SII-SWORD/CoKE huggingface dataset:
Interleukin-1 propeptide (IL-1_propep)
Type: Domain

The N-terminal of Interleukin-1 is approximately 115 amino acids long, it forms a propeptide that is cleaved off to release the active interleukin-1. This entry represents the propeptide.

Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis . Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors . The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.

Both IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location . The receptors can both bind all three forms of IL-1 (IL-1 alpha, IL-1 beta and IL-1RA).

The crystal structures of IL1A and IL1B have been solved, showing them to share the same 12-stranded β-sheet structure as both the heparin binding growth factors and the Kunitz-type soybean trypsin inhibitors . The β-sheets are arranged in 3 similar lobes around a central axis, 6 strands forming an anti-parallel β-barrel. Several regions, especially the loop between strands 4 and 5, have been implicated in receptor binding.

The Vaccinia virus genes B15R and B18R each encode proteins with N-terminal hydrophobic sequences, possible sites for attachment of N-linked carbohydrate and a short C-terminal hydrophobic domain . These properties are consistent with the mature proteins being either virion, cell surface or secretory glycoproteins. Protein sequence comparisons reveal that the gene products are related to each other (20% identity) and to the Ig superfamily. The highest degree of similarity is to the human and murine interleukin-1 receptors, although both proteins are related to a wide range of Ig superfamily members, including the interleukin-6 receptor. A novel method for virus immune evasion has been proposed in which the product of one or both of these proteins may bind interleukin-1 and/or interleukin-6, preventing these cytokines reaching their natural receptors . A similar gene product from Cowpox virus (CPV) has also been shown to specifically bind murine IL-1 beta .
Glial cell line-derived neurotrophic factor receptor, alpha 1 (GDNF_rcpt_A1)
Type: Family

Glial cell line-derived neurotrophic factor (GDNF) and its related factors neurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNF family of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved in the promotion of neurone survival, exerting their effects through specific receptors.

The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked, cell surface receptors . Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-1 receptor subtype have been cloned from mammalian and avian tissue. The receptor is activated by GDNF , although there is evidence it can also bind neurturin, the principal ligand for GFRalpha-2 .

Activation of GFRalpha-1 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways .
Glial cell line-derived neurotrophic factor receptor alpha 2 (GDNF_rcpt_a2)
Type: Family

Glial cell line-derived neurotrophic factor (GDNF) and its related factors neurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNF family of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved in the promotion of neurone survival, exerting their effects through specific receptors.

The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked, cell surface receptors . Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. Homologues for the GFRalpha-2 receptor subtype have been cloned from mammalian and avian tissue. The receptor is preferentially activated by neurturin, although there is evidence that GFRalpha-2 can also bind GDNF if pre-coupled to its effector molecule .

Activation of GFRalpha-2 triggers its interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways .
Glial cell line-derived neurotrophic factor receptor, alpha 3 (GDNF_rcpt_A3)
Type: Family

Glial cell line-derived neurotrophic factor (GDNF) and its related factors neurturin (NTN), artemin (ART) and persephin (PSP), are members of the GDNF family of neurotrophic factors. They form a sub-group in the transforming growth factor-beta (TGF-beta) superfamily. These factors are involved in the promotion of neurone survival, exerting their effects through specific receptors.

The GDNF family receptors (GFRs) are glycosyl-phosphatidylinositol-linked, cell surface receptors . Four receptor subtypes, termed GFRalpha-1 to 4, are currently recognised. GFRalpha-3 has been cloned from mammalian tissue . It represents the least conserved member of the GFR family in terms of amino acid sequence, and is activated by artemin .

Activation of GFR family members triggers their interaction with the membrane-bound receptor kinase Ret. This induces Ret homo-dimerisation, triggering a cascade of intracellular signalling events such as the activation of the Ras-mitogen-activated protein kinase (MAPK), phosphoinositol-3-kinase (PI3K), Jun N-terminal kinase (JNK) and phospholipase C gamma (PLC gamma) dependent pathways .
Chlamydia cysteine-rich outer membrane protein 6 (Chlam_OMP6)
Type: Family

Three cysteine-rich proteins (also believed to be lipoproteins) make up the extracellular matrix of the Chlamydial outer membrane . They are involved in the essential structural integrity of both the elementary body (EB) and recticulate body (RB) phase. As these bacteria lack the peptidoglycan layer common to most Gram-negative microbes, such proteins are highly important in the pathogenicity of the organism.

The largest of these is the major outer membrane protein (MOMP), and constitutes around 60% of the total protein for the membrane . OMP6 is the second largest, with a molecular mass of 58kDa, while the OMP3 protein is ~15kDa . MOMP is believed to elicit the strongest immune response, and has recently been linked to heart disease through its sequence similarity to a murine heart-muscle specific alpha myosin .

The OMP6 family plays a structural role in the outer membrane during the EB stage of the Chlamydial cell, and different biovars show a small, yet highly significant, change at peptide charge level . Members of this family include Chlamydia trachomatis, Chlamydia pneumoniae and Chlamydia psittaci.
Peptidase family S66 (S66_fam)
Type: Family

This entry includes proteins belonging to the MEROPS peptidase family S66, such as muramoyl-tetrapeptide carboxypeptidase and the microcin c7 self-immunity protein

.
CIDE-N domain (CIDE-N_dom)
Type: Domain

The CIDE-N or CAD domain is a ~78 amino acid protein-protein interaction domain in the N-terminal part of Cell death-Inducing DFF45-like Effector (CIDE) proteins, involved in apoptosis. At the final stage of programmed cell death, chromosomal DNA is degraded into fragments by Caspase-activated DNase (CAD), also named DNA fragmentation factor 40kDa (DFF40). In normal cells CAD/DFF40 is completely inhibited by its binding to DFF45 or Inhibitor of CAD (ICAD). Apoptotic stimuli provoke cleavage of ICAD/DFF45 by caspases, resulting in self-assembly of CAD/DFF40 into the active dimer .

Both CAD/DFF40 and ICAD/DFF45 possess an N-terminal CIDE-N domain that is involved in their interaction. The name of the CIDE-N domain refers to the CIDE proteins and CAD, where the domain forms the N-terminal part . The CIDE-N domains from different proteins can interact, e.g. CIDE-N of CIDE-B and ICAD/DFF45 with CIDE-N of CAD/DFF40, and such interactions can also be needed for proper folding .

Tertiary structures show that the CIDE-N domain forms an α/β roll fold of five β-strands forming a single, mixed parallel/anti-parallel β-sheet with one or two α-helices packed against the sheet. Binding surfaces of the CIDE-N domain form a central hydrophobic cluster, while specific binding interfaces can be formed by charged patches.

Some proteins known to contain a CIDE-N domain include:

Mammalian DNA fragmentation factor 40kDa (DFF40) or Caspase-activated deoxyribonuclease (CAD), an endonuclease that induces DNA fragmentation and chromatin condensation during apoptosis. The degradation of chromosomal DNA by CAD/DFF40 will kill the cells.

Mammalian DNA fragmentation factor 45kDa (DFF45) or Inhibitor of CAD (ICAD), which controls the activity and proper folding of CAD/DFF40.

Mammalian CIDE-A and CIDE-B, activators of cell death and DNA fragmentation that can be inhibited by ICAD/DFF45. In contrast with CAD and ICAD, the CIDE proteins are expressed in a highly restricted way and show pronounced tissue specificity.

Fruit fly DNAation factor DREP1, a DFF45 homologue that can inhibit CIDE-A-induced apoptosis.
UPF0102 protein YraN-like (UPF0102_YraN-like)
Type: Family

The proteins in this entry are functionally uncharacterised.
Fumarate reductase, subunit C (Fumarate_red_C)
Type: Family

Fumarate reductase is a membrane-bound flavoenzyme consisting of four subunits, A-D. A and B comprise the membrane-extrinsic catalytic domain and C and D link the catalytic centres to the electron-transport chain. This family consists of the 15kDa hydrophobic subunit C. Members of this subfamily are classified as Type D as they contain two transmembrane subunits (C and D) and no heme groups. The structural arrangement allows efficient electron transfer between the catalytic subunit, through iron-sulfur centres, and the transmembrane subunit containing the electron donor (quinol). The quinone binding site resides in the transmembrane subunits.

Quinol:fumarate reductase (QFR) couples the reduction of fumarate to succinate to the oxidation of quinol to quinone, the opposite reaction to that catalyzed by the related protein, succinate:quinine oxidoreductase (SQR). QFRs oxidize low potential quinols such as menaquinol and are involved in anaerobic respiration with fumarate as the terminal electron acceptor. SQR and QFR share a common subunit arrangement, composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits .
HORMA domain (HORMA_dom)
Type: Domain

The HORMA domain (for HOP1, REV7 and MAD2) is an about 180-240 amino acids region containing several conserved motifs. Whereas the MAD2 and the REV7 proteins are almost entirely made up of HORMA domains, HOP1 contains a HORMA domain in its N-terminal region and a Zn-finger domain, whose general arrangement of metal-chelating residues is similar to that of the PHD finger, in the C-terminal region. The HORMA domain is found in proteins showing a direct association with chromatin of all crown group eukaryotes. It has been suggested that the HORMA domain recognises chromatin states that result from DNA adducts, double-stranded breaks or non-attachment to the spindle and acts as an adaptor that recruits other proteins involved in repair .

Secondary structure prediction suggests that the HORMA domain is globular and could potentially form a complex β-sheet(s) with associated α-helices .

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

Eukaryotic HOP1, a conserved protein that is involved in meiotic-synaptonemal-complex assembly.

Eukaryotic mitotic-arrest-deficient 2 protein (MAD2), a key component of the mitotic-spindle-assembly checkpoint .

Eukaryotic REV7, a subunit of the DNA polymerase zeta that is involved in translesion, template-independent DNA synthesis.
Bacteriophage M13, G5P, DNA-binding (Phage_M13_G5P_DNA-bd)
Type: Family

This entry is represented by the Bacteriophage M13, G5P, DNA-binding protein. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.

G5P is the bacteriophage helix-destabilising protein, or single-stranded DNA binding protein, required for DNA synthesis. The protein binds to DNA in a highly cooperative manner without pronounced sequence specificity. In the presence of single-stranded DNA it binds cooperatively to form a helical protein-DNA complex. It prevents the conversion during synthesis of the single-stranded (progeny) viral DNA back into the double-stranded replicative form.
Scaffold protein B (Phage_B)
Type: Family

This is a family of proteins from single-stranded DNA bacteriophages. Scaffold proteins B and D are required for procapsid formation. Sixty copies of the internal scaffold protein B are found in the procapsid .
Microviridae F protein (Microviridae_protein_F)
Type: Family

This entry represents the Microviridae F protein family, including capsid protein F and capsid protein VP1. Capsid protein F is the major capsid component in single-stranded DNA bacteriophages. 60 copies of this protein are present in the virion .
Major spike protein G (Spike_G)
Type: Family

This is a family of proteins from single-stranded DNA bacteriophages. The G protein is a major spike protein involved in attachment to the bacterial host cell. The virion is composed of sixty copies of each of the F, G and J proteins, and 12 copies of the H protein. There are twelve spikes formed by five G proteins, each a tight β barrel, and one H protein .
Fanconi anaemia group A protein (FANCA)
Type: Family

This entry represents FANCA .

Fanconi anemia (FA) is a human disorder characterised by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. The FA complex repairs the interstrand cross-linking (ICL) lesions and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. It is required for the monoubiquitylation of FANCD2 and FANCI heterodimer. The FA core complex consists of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FANCT (UBET2), FAAP100 and FAAP24 .
Cysteine-rich outer membrane protein 3, Chlamydia (Cys-rich_OMP3_Chlamydia)
Type: Family

Three cysteine-rich proteins (also believed to be lipoproteins) make up the extracellular matrix of the Chlamydial outer membrane . They are involved in the essential structural integrity of both the elementary body (EB) and recticulate body (RB) phase. As these bacteria lack the peptidoglycan layer common to most Gram-negative microbes, such proteins are highly important in the pathogenicity of the organism.

The largest of these is the major outer membrane protein (MOMP), and constitutes around 60% of the total protein for the membrane . OMP2 is the second largest, with a molecular mass of 58kDa, while the OMP3 protein is ~15kDa . MOMP is believed to elicit the strongest immune response, and has recently been linked to heart disease through its sequence similarity to a murine heart-muscle specific alpha myosin .

The OMP3 family plays a structural role in the outer membrane during the EB stage of the Chlamydial cell, and different biovars show a small, yet highly significant, change at peptide charge level . Members of this family include Chlamydia trachomatis, Chlamydia pneumoniae, and Chlamydia psittaci.
Salmonella plasmid virulence SpvA (Sal_SpvA)
Type: Family

Salmonella typhimurium contains a 90kb plasmid that is associated with virulence. This plasmid encodes at least 6 genes needed by the bacterium for invading host macrophages during infection. These include the 70kDa mkaA protein , a recognised virulence factor, and more recently described, four spv genes under the control of a regulator .

Deletion studies on the virulence plasmid have shown that an open reading frame encoding a 28kDa protein was needed for successful invasion of the host. This protein, designated mkfA , VRP4 or VirA by different groups, is utilised by the microbe upon entry into macrophages, although the exact mechanism is unclear.
OspF/SpvC (OspF/SpvC)
Type: Family

This entry includes the virulence protein SpvC and the phosphothreonine lyase OspF.

The spv region of the Salmonella virulence plasmids consists of five genes located on an 8-kb fragment, shown to be essential for virulence in mice . SpvC (also known as mkfA and VirA ) is part of this gene cluster and is utilised by the microbe upon entry into macrophages, although the exact mechanism is unclear.
Salmonella/Shigella invasion protein E (Invas_InvE)
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 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.

The Salmonella/Shigella invasion protein E gene (InvE) is one such type III secretion protein subunit, and is localised to the outer membrane of the SPI I pathogenicity island, and is involved in the surface presentation.
ICln (ICln)
Type: Family

ICln, known as methylosome subunit pICln or chloride conductance regulatory protein ICln, owes these different names to its function in multiple regulatory pathways as different as ion permeation, ribonucleoprotein biosynthesis and cytoskeletal organisation . ICln can be identified both in the cytosol and in the cellular membrane, where it functions as a chloride current regulator and is important in regulating volume decrease after cellular swelling .

pLCln also functions as a Sm chaperone in the stepwise snRNP assembly process . snRNPs is a RNA-protein complex esessential to the removal of introns from pre-mRNA . In humans, the core of snRNPs is composed of seven Sm proteins bound to snRNA. pLCln tethers the hetero-oligomers SmD1/D2 and SmE/F/G into a ring-shaped 6S complex, which subsequently docks onto the SMN complex. The SMN complex then removes pICln and enables the transfer of pre-assembled Sm proteins onto snRNA . Consistent with the role of human pICln, the orthologue from S. pombe is required for optimal production of the spliceosomal snRNPs and for efficient splicing .
Type III secretion system outer membrane pore YscC/HrcC (T3SS_OM_pore_YscC)
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. The structure core of this system consists of the needle complex, a continuous channel formed by the highly oligomerized inner and outer membrane hollow rings and a polymerized helical needle filament which spans through and projects into the infected host cell .

This family aids in the structural assembly of the invasion complex . Another characteristic of this family is its ability to form a channel through the outer bacterial membrane, allowing secretion to take place. Members include the Salmonella InvG and SpiA gene, the Shigella MxiD, and the Yersinia Kim5 and YscC proteins . Plant pathogen members include the Hypersensitivity Response (HR) genes of Burkholderia and Erwinia.
Transcription factor COE (Transcription_factor_COE)
Type: Family

The independent cloning of rodent EBF/Olf-1 and Drosophila melanogaster Collier has defined a family of transcription factors, the Collier or COE family . COE proteins have various functions in different organisms.

In mouse, COE1 has a role in B-cell differentiation, and could also perform a role in neuronal differentiation. All three COE are expressed in immature olfactory neuronal precursors and mature olfactory neurons as well as in developping nervous system during embryogenesis.

In Drosophila, Collier is involved in the formation of the embryonic somatic muscle DA3, in the patterning of the wing by mediating Hedgehog activity. It could also act as a second-level regulator in the patterning of embryonic head.
Phospho-N-acetylmuramoyl-pentapeptide transferase (PNAcMuramoyl-5peptid_Trfase)
Type: Family

Phospho-N-acetylmuramoyl-pentapeptide-transferase (

) (MraY) is a bacterial enzyme responsible for the formation of the first lipid intermediate of the cell wall peptidoglycan synthesis . It catalyses the formation of undecaprenyl-pyrophosphoryl-N-acetylmuramoyl-pentapeptide from UDP-MurNAc-pentapeptide and undecaprenyl-phosphate.
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (MECDP_synthase)
Type: Domain

IspF is a MECDP (2-C-methyl-D-erythritol 2,4-cyclodiphosphate) synthetase, also known as YgbB. It is an enzyme in the non-mevalonate pathway of isoprenoid synthesis. Isoprenoids are essential in all organisms, and can also be synthesized through the mevalonate pathway. The non-mevolante route is used by many bacteria and human pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum. This route appears to involve seven enzymes. MECDP synthetase catalyses the intramolecular attack by a phosphate group on a diphosphate, with cytidine monophosphate (CMP) acting as the leaving group to give the cyclic diphosphate product MEDCP. The enzyme is a trimer with three active sites shared between adjacent copies of the protein. The enzyme also has two metal binding sites, the metals playing key roles in catalysis.

A number of proteins from eukaryotes and prokaryotes are bifunctional proteins with an N-terminal IspD domain and a C-terminal IspF domain .