SII-SWORD/CoKE huggingface dataset:
Immunoglobulin C2-set (Ig_C2-set)
Type: Domain

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable;

), C1-set (constant-1;

), C2-set (constant-2;

) and I-set (intermediate;

) . Structural studies have shown that these domains share a common core Greek-key β-sandwich structure, with the types differing in the number of strands in the β-sheets as well as in their sequence patterns .

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system .

This entry represents C2-set domains, which are Ig-like domains resembling the antibody constant domain. C2-set domains are found primarily in the mammalian T-cell surface antigens CD2 (Cluster of Differentiation 2), CD4 and CD80, as well as in vascular (VCAM) and intercellular (ICAM) cell adhesion molecules.

CD2 mediates T-cell adhesion via its ectodomain, and signal transduction utilising its 117-amino acid cytoplasmic tail . CD2 displays structural and functional similarities with African swine fever virus (ASFV) LMW8-DR, a protein that is involved in cell-cell adhesion and immune response modulation, suggesting a possible role in the pathogenesis of ASFV infection . CD4 is the primary receptor for HIV-1. CD4 has four immunoglobulin-like domains in its extracellular region that share the same structure, but can differ in sequence. Certain extracellular domains may be involved in dimerisation .
Cyclin-dependent kinase inhibitor 3 (CDK_inhib_3)
Type: Family

This family consists of cyclin-dependent kinase inhibitor 3 or kinase associated phosphatase proteins from several mammalian species. The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is a Homo sapiens dual specificity protein phosphatase that dephosphorylates Cdk2 on threonine 160 in a cyclin-dependent manner .
Centromere protein H, C-terminal (CENP-H_C)
Type: Domain

Chromosome segregation in eukaryotes requires the kinetochore, a multi-protein structure that assembles on centromeric DNA, and which acts to link chromosomes to spindle microtubules. Kinetochore structure and composition is highly conserved among vertebrates. The inner kinetochore is essential for kinetochore assembly, and is involved in chromosome segregation via regulation of the spindle. Inner kinetochore components include the multi-subunit CENP-H/I complex, which may function, in part, in directing centromere protein A (CENP-A) deposition to centromeres, where CENP-A is a centromere-specific histone H3 variant required for the organisation of centromeric chromatin during interphase. The CENP-H/I complex contains three functional classes of proteins :

CENP-H class (includes CENP-H, -I, -K, -L)

CENP-M class (includes CENP-M)

CENP-O class (includes CENP-O, -P, -Q, -R, -50)

CENP-H is required for the localisation of CENP-C, but not CENP-A, to the centromere. However, it may be involved in the incorporation of newly synthesised CENP-A into centromeres via its interaction with the CENP-A/CENP-HI complex. CENP-H contains a coiled-coil structure and a nuclear localisation signal. CENP-H is specifically and constitutively localised in kinetochores throughout the cell cycle, and may play a role in kinetochore organisation and function throughout the cell cycle .

Studies show that CENP-H may be associated with certain human cancers .

This entry represents the C-terminal domain of CENP-H. Proteins containing this domain also include Schizosaccharomyces pombe Kinetochore protein Fta3, which is a subunit of the Sim4 complex. This complex is required for loading the DASH complex onto the kinetochore via interaction with dad1. Fta2, Fta3 and Fta4 associate with the central core and inner repeat region of the centromere .
Extracellular membrane protein, CFEM domain (Extracellular_membr_CFEM_dom)
Type: Domain

The CFEM domain is a fungal-specific domain that contains eight cysteines and is found in some proteins with proposed roles in fungal pathogenesis .

The structure of the CFEM domain containing protein 'Surface antigen protein 2' from Candida albicans (

) has been solved .

The CFEM (Common in Fungal Extracellular Membrane) protein domain is unique to fungi, but it is not found in all fungi. Many CFEM domain proteins have been found exclusively from Ascomycota and Basidiomycota, and they were found to be enriched in pathogenic fungi. The CFEM domain is found primarily in glycosylphosphatidylinositol (GPI)-anchored cell-wall proteins, and present in one or more copies, normally with one copy near the N terminus of proteins. CFEM-containing proteins are involved in differentiation, stress response and pathogenicity. CFEM-containing proteins systematically contribute to iron acquisition during saprotrophic and pathogenic growth in filamentous mycopathogens as well as inter-species competition. CFEM proteins have been shown to bind haem and to play crucial roles in extracting it from the host haemoglobin, as well as in mediating its delivery to the fungal cel .

The CFEM domain is predominantly comprised of hybrophobic residues. CFEM domains contain eight characteristically spaced cysteine residues with the consensus sequence P-x-C-[AG]-x(2)-C-x(8,12)-C-x(1,4)-D-x(2,5)-C-x-C-x(9,14)-C-x(3,4)-C-x(15,16) (where x is any residue with its range shown). The CFEM domain adopts a helical-basket fold that consists of six α-helices, the third of which is perpendicular to a central bundle of five antiparallel helices. Overall, the shape of the helical portion resembles a basket that is 'capped' from the top by Helix 3, whereas the long N-terminal
loop appears as its 'handle'.

The uniqueness of the helical-basket fold appears to stem primarily from the formation of four distinctive disulfide bonds that probably contribute to its rigidity and compactness, as well as to the distinctive orientation between its helices. These S-S bridges are formed between the eight canonical cysteine residues of the CFEM domain.Topologically, helices 2 and 4 are held together via two disulfide bridges, one formed by the first and the seventh cysteine residues (C1-C7) and the second by the second and sixth (C2-C6). Helices 3 and 5 are linked via a single disulfide bond (C5-C8), and Helix 3 is linked to an important haem-interacting loop via the C3-C4 disulfide bridge. The planar haem molecule is bound between a flat hydrophobic platform located on top of the helical basket and a peripheral N-terminal 'handle' extension. Exceptionally, an aspartic residue serves as the CFEM axial ligand, and so confers coordination of Fe(3) haem, but not of Fe(2) .
Chondroitin N-acetylgalactosaminyltransferase (Chond_GalNAc)
Type: Family

This family represents Chondroitin N-acetylgalactosaminyltransferase. Proteins have a type II transmembrane topology. The enzyme is involved in the biosynthetic initiation and elongation of chondroitin sulphate and is the key enzyme responsible for the selective chain assembly of chondroitin/dermatan sulphate on the linkage region tetrasaccharide common to various proteoglycans containing chondroitin/dermatan sulphate or heparin/heparan sulphate chains .
Cleft lip and palate transmembrane 1 (CLPTM1)
Type: Family

This entry includes cleft lip and palate transmembrane protein 1 (CLPTM1) and cleft lip and palate transmembrane protein 1-like protein (CLPTM1L, also known as CRR9). This entry also includes uncharacterised proteins from fungi and plants.

Clefts of the lip and/or palate (CL/P) are some of the most common birth defects. They may be categorised into syndromic or non-syndromic types, with syndromic defects having an underlying chromosomal or teratogenic cause. Around 70% of clefts are non-syndromic and individuals have no typical physical or developmental abnormalities; these clefts generally show polygenetic behaviour and complex inheritance . Studies have identified regions on chromosomes 19 and 11 which may be involved in non-syndromic cleft lip and palates; this included a novel gene on chromosome 19, cleft lip and palate-associated transmembrane protein 1 (CLPTM1) . The Poliovirus receptor-related 1 gene (PVRL1), which is located on chromosome 11, has also been shown to associate with non-syndromic cleft lip and palates .

Human CLPTM1L is a scramblase that mediates the translocation glucosaminylphosphatidylinositol (alpha-D-GlcN-1-6-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol, GlcN-PI) across the endoplasmic reticulum (ER) membrane, from the cytosolic leaflet to the luminal leaflet of the ER membrane, where it participates in the biosynthesis of glycosylphosphatidylinositol (GPI) . It protects non-small cell lung cancer tumour cells from genotoxic apoptosis and may contribute to lung cancer risk .
Cytotoxic necrotizing factor, Rho-activating domain (CNF_Rho-act)
Type: Domain

This domain is found in several bacterial cytotoxic necrotizing factor proteins as well as related dermonecrotic toxin (DNT) from Bordetella species .

Cytotoxic necrotizing factor 1 (CNF1) is a toxin whose structure from Escherichia coli revealed a 4-layer α/β/β/α structure containing mixed β-sheets . CNF1 is expressed in strains of E. coli causing uropathogenic and neonatal meningitis. CNF1 alters host cell actin cytoskeleton and promotes bacterial invasion of the blood-brain barrier endothelial cells . CNF1 belongs to a unique group of large cytotoxins that cause constitutive activation of Rho guanosine triphosphatases (GTPases), which are key regulators of the actin cytoskeleton .

Bordetella dermonecrotic toxin (DNT) stimulates the assembly of actin stress fibres and focal adhesions by deamidating or polyaminating Gln63 of the small GTPase Rho. DNT is an A-B toxin composed of an N-terminal receptor-binding (B) domain and a C-terminal enzymatically active (A) domain .
Cyclic nucleotide phosphodiesterase (CNPase)
Type: Family

This entry includes the eukaryotic protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) . CNPase is one of the earliest myelin-related proteins expressed in differentiating oligodendrocytes and Schwann cells. CNPase is abundant in the central nervous system and in oligodendrocytes . This protein is also found in mammalian photoreceptor cells, testis and lymphocytes. It may participate in RNA metabolism in the myelinating cell, CNP is the third most abundant protein in central nervous system myelin . CNP selectively cleaves 2',3'-cyclic nucleotides to produce 2'-nucleotides. Although physiologically relevant substrates with 2',3'-cyclic termini are still unknown, numerous cyclic phosphate containing RNAs occur transiently within eukaryotic cells. Other known protein families capable of hydrolysing 2',3'-cyclic nucleotides include tRNA ligases and plant cyclic phosphodiesterases. The catalytic domains from all these proteins contain two tetra-peptide motifs H-X-T/S-X, where X is usually a hydrophobic residue. Mutation of either histidine in CNPase abolishes enzymatic activity .
Cytochrome c oxidase subunit 5c (COX5C)
Type: Family

COX5C is one of the nuclear-coded polypeptide chains of cytochrome c oxidase, the terminal oxidase in mitochondrial electron transport .
Cytochrome C oxidase, subunit VIIB (Cyt_c_oxidase_suVIIB)
Type: Family

Cytochrome oxidase subunit VIIB is one of the nuclear-coded polypeptide chains of cytochrome c oxidase, the terminal oxidase in mitochondrial electron transport . The X-ray structure of azide-bound fully oxidized cytochrome c oxidase from bovine heart at 2.9 A resolution has been determined .
Magnesium-protoporphyrin IX monomethyl ester [oxidative] cyclase (AcsF)
Type: Family

This family represents the oxidative cyclase responsible for forming the distinctive E-ring of the chlorin ring system under aerobic conditions . This enzyme is believed to utilise a binuclear iron centre and molecular oxygen. There are two isoforms of this enzyme in some plants and cyanobacteria, which are differentially regulated based on the levels of copper and oxygen . This step is essential in the biosynthesis of both bacteriochlorophyll and chlorophyll under aerobic conditions (a separate enzyme, BchE, acts under anaerobic conditions). This enzyme is found in plants, cyanobacteria and other photosynthetic bacteria.

CRD1 (AcsF) is required for the maintenance of photosystem I and its associated light-harvesting complexes in copper-deficient (-Cu) and oxygen-deficient (-O(2)) Chlamydomonas reinhardtii cells and is localised to the thylakoid membrane. The family also contains the Rhodocyclus gelatinosus (Rhodopseudomonas gelatinosa or Rubrivivax gelatinosus) AcsF protein, which codes for a conserved, putative binuclear iron-cluster-containing protein involved in aerobic oxidative cyclization of Mg-protoporphyrin IX monomethyl ester. AcsF and homologs have a leucine zipper and two copies of the conserved glutamate and histidine residues predicted to act as ligands for iron in the Ex(29-35)DExRH motifs. Several homologs of AcsF are found in a wide range of photosynthetic organisms, including Chlamydomonas reinhardtii Crd1 and Pharbitis nil PNZIP, suggesting that this aerobic oxidative cyclization mechanism is conserved from bacteria to plants .
Corticotropin-releasing factor-binding protein (CRF-bd)
Type: Family

This family consists of several eukaryotic corticotropin-releasing factor binding proteins (CRF-BP or CRH-BP). Corticotropin-releasing hormone (CRH) plays multiple roles in vertebrate species. In mammals, it is the major hypothalamic releasing factor for pituitary adrenocorticotropin secretion, and is a neurotransmitter or neuromodulator at other sites in the central nervous system. In non-mammalian vertebrates, CRH not only acts as a neurotransmitter and hypophysiotropin, it also acts as a potent thyrotropin-releasing factor, allowing CRH to regulate both the adrenal and thyroid axes, especially in development. CRH-BP is thought to play an inhibitory role in which it binds CRH and other CRH-like ligands and prevents the activation of CRH receptors. There is however evidence that CRH-BP may also exhibit diverse extra and intracellular roles in a cell specific fashion and at specific times in development .
Chlamydia 15kDa cysteine-rich outer membrane (CRPA)
Type: Family

Chlamydia is a genus of bacteria, which causes the most common bacterial sexually transmitted diseases. They are obligate intracellular bacterial pathogens. Members of this genus lack a peptidoglycan layer, but as a substitute, it has been proposed that they have several cysteine rich membrane proteins. This includes the major outer membrane protein (MOMP). These form disulphide bonds to provide rigidity to the cell wall. The alignment of the amino acid sequences of the MOMP from various serovars of Chlamydia show that they have between seven and ten cysteine residues; seven of which are highly conserved . The MOMP has been the focus of efforts to produce a vaccine for Chlamydia trachomatis .

The 15kDa cysteine-rich protein in this entry is a multi-pass outer membrane protein. They are associated with the differentiation of reticulate bodies (RBs) into elementary bodies (EBs) . They immunolocalise to the inclusion membrane, which is the membrane that surrounds the intracellular parasite. These proteins are recognised by CD8+ T cells in both human and mouse infections, suggesting they gain access to the host cytoplasm.
Minor structural protein VP2, calicivirus (Minor_structural_calicivir)
Type: Family

This family consists of minor structural proteins largely from the Caliciviridaei family of viruses, including Sapporo virus (Hu/Chiba/041413/2004/JP) and Sapporo virus (Hu/Ehime/04-1680/2004/JP). These viruses cause gastroenteritis. This protein may form a portal-like structure at a unique three-fold axis of symmetry, following binding to the host receptor. The channel formed by VP2 may allow the delivery of the viral genome through the host endosomal membrane.
Myozenin (MYOZ)
Type: Family

This family consists of several mammalian calcineurin-binding proteins. Calcineurin is a Ca/calmodulin-dependent serine-threonine phosphatase and has been implicated in the transduction of signals that control the hypertrophy of cardiac muscle and slow fibre gene expression in striated muscle.
A novel family of striated muscle-specific calcineurin-interacting proteins called calsarcins or myozenins has been identified that interact and co-localize with the Z-disc protein alpha-actinin thereby coupling muscle activity to calcineurin activation .

Because calcineurin responds to sustained, low amplitude calcium signals, calsarcins may serve to localize calcineurin in the vicinity of unique intracellular pool, where it can interact with specific upstream activators or downstream substrates. Therefore, calsarcins may play an important role in modulating the function and substrate specificity of calcineurin in striated muscle cells.

Three isoforms of calsarcins that have been identified in human, rat and mouse: Calsarcin-1 (CALS-1, Myozenin-2, MYOZ2). Calsarcin-2 (CALS-2, Myozenin-1, FATZ)
Calsarcin-3 (Myozenin-3, MYOZ3).

Calsarcin-1, is expressed, throughout the development-cycle, in all striated muscle tissues. However, CALS-1 expression is localized in slow-twitch fibres. Calsarcin-2, has an approximate ~30% identity with CALS-1 is a globular protein with central glycine-rich domain flanked by a-helical regions. CALS-2 is expressed transiently in heart during early embryogenesis and later becomes restricted to skeletal muscle with weaker signals in adult prostate, placenta and pancreas. In contrast to CALS-1, the expression of Calsarcin-2 is restricted to fast-twitch skeletal fibre. Calsarcin-3, is expressed specifically in skeletal muscle and is enriched in fast-twitch muscle fibres. Like calsarcin-1 and calsarcin-2, calsarcin-3 interacts with calcineurin, and the Z-disc proteins alpha-actinin, gamma-filamin, and telethonin .
Campylobacter major outer membrane (Campylo_MOMP)
Type: Family

Campylobacter are Gram-negative, spiral, microaerophilic bacteria. Campylobacter jejuni is one of the main causative agents of food poisoning in the developed world.
This family consists of Campylobacter major outer membrane proteins. The major outer membrane protein (MOMP), a putative porin and a multifunction surface protein of Campylobacter jejuni, may play an important role in the adaptation of the organism to various host environments .
Agglutinin-like protein repeat (Agglutinin-like_ALS_rpt)
Type: Repeat

Adhesive properties in fungi are conveyed by a group of cell-surface proteins called adhesins (sometimes also referred to as agglutinins or flocculins). Several fungal adhesins have been described to date, including the the Candida albicans Als (agglutinin-like sequence) proteins . Als proteins are cell-surface glycoproteins and have a three-domain structure. Each Als protein has a relatively conserved N-terminal domain, a central domain consisting of a tandemly repeated motif of variable number, and a serine-threonine-rich C-terminal domain that is relatively variable across the family. The Als family exhibits several types of variability that indicate the importance of considering strain and allelic differences when studying als genes and their encoded proteins .

This entry represents the tandem repeat found in the central domain of the Als proteins.
AfumC-like glycosyltransferase (AfumC-like_glycosyl_Trfase)
Type: Family

This entry includes several O-glycosyltransferases from the afumC family. afumC from Aspergillus fumigatus is part of the gene cluster that mediates the biosynthesis fumihopaside A, a hopane-type glucoside that enhances the thermotolerance and UV resistance . PaGT from the yeast Phomopsis amygdali is important for the biosynthesis of the mycotoxins known as fusicoccins, diterpene glycosides which are potent activators of plasma membrane H+-ATPases in plants, leading to disease constriction canker . Also included in this entry is the probable glycosyltransferase FCK3, which is part of the gene cluster that mediates the biosynthesis of cytokinins such as fusatin, fusatinic acids or 8-oxofusatin, known for their growth promoting and anti-senescence activities toward host plants .

These entry also includes several uncharacterised bacterial sequences annotated as capsular polysaccharide proteins, which in Streptococcus pneumoniae are the major virulence factors. These sequences are thought to be transcribed with putative glycosyltransferases to give rise to bifunctional proteins .
Propeptide, carboxypeptidase Y (Propeptide_carboxypepY)
Type: Domain

This signature is found at the N terminus of carboxypeptidase Y, which belong to MEROPS peptidase family S10. This region contains the signal peptide and pro-peptide regions .
Chlamydia virulence plasmid protein pGP3 (Chlamydia_pGP3)
Type: Family

This family consists of Chlamydia virulence proteins which are thought to be required for the growth of these bacteria in mammalian cells . Humans mount a humoral and mucosal immune response to plasmid protein pGP3 from Chlamydia trachomatis infections . This immune response to pGP3 in humans and animal models of chlamydia-induced disease has potential uses in diagnostic assays and protective immunisation strategies .
Core protein A15 (A15)
Type: Family

This entry represents Protein A15 from Variola virus, also known as Core protein OPG142, and similar sequences from poxvirus.
A15 is a late protein which is a part of a large complex required for early virion morphogenesis. This complex participates in the formation of virosomes and the incorporation of virosomal contents into nascent immature virions. It is required for the stability and kinase activity of OPG054 .
Chordopoxvirus G2 (Chordopox_G2)
Type: Family

This entry represents Protein G2 from Vaccinia virus, also known as Late transcription elongation factor OPG087, and similar sequences from poxvirus. G2 is involved in postreplicative transcription elongation on intermediate and late genes . Most members of this family are Chordopoxvirus isatin-beta-thiosemicarbazone dependent protein (protein G2) sequences. Inactivation of the gene coding for this protein renders the virus dependent upon isatin-beta-thiosemicarbazone (IBT) for growth .
Protein L2 (Prot_L2)
Type: Family

This entry represents Protein L2 from Vaccinia virus, also known as Protein OPG096, and similar sequences from poxvirus. L2 is involved in early virion morphogenesis. It is required for the formation or elongation of crescent-shaped membrane precursors of immature virions in cytoplasmic factories .