal migration in the developing brain .

Retinitis pigmentosa 1 protein. It is required for the differentiation of photoreceptor cells. Mutation in the human RP1 gene cause retinitis pigmentosa of type 1 .
Intimin/invasin bacterial adhesion mediator protein (Intimin/invasin_bac)
Type: Family

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior. There have been four secretion systems described in animal enteropathogens, such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia .

The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis. However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part of the flagellum itself , type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.

Exotoxins secreted by the type III system do not possess a secretion signal, and are considered unique for this reason . Enteropathogenic and entero-haemorrhagic Escherichia coli secrete the bacterial adhesion mediation molecule intimin , which targets the translocated intimin receptor, Tir. Tir is secreted by the bacteria and is embedded in the target cell's plasma membrane . This facilitates bacterial cell attachment to the host.

The crystal structure of an enteropathogenic E. coli intimin C-terminal fragment has been determined to 1.9A resolution. The structure has also been resolved in complex with the Tir intimin-binding domain, giving insight into the molecular mechanisms of adhesion in attaching and effacing pathogens .

Invasin is a protein that allows enteric bacteria to penetrate cultured mammalian cells . The entry of invasin in the cell is mediated by binding several beta-1 chain integrins .

This entry also includes Inverse autotransporter adhesin YeeJ which may be involved in biofilm formation and cell adhesion. Overexpression of YeeJ shows increased mature biofilm formation .
Translocated intimin receptor, central domain (Transloc_intimin_rcpt_cen_dom)
Type: Domain

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior. There have been four secretion systems described in animal enteropathogens, such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia .

The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis. However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part of the flagellum itself , type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.

Exotoxins secreted by the type III system do not possess a secretion signal, and are considered unique for this reason . Enteropathogenic and entero-haemorrhagic Escherichia coli secrete the bacterial adhesion mediation molecule intimin , which targets the translocated intimin receptor (Tir). Tir is secreted by the bacteria and is embedded in the target cell's plasma membrane . This facilitates bacterial cell attachment to the host.
Type III secretion system effector protein YopE-like (YopE-like)
Type: Family

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior. There have been four secretion systems described in animal enteropathogens, such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia .

The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis. However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part of the flagellum itself , type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.

Exotoxins secreted by the type III system do not possess a secretion signal, and are considered unique for this reason . Yersinia secrete a Rho GTPase-activating protein, YopE , that disrupts the host cell actin cytoskeleton. YopE is regulated by another bacterial gene, SycE , that enables the exotoxin to remain soluble in the bacterial cytoplasm. A similar protein, exoenzyme S from Pseudomonas aeruginosa, has both ADP-ribosylation and GTPase activity . This entry also includes ADP-ribosyltransferase toxin AexT from Aeromonas salmonicida that is directly involved in the toxicity for RTG-2 (rainbow trout gonad) fish cells .

This entry also includes Exoenzyme T (ExoT) from Pseudomonas aeruginosa. ExoT contains an N-terminal GTPase-activating protein (GAP) domain and a C-terminal ADP-ribosyltransferase (ADPRT) domain. Its ADPRT domain induces atypical anoikis by transforming an innocuous cellular protein, Crk, into a cytotoxin, which interferes with integrin survival signaling. Its GAP domain activity induces mitochondrial disruption in the target host cell by activating host caspases 3 and 9 that execute cellular death .
Gram-negative bacterial TonB protein (TonB)
Type: Family

TonB-dependent transporters (TBDT) are bacterial outer membrane (OM) proteins that bind and transport ferric chelates called siderophores. While iron complexes constitute the majority of substrates for TBDTs, others, like vitamin B12, are also transported by this mechanism . These transporters show high affinity and specificity for siderophores and require energy derived from the proton motive force across the inner membrane to transport them. The energy force is provided through interaction with an inner membrane protein complex consisting of TonB, ExbB, and ExbD . The source of this energy is the ion electrochemical gradient of the cytoplasmic membrane, harvested by heteromultimeric complexes of ExbB and ExbD proteins, and transduced to the OM high affinity siderophore transporters by the protein TonB .

TonB is composed of three domains. The N-terminal transmembrane helix anchors the protein to the inner membrane and makes contact with ExbB and ExbD to form an energy transducing complex. The C-terminal globular domain directly contacts the transporters in the OM. These two domains are separated by a flexible, unstructured proline-rich domain that resides within the periplasm .

Escherichia coli has only one TonB protein which is shared by different TBDTs involved in in the acquisition of various substrates, but most bacteria have more than one tonB gene .
Cytolethal distending toxin B (CD_toxinB)
Type: Family

Cytolethal distending toxin (CDT) is a secreted protein toxin produced by a number of Gram-negative disease-causing bacteria. CDT causes cell cycle arrest and eventual cell death in eukaryotic cells, as a result of chromosomal DNA damage caused by the catalytic, DNase I-like, CdtB subunit. Bacterial CDTs are generally comprised of three subunits, CdtA, -B and -C . CdtB is translocated into the host cell, where it acts as a genotoxin . CdtA and CdtC are needed for cell surface binding and cellular entry, and it is likely that they remain associated with the membrane, when CdtB is internalized. CdtB enters the target nucleus via nuclear translocation signal domain(s) .
ADP ribosyltransferase (ADP-ribosyltransferase)
Type: Domain

ADP-ribosylation is a posttranslational modification of proteins involving the addition of one or more ADP-ribose moieties . These reactions are involved in cell signalling and the control of many cell processes, including DNA repair and apoptosis .

This entry represents an ADP-ribosyltransferase domain found in various proteins, including bacterial and viral toxins such as ExoS and ExoT from Pseudomona aeruginosa which contain a C-terminal ADP-ribosyltransferase (ADPRT) domain . This domain is also found in a number of uncharacterised sequences from rotifers (commonly known as wheel animals).
Anthrax toxin, lethal/endema factor (Anthrax_toxin_lethal/edema)
Type: Family

Anthrax toxin is a plasmid-encoded toxin complex produced by the Gram-positive, spore-forming bacteria, Bacillus anthracis. The toxin consists of three non-toxic proteins: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF) . These component proteins self-assemble at the surface of host cell receptors, yielding a series of toxic complexes that can produce shock-like symptoms and death. Anthrax toxin is one of a large group of Bacillus and Clostridium exotoxins referred to as binary toxins, forming independent enzymatic (A moiety) and binding (B moiety) components. The LF and EF proteins are the enzymes (A moiety) that act on cytosolic substrates, while PA is a multi-functional protein (B moiety) that binds to cell surface receptors, mediates the assembly and internalisation of the complexes, and delivers them to the host cell endosome . Once PA is attached to the host receptor , it must then be cleaved by a host cell surface (furin family) protease before it is able to bind EF and LF. The cleavage of the N terminus of PA enables the C-terminal fragment to self-associate into a ring-shaped heptameric complex (prepore) that can bind LF or EF competitively. The PA-LF/EF complex is then internalised by endocytosis, and delivered to the endosome, where PA forms a pore in the endosomal membrane in order to translocate LF and EF to the cytosol. LF is a Zn-dependent metalloprotease that cleaves and inactivates mitogen-activated protein (MAP) kinases, kills macrophages, and causes death of the host by inhibiting cell proliferation . EF is a calcium-and calmodulin-dependent adenylyl cyclase that can cause edema (fluid-filled swelling) when associated with PA. EF is not toxic by itself, and is required for the survival of germinated Bacillus spores within macrophages at the early stages of infection. EF dramatically elevates the level of host intracellular cAMP, a ubiquitous messenger that integrates many processes of the cell; increases in cAMP can interfere with host intracellular signalling .

This entry includes lethal factor and edema factor proteins of anthrax toxin.
Enterobactin synthetase-like, component D (Enbac_synth_compD-like)
Type: Family

Iron is essential for growth in both bacteria and mammals. Controlling the amount of free iron in solution is often used as a tactic by hosts to limit invasion of pathogenic microbes; binding iron tightly within protein molecules can accomplish this. Such iron-protein complexes include haem in blood, lactoferrin in tears/saliva and transferrin in blood plasma. Some bacteria express surface receptors to capture eukaryotic iron-binding compounds, while others have evolved siderophores to scavenge iron from iron-binding host proteins .

The absence of free iron molecules in the surrounding environment triggers transcription of gene clusters that encode both siderophore-synthesis enzymes, and receptors that recognise iron-bound siderophores . Classic examples are the enterobactin/enterochelin clusters found in Escherichia coli and Salmonella, although similar moieties in other pathogens have been identified. The enzymic machinery that produces vibrionectin in Vibrio cholerae is such a homologue .

EntD (also known as 4'-phosphopantetheinyl transferase EntD) forms part of the enterobactin-synthetase enzyme complex. It plays an essential role in the assembly of the enterobactin by catalysing the transfer of the 4'-phosphopantetheine (Ppant) moiety from coenzyme A to the apo-domains of both EntB (ArCP domain) and EntF (PCP domain) to yield their holo-forms which make them competent for the activation of 2,3-dihydroxybenzoate (DHB) and L-serine, respectively . Deletion studies involving EntD- mutants have shown that it is essential for virulence .

This entry also identifies some 4'-phosphopantetheinyl transferase proteins.
Macrophage scavenger receptor, Class A-I/II (SR-AI/II)
Type: Family

Scavenger receptors type I and II were the first scavenger receptors purified and are products of alternative splicing of a single gene. They are now named as class A, type I and type II (SR-AI/II) or collectively SR-A member 1. They can recognise a wide variety of ligands, from bacteria and yeast to self (native proteins) and self-modified ligands and they are involved in host defense, homeostasis, antigen presentation, pathogenesis of neurodegenerative disorders and atherosclerosis .