SII-SWORD/CoKE huggingface dataset:
Haemagglutinin-esterase glycoprotein, haemagglutinin domain (Hemagglutn-estrase_hemagglutn)
Type: Domain

Haemagglutinin-esterase fusion glycoprotein (HEF) is a multi-functional protein embedded in the viral envelope of several viruses, including influenza C virus, coronaviruses and toroviruses . HEF is required for infectivity, and functions to recognise the host cell surface receptor, to fuse the viral and host cell membranes, and to destroy the receptor upon host cell infection. The haemagglutinin region of HEF is responsible for receptor recognition and membrane fusion, and bears a strong resemblance to the sialic acid-binding haemagglutinin found in influenza A and B viruses, except that it binds 9-O-acetylsialic acid. The esterase region of HEF is responsible for the destruction of the receptor, an action that is carried out by neuraminidase in influenza A and B viruses. The esterase domain is similar in structure to Streptomyces scabies esterase, and to acetylhydrolase, thioesterase I and rhamnogalacturonan acetylesterase.

The haemagglutinin-esterase glycoprotein HEF must be cleaved by the host's trypsin-like proteases to produce two peptides (HEF1 and HEF2) in order for the virus to be infectious. Once HEF is cleaved, the newly exposed N-terminal of the HEF2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the virus to infect the host cell.

The haemagglutinin-esterase glycoprotein is a trimer, where each monomer is composed of three domains: an elongated stem active in membrane fusion, an esterase domain, and a receptor-binding domain, where the stem and receptor-binding domains together resemble influenza A virus haemagglutinin. Two of these domains are composed of non-contiguous sequence: the receptor-binding haemagglutinin domain is inserted into a surface loop of the esterase domain, and the esterase domain is inserted into a surface loop of the haemagglutinin stem.

This entry represents the receptor-binding haemagglutinin domain of the haemagglutinin-esterase glycoprotein.
E4 protein (Papilloma_E4)
Type: Family

This is is a family of Papillomavirus proteins, E4, coded for by ORF4. A splice variant, E1--E4, exists but the function of neither E4 nor E1--E4 is known .
Domain of unknown function DUF220 (DUF220)
Type: Domain

This entry consists of several Arabidopsis thaliana hypothetical proteins, none of which have any known function. They contain a conserved region with two cysteine residues. This domain exhibits structural similarities with members of the Bet v1-like superfamily and may play a role in lipid binding .
CSC1/OSCA1-like, 7TM region (CSC1/OSCA1-like_7TM)
Type: Domain

This entry represents the seven transmembrane domain region of plant OSCA1, yeast PHM7 and RSN1 and CSC1-like protein 1 (also known as TRANSMEMBRANE PROTEIN 63A) . Members of this entry are mechanosensitive calcium-permeable ion channels consisting of an N-terminal transmembrane domain (RSN1_TM), a cytosolic domain and a 7TM region at the C-terminal. This domain is found in eukaryotic transmembrane proteins that are involved in diverse functions, including phosphate metabolism (

) and spore wall assembly (

) .
Polysaccharide biosynthesis protein, CapD-like domain (Polysac_CapD-like)
Type: Domain

This domain is found in diverse bacterial polysaccharide biosynthesis proteins including the CapD protein from Staphylococcus aureus , the WalL protein, mannosyl-transferase , and several putative epimerases. The CapD protein is required for biosynthesis of type 1 capsular polysaccharide.
Domain of unknown function DUF222 (DUF222)
Type: Domain

This domain is found in hypothetical proteins, many of them from Mycobacterium tuberculosis. The family has been called the 13E12 repeat family . The function of this domain is uncertain.
Replication protein A 70 kDa DNA-binding subunit B/D, first OB fold domain (RFA1B/D_OB_1st)
Type: Domain

This entry represents the first OB fold found Replication protein A 70 kDa DNA-binding subunit B/D from plants which are similar to human RPA1 (also called RPA70) and are part of the RPA complex. RPA1 is the large subunit of Replication protein A (RPA). RPA is a nuclear ssDNA-binding protein (SSB) which appears to be involved in all aspects of DNA metabolism including replication, recombination, and repair. RPA also mediates specific interactions of various nuclear proteins. In animals, plants, and fungi, RPA is a heterotrimer with subunits of 70kDa (RPA1), 32kDa (RPA2), and 14kDa (RPA3) . The ssDNA-binding mechanism is believed to be multistep and to involve conformational change.
Major outer sheath protein, C-terminal (MOSP_C)
Type: Domain

This entry represents the C-terminal region of major outer sheath proteins from spirochaetales. These proteins are present on the bacterial cell surface. In Treponema denticola the major outer sheath protein (Msp) binds immobilized laminin and fibronectin supporting the hypothesis that Msp mediates the extracellular matrix binding activity of T. denticola .
Envelope small membrane protein, coronavirus (E_protein_CoV)
Type: Family

E protein is the smallest of the major structural proteins. It is conserved among Coronavirus strains. It is an integral membrane protein involved in several aspects of the virus' life cycle, such as assembly, budding, envelope formation, and pathogenesis . During the replication cycle, E is abundantly expressed inside the infected cell, but only a small portion is incorporated into the virus envelope. The majority of the protein participates in viral assembly and budding . It can act as a viroporin by oligomerizing after insertion in host membranes to create a hydrophilic pore that allows ion transport . Additionally, the E protein is thought to prevent M protein aggregation and induce membrane curvature .

SARS-CoV E protein forms a Ca2+ permeable channel in the endoplasmic reticulum Golgi apparatus intermediate compartment (ERGIC)/Golgi membranes. The E protein ion channel activity alters Ca2+ homeostasis within cells boosting the activation of the NLRP3 inflammasome, which leads to the overproduction of IL-1beta. SARS-CoV overstimulates the NF-kappaB inflammatory pathway and interacts with the cellular protein syntenin, triggering p38 MARK activation. These signalling cascades result in exacerbated inflammation and immunopathology .

Cov E proteins have a short hydrophilic N terminus, followed by a large hydrophobic transmembrane (TM) domain, and end with a long, hydrophilic C terminus, which comprises the majority of the protein. The hydrophobic region of the TM domain contains at least one predicted amphipathic α-helix that pentamerizes to form an ion-conductive pore in membranes. CoV E proteins have been proposed to have at least two roles. One is related to their TM channel domain. This would be active in the secretory pathway, altering lumenal environments and rearranging secretory organelles and leading to efficient trafficking of virions. The other would be related to their extramembrane domains, particularly the C-terminal domain. This is involved in protein-protein interactions and targeting, among other roles .
CDC45 (CDC45)
Type: Family

CDC45 is an essential gene required for initiation of DNA replication in Saccharomyces cerevisiae (cell division control protein 45), forming a complex with MCM5/CDC46. Homologs of CDC45 have been identified in human , mouse and the smut fungus, Melampsora spp., (tsd2 protein) among others.
Paramyxoviridae nonstructural protein C (Paramyxovir_NSC)
Type: Family

This family consists of the polymerase accessory protein C from members of the paramyxoviridae.
Arginine deiminase (Arg_deiminase)
Type: Family

This is a family of arginine deiminases,

. These enzymes catalyse the conversion of arginine + H2O to citrulline + NH3. The family member from Streptococcus pyogenes has been characterised as an antitumour protein .
SPRY domain (SPRY_dom)
Type: Domain

The SPRY domain is a ~140-amino-acid protein interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity, or embryonic development . It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. Functionally, SPRY domains mediate critical interactions in diverse pathways: SSB-2 binds Par-4 to regulate apoptosis, RanBPM/SSB-1 interact with c-Met for signalling modulation, and SPSB proteins target iNOS for ubiquitination in immune regulation .

The B30.2 domain was first identified as a protein domain encoded by an exon (named B30-2) in the Homo sapiens class I major histocompatibility complex region , whereas the SPRY domain was first identified in a Dictyostelium discoideum kinase splA and mammalian calcium-release channels ryanodine receptors . B30.2 domain consists of PRY and SPRY subdomains. The SPRY domains (after SPla and the RYanodine Receptor) are shorter at the N terminus than the B30.2 domains. The ~200-residue B30.2/SPRY (for B30.2 and/or SPRY) domain is present in a large number of proteins with diverse individual functions in different biological processes. The B30.2/SPRY domain in these proteins is likely to function through protein-protein interaction .
The N-terminal ~60 residues of B30.2/SPRY domains are poorly conserved and, as a consequence, a new domain name PRY was coined for a group of similar sequence segments N-terminal to the SPRY domains . The B30.2/SPRY domain contains three highly conserved motifs (LDP, WEVE and LDYE) . The B30.2/SPRY domain adopts a highly distorted, compact β-sandwich fold with two additional short β-helices at the N terminus. The β-sandwich of the B30.2/SPRY domain consists of two layers of β-sheets: sheet A composed of eight strands and sheet B composed of seven strands. All the β-strands are in antiparallel arrangement . The 5th β-strand corresponding to WEVE motif . Both the N- and C-terminal ends of the B30.2/SPRY domains in general are close to each other .
Butyrophylin-like, SPRY domain (Butyrophylin_SPRY)
Type: Domain

Several proteins that contain RING fingers also contain a well-conserved 40-residue cysteine-rich domain termed a B-box zinc finger. Often, one or two copies of the B-box are associated with a coiled coil domain (

) in addition to the ring finger (

), forming a tripartite motif. The tripartite motif is found in transcription factors, ribonucleoproteins and proto-oncoproteins, but no function has yet been ascribed to the domain .

The solution structure of the B-box motif has been determined by NMR. The protein is a monomer, with 2 β-strands, 2 helical turns and 3 extended loop regions packed in a novel topology . Of 7 potential zinc ligands, only 4 are used, binding a single zinc atom in a C2-H2 tetrahedral arrangement. The B-box structure differs in tertiary fold from all other known zinc-binding motifs.

A group of proteins that contain the B-box motif also host a well conserved domain of unknown function. Proteins that include this domain are, e.g.: butyrophilin, the RET finger protein, the 52kDa Ro protein and the Xenopus nuclear factor protein. The C-terminal portion of this region has been termed the SPRY domain (after SPla and the RYanodine Receptor) .
Pistil-specific extensin-like protein (Pistil_extensin)
Type: Family

Extensins are plant cell-wall proteins; they can account for up to 20% of the dry weight of the cell wall. They are highly-glycosylated, possibly reflecting their interactions with cell-wall carbohydrates. Amongst their functions is cell wall strengthening in response to mechanical stress (e.g., during attack by pests, plant-bending in the wind, etc.). By contrast with extensin genes, pistil-specific extensin-like genes are not induced under stress conditions. Gene expression is organ-specific and temporally regulated during pistil development. After pollination, transcript levels of pistil-specific extensin-like genes change relative to levels in unpollinated pistils . The protein sequence is characterised by multiple tandem ser-pro-pro-pro-pro pentapeptide repeats.
Extensin-like (Extensin-like)
Type: Family

Extensins are plant cell-wall proteins; they can account for up to 20% of the dry weight of the cell wall. They are highly-glycosylated, possibly reflecting their interactions with cell-wall carbohydrates. Amongst their functions is cell wall strengthening in response to mechanical stress (e.g., during attack by pests, plant-bending in the wind, etc.). Members of this entry are disordered, according to structure predictions.
Factor I / membrane attack complex (FacI_MAC)
Type: Domain

This domain is found in complement component proteins, complement component factor 1 and agrin. Complement components C5b, C6, C7 C8 and C9 are the constituents of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. Its assembly is initiated by protelytic cleavage of C5 into C5a and C5b. C5b binds sequentially C6, C7, C8 and multiple copies of the pore-forming subunit C9. Factor I is responsible for cleaving alpha chains of C4B and C3B in the presence of the cofactors C4-binding protein and factor H respectively. Agrin is a component of the basal lamina that causes the aggregation of acetylcholine receptors and acetylcholine-esterase on the surface of muscle fibres of the neuromuscular junction.
NIDO domain (NIDO_dom)
Type: Domain

The ~180-residue NIDO domain is an extracellular domain of unknown function, found in nidogen (entactin) and hypothetical proteins. The NIDO domain is found in association with other domains, such as nidogen G2 β-barrel (

), thyroglobulin type-1 (

), LDLRB (

), AMOP (

), EGF-like (

), VWFD, IPT/TIG, or sushi/CCP/SCR (

) .

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

Vertebrate nidogen-1 (NID-1) or entactin, a sulphated glycoprotein widely distributed in basement membranes.

Vertebrate nidogen-2 (NID-2) or osteonidogen, a cell adhesion glycoprotein which is widely distributed in basement membranes.

Vertebrate alpha-tectorin.

Mammalian mucin-4 (MUC4), a highly glycosylated membrane-bound protein.

Xenopus ID14, a putative matrix protein.
LEM domain (LEM_dom)
Type: Domain

The LEM (LAP2, emerin, MAN1) domain is a globular module of approximately 40 amino acids, which is mostly found in the nucleoplasmic portions of metazoan inner nuclear membrane proteins. The LEM domain has been shown to mediate binding to BAF (barrier-to-autointegration factor) and BAF-DNA complexes. BAF dimers bind to double-stranded DNA non-specifically and thereby bridge DNA molecules to form a large, discrete nucleoprotein complex .

The resolution of the solution structure of the LEM domain reveals that it is composed of a three-residue N-terminal helical turn and two large parallel α helices interacting through a set of conserved hydrophobic amino acids. The two helices, which are connected by a long loop are oriented at an angle of ~45 degree .

Proteins known to contain a LEM domain include:

Vertebrate inner nuclear membrane protein MAN1.

Vertebrate lamina-associated polypeptide 2 (LAP2) or thymopoietin.

Mammalian emerin (EMD). In human, defects in EMD are a cause of X-linked Emery-Dreifuss muscular dystrophy (X-EDMD), an X-linked disorder, characterised by early contractures, muscle wasting and weakness and cardiomyopathy.

Xenopus laevis Smad1 antagonistic effector (SANE).

Drosophila melanogaster otefin (OTE).

Caenorhabditis elegans W01G7.5 protein.
FY-rich, N-terminal (FYrich_N)
Type: Conserved_site

The "FY-rich" domain N-terminal (FYRN) and "FY-rich" domain C-terminal (FYRC) sequence motifs are two poorly characterised phenylalanine/ tyrosine-rich regions of around 50 and 100 amino acids, respectively, that are found in a variety of chromatin-associated proteins . They are particularly common in histone H3K4 methyltransferases most notably in a family of proteins that includes human mixed lineage leukemia (MLL) and the Drosophila melanogaster protein trithorax. Both of these enzymes play a key role in the epigenetic regulation of gene expression during development, and the gene coding for MLL is frequently rearranged in infant and secondary therapy-related acute leukemias. They are also found in transforming growth factor beta regulator 1 (TBRG1), a growth inhibitory protein induced in cells undergoing arrest in response to DNA damage and transforming growth factor (TGF)-beta1. As TBRG1 has been shown to bind to both the tumor suppressor p14ARF and MDM2, a key regulator of p53, it is also known as nuclear interactor of ARF and MDM2 (NIAM). In most proteins, the FYRN and FYRC regions are closely juxtaposed, however, in MLL and its homologues they are far distant. To be fully active, MLL must be proteolytically processed by taspase1, which cleaves the protein between the FYRN and FYRC regions . The N-terminal and C-terminal fragments remain associated after proteolysis apparently as a result of an interaction between the FYRN and FYRC regions. How proteolytic processing regulates the activity of MLL is not known. Intriguingly, the FYRN and FYRC motifs of a second family of histone H3K4 methyltransferases, represented by MLL2 and MLL4 in humans and TRR in Drosophila melanogaster, are closely juxtaposed. FYRN and FYRC motifs are found in association with modules that create or recognise histone modifications in proteins from a wide range of eukaryotes, and it is likely that in these proteins they have a conserved role related to some aspect of chromatin biology .

The FYRN and FYRC regions are not separate independently folded domains, but are components of a distinct protein module. The FYRN and FYRC motifs both form part of a single folded module (the FYR domain), which adopts an α+β fold consisting of a six-stranded antiparallel β-sheet followed by four consecutive α-helices. The FYRN region corresponds to β-strands 1-4 and their connecting loops, whereas the FYRC motif maps to β-strand 5, β-strand 6 and helices α1 to α4. Most of the conserved tyrosine and phenylalanine residues, after which these motifs are named are involved in interactions that stabilise the fold. Proteins such as MLL, in which the FYRN and FYRC regions are separated by hundreds of amino acids, are expected to contain FYR domains with a large insertion between two of the strands of the β-sheet (strands 4 and 5) .
FY-rich, C-terminal (FYrich_C)
Type: Conserved_site

The "FY-rich" domain N-terminal (FYRN) and "FY-rich" domain C-terminal (FYRC) sequence motifs are two poorly characterised phenylalanine/ tyrosine-rich regions of around 50 and 100 amino acids, respectively, that are found in a variety of chromatin-associated proteins . They are particularly common in histone H3K4 methyltransferases most notably in a family of proteins that includes human mixed lineage leukemia (MLL) and the Drosophila melanogaster protein trithorax. Both of these enzymes play a key role in the epigenetic regulation of gene expression during development, and the gene coding for MLL is frequently rearranged in infant and secondary therapy-related acute leukemias. They are also found in transforming growth factor beta regulator 1 (TBRG1), a growth inhibitory protein induced in cells undergoing arrest in response to DNA damage and transforming growth factor (TGF)-beta1. As TBRG1 has been shown to bind to both the tumor suppressor p14ARF and MDM2, a key regulator of p53, it is also known as nuclear interactor of ARF and MDM2 (NIAM). In most proteins, the FYRN and FYRC regions are closely juxtaposed, however, in MLL and its homologues they are far distant. To be fully active, MLL must be proteolytically processed by taspase1, which cleaves the protein between the FYRN and FYRC regions . The N-terminal and C-terminal fragments remain associated after proteolysis apparently as a result of an interaction between the FYRN and FYRC regions. How proteolytic processing regulates the activity of MLL is not known. Intriguingly, the FYRN and FYRC motifs of a second family of histone H3K4 methyltransferases, represented by MLL2 and MLL4 in humans and TRR in Drosophila melanogaster, are closely juxtaposed. FYRN and FYRC motifs are found in association with modules that create or recognise histone modifications in proteins from a wide range of eukaryotes, and it is likely that in these proteins they have a conserved role related to some aspect of chromatin biology .

The FYRN and FYRC regions are not separate independently folded domains, but are components of a distinct protein module. The FYRN and FYRC motifs both form part of a single folded module (the FYR domain), which adopts an α+β fold consisting of a six-stranded antiparallel β-sheet followed by four consecutive α-helices. The FYRN region corresponds to β-strands 1-4 and their connecting loops, whereas the FYRC motif maps to β-strand 5, β-strand 6 and helices α1 to α4. Most of the conserved tyrosine and phenylalanine residues, after which these motifs are named are involved in interactions that stabilise the fold. Proteins such as MLL, in which the FYRN and FYRC regions are separated by hundreds of amino acids, are expected to contain FYR domains with a large insertion between two of the strands of the β-sheet (strands 4 and 5) .
MIF4G-like, type 3 (MIF4G-like_typ-3)
Type: Domain

MIF4G stands for middle domain of eukaryotic initiation factor 4G (eIF4G). eIF4G is a component of the translation initiation factor eIF4F complex and the cytoplasmic cap-binding protein complex (CBC). In the cytoplasm, cap binding complexes, distinct in their composition from nuclear cap-binding complexes, have important roles in the initiation of mRNA translation.

The MIF4G domain also occurs in other proteins, including CBP80, a component of the nuclear CBC and NMD2, involved in the cytoplasmic nonsense-mediated mRNA decay. The domain is rich in α-helices and may contain multiple α-helical repeats. In eIF4G, this domain binds to the two other components of the eIF4F complex, eIF4A and eIF3E, and to RNA and DNA .
Initiation factor eIF-4 gamma, MA3 (Initiation_fac_eIF4g_MI)
Type: Domain

This entry represents the MI domain (after MA-3 and eIF4G), it is a protein-protein interaction module of ~130 amino acids . It appears in several translation factors and is found in:

One copy in plant and animal eIF4G 1 and 2 (DAP-5/NAT1/p97)

Two copies in the animal programmed cell death protein 4 (PDCD4) or MA-3 that is induced during programmed cell death and inhibits neoplastic transformation

Four tandem-repeated copies in a group of uncharacterised plant proteins

The MI domain consists of seven α-helices, which pack into a globular form. The packing arrangement consists of repeating pairs of antiparallel helices packed one upon the other such that a superhelical axis is generated perpendicular to the α-helical axes .
Ubiquitin system component CUE (CUE)
Type: Domain

This domain promotes intramolecular monoubiquitination and has a dual role in mono- and poly-ubiquitination recognition, being involved in binding ubiquitin-conjugating enzymes (UBCs) . CUE domains also occur in two proteins of the IL-1 signal transduction pathway, tollip and TAB2.
Iroquois-class homeodomain protein (Iroquois_homeo)
Type: Domain

This is a motif found only in Iroquois-class homeodomain proteins. It has unknown function. Examples include iroquois-class homeodomain protein IRX-4, and homeobox proteins caupolican and araucan, which control proneural and vein forming genesand are positive transcriptional controllers of achaete-scute. They may act as activators that interact with the transcriptional initiation complex assembled on the achaete and scute promoters.