SII-SWORD/CoKE huggingface dataset:
Bvu_2165-like, IHF-HU-like DNA-binding domain (Bvu_2165-like_IHF-HU-DNA_bdg)
Type: Domain

This entry includes uncharacterised bacterial proteins, such as the hypothetical protein Bvu_2165 from Bacteroides vulgatus. These proteins consist of two domains, an N-terminal one similar to DNA sequence specific (integration host factor) IHF and non-specific (HU) domains which is represented in this entry, and a C-terminal Ig-like domain (

).
Coronavirus NSP3, 3Ecto domain (COV_NSP3_3ECTO)
Type: Domain

This entry represents the Nsp3 ectodomain (3Ecto) from coronaviruses.

The CoV 3Ecto domain is a glycosylated domain and it is predicted to be located on the lumenal side of the membrane. The transmembrane regions plus the 3Ecto are important for the PL2pro to process the Nsp3-4 cleavage site; a possible reason is that the transmembrane part could bring the PL2pro close to the cleavage site between the membrane-associated proteins Nsp3 and Nsp4. Asparagine (N)-linked glycosylation has been found in 3Ecto domains. It is unclear if the N-glycan modification affects the 3Ecto conformation or stability. Frequently, N-linked glycans serve as recognition points for partner molecules. It has been shown that interaction of the 3Ecto domain with the large lumenal loop of Nsp4 is essential for the endoplasmic reticulum (ER) rearrangements and double-membrane vesicles (DMVs) formation occurring in cells infected by SARS-CoV or mouse hepatitis virus (MHV) .

The CoV 3Ecto domain is predicted to mostly contain α-helices and to form two disulphide bonds between C1 and C4 as well as C2 and C3 .

Coronaviruses (CoVs) are enveloped positive-strand RNA viruses that infect many species, including humans, other mammals, and birds. After infection, the host may develop respiratory, bowel, liver, and neurological diseases. Coronaviruses are divided into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. SARS, SARS-CoV-2, BatCoV RaTG13 and Bat-SARS-like coronavirus (BATSL-CoVZXC21 and BAT-SL-CoVZC45) belong to the Sarbecovirus subgenus of Betacoronavirus [E1].

The CoV replicase gene encodes two overlapping polyproteins, termed pp1a and pp1ab, which mediate viral replication and transcription. The polypeptides pp1a and pp1ab are processed by the action of a main protease (Nsp5) and of one or two papain-like proteases (PLpro) found in Nsp3 into non-structural proteins (Nsps) to form the replication/transcription complex (RTC). Among these, Nsp3 is the largest multi-domain protein produced by coronaviruses. This glycosylated, multi-domain, integral membrane protein plays many roles in the viral life cycle. It can act as a scaffold protein to interact with itself and to bind other viral Nsps or host proteins. In particular, Nsp3 is essential for RTC formation. Nsp3 comprises various domains of functional and structural importance for virus replication, the organization of which differs between CoV genera, due to duplication or absence of some domains.

However, eight domains of Nsp3 exist in all knownCoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro), the Nsp3 ectodomain (3Ecto), as well as the Y domain which includes a widely-conserved initial domain (Y1), and an apparently coronavirus-specific carboxyl-terminal domain (CoV-Y). In addition, two transmembrane regions, TM1 and TM2, exist in all CoVs .
Streptococcal M protein, D repeats (SMDRR)
Type: Repeat

This entry represents the entire D repeats found in the streptococcal M protein family.

M proteins belong to a family of fibrous streptococcal surface proteins that interact with the immune system of the host and represent major virulence factors due to their antiphagocytic activities. These antiphagocytic properties are explained by binding to a variety of different host proteins,
with the most prominent one being fibrinogen. Another hypothesis relies on the M-protein-mediated formation of large bacterial aggregates, thereby inhibiting phagocytic engulfment. All M proteins share a common framework that includes a conserved signal peptide, a hypervariable amino terminus, a less variable central domain, and a highly conserved C terminus. A number of repeat sequences (A, B, C and D repeats) follow the hypervariable region. Sequence conservation increases from the A repeats to D repeats. The size and number of the A and B repeats varies between different M proteins. Most M proteins do not possess any A repeats. The C repeats are present in all M proteins, although the number of repeat sequences varies from two (M6) to four (M12). The amino acid identity in the C repeat region increases from C1 to C3. The conserved repetitive C units are responsible for several biological activities of M and M-like proteins. The C units are involved in the binding of human serum albumin (HSA) to the M protein. Furthermore, the binding of complement factor H and streptococcal adherence to keratinocytes in human skin are mediated by the C units. Region D is composed of four seven-residue "quasirepeats" .

The M molecules exist as stable dimers the molecules are almost entirely α-helical. A common periodicity in the placement of nonpolar or hydrophobic residues is responsible for maintaining the α-helical character of the proteins . The streptococcal M proteins C repeat can adopt an α-helical structure .
Streptococcal M proteins C repeat (SMCR)
Type: Repeat

This entry represents the entire C repeat found in the streptococcal M protein family.

M proteins belong to a family of fibrous streptococcal surface proteins that interact with the immune system of the host and represent major virulence factors due to their antiphagocytic activities. These antiphagocytic properties are explained by binding to a variety of different host proteins,
with the most prominent one being fibrinogen. Another hypothesis relies on the M-protein-mediated formation of large bacterial aggregates, thereby inhibiting phagocytic engulfment. All M proteins share a common framework that includes a conserved signal peptide, a hypervariable amino terminus, a less variable central domain, and a highly conserved C terminus. A number of repeat sequences (A, B, C and D repeats) follow the hypervariable region. Sequence conservation increases from the A repeats to D repeats. The size and number of the A and B repeats varies between different M proteins. Most M proteins do not possess any A repeats. The C repeats are present in all M proteins, although the number of repeat sequences varies from two (M6) to four (M12). The amino acid identity in the C repeat region increases from C1 to C3. The conserved repetitive C units are responsible for several biological activities of M and M-like proteins. The C units are involved in the binding of human serum albumin (HSA) to the M protein. Furthermore, the binding of complement factor H and streptococcal adherence to keratinocytes in human skin are mediated by the C units. Region D is composed of four seven-residue "quasirepeats" .

The M molecules exist as stable dimers the molecules are almost entirely α-helical. A common periodicity in the placement of nonpolar or hydrophobic residues is responsible for maintaining the α-helical character of the proteins . The streptococcal M proteins C repeat can adopt an α-helical structure .
Latexin-type cystatin domain (CYSTATIN_LXN)
Type: Domain

This entry represents the Latexin-type cystatin domain.

Latexin (LXN), or tissue carboxypeptidase inhibitor (TCI), is the only known mammalian carboxypeptidase inhibitor (CPI). It is expressed in a cell type-specific manner in both central and peripheral nervous systems in the rat . LTX has no detectable sequence similarity with plant and parasite inhibitors, but it is related to a human putative tumor suppressor protein, TIG1 (

). TIG1 is larger than latexin, and the additional residues are thought to encode a membrane anchor at the N terminus. Other proteins with sequence identity to LXN are found in chicken (Ovocalyxin-32,

) and Xenopus, but no related proteins were found in nonvertebrates. Chicken Ovocalyxin-32 is a protein involved in egg shell production .

The structure of LXN (

) shows no structural relationship with other CPIs. Furthermore, despite a lack of detectable sequence duplication, the structure incorporates two topologically analogous domains related by pseudo two-fold symmetry. Each domain comprises a curved five-stranded antiparallel β-sheet wrapped around an α-helix. These domains share a cystatin fold architecture found in proteins that inhibit cysteine proteases, suggesting an evolutionary and possibly functional relationship. LXN may have evolved from an ancestral cystatin-like protein as a consequence of a gene duplication event. The LXN-type cystatin domains are packed against each other through the helices and linked by a connecting segment encompassing a third α-helix. The two domains are arranged so that there is a cleft in this part of the structure that can accommodate a peptide chain .
MarR-like, BRCT and chromo domains module (MARR_BRCT_CHROMO)
Type: Domain

This entry represents the entire MarR-like, BRCT and chromo domains module found in SWI/SNF complex subunit SMARCC1 and subunit SMARCC2.

Mammalian SWI/SNF (mSWI/SNF) of BAF complexes are a subfamily of SWI/SNF ATP-dependent chromatin remodellers that dynamically modulate chromatin structure to regulate fundamental cellular processes including gene transcription, cell cycle control, and DNA damage response . The BAF155/SMARCC1 subunit is a component of all complexes identified to date, incorporated either as a homodimer or as a heterodimer with its paralogue BAF170/SMARCC2. The BAF155 subunit predominates in stem cells, while the BAF170 subunit is incorporated during differentiation. The N-terminal of the BAF155/SMARCC1 and BAF170/ SMARCC2 subunits contain a putative DNA-binding MarR-like domain, a
chromo domain and a BRCT domain that are interconnected to each other to form a distinct module. This N-terminal module could participate
in an interaction involving both protein and nucleic acid components .

The MarR-like domain forms a four-helix-bundle that resembles the MarR-like helix-turn-helix domain. The BRCT domain contains an inserted chromo domain between the second and third strands of the canonical fold. The chromo domain consists of the curved antiparallel three-stranded
β-sheet characteristic of this domain. The individual domains are linked via a network of hydrogen bonds to form a single structural unit (

}. The architecture of the fold produces a cleft containing two deep pockets at the interface between the domains .
Zinc finger, C2HC/C3H-type (Znf_C2HC_C3H)
Type: Domain

This entry represents the C2HC/C3H-type zinc finger domain found in a group of proteins mainly from animals, including members of the ZC2HC1 family and bryophyte SOSEKI proteins that locally interpret global polarity cues and can influence cell division orientation to coordinate cell polarisation relative to body axes.

The C2HC/C3H-type zinc finger was first identified in four copies in Zfp474, a protein exclusively found in testis and ovary and thought to function as a germ cell specific transcription factor that plays important roles in spermatid differentiation and oocyte development .
Polyketide synthase, dehydratase domain (PKS_mFAS_DH)
Type: Domain

This entry represents the dehydratase domain (DH) found in polyketide synthases and related fatty acid synthases . This domain is associated with

, representing the N-terminal and

, representing the C-terminal.

Structural analysis shows these DH domains are double hotdogs in which the active site contains a histidine from the N-terminal hotdog and an aspartate from the C-terminal hotdog. Studies have uncovered that a substrate tunnel formed between the DH domains may be essential for loading substrates and unloading products .

Polyketide synthases (PKSs) are large, multifunctional enzyme complexes that catalyse the biosynthesis of diverse secondary metabolites known as polyketides . These enzymes operate in an assembly line-like manner, utilising multiple domains such as acyltransferase (AT)

, and acyl carrier protein (ACP)

to perform stepwise condensation of simple carboxylic acid units . PKSs can be classified into three main types: type I (modular), type II (iterative), and type III, each with distinct structural and functional characteristics . The modular type I PKSs, in particular, contain additional domains like ketoreductase (KR)

, dehydratase (DH)

, and enoylreductase (ER)

that modify the growing polyketide chain .
NS1 nuclease, NS1-Nuc domain, Parvovirus (PV_NS1-NUC)
Type: Domain

This entry represents the NS1-Nuc domain found mainly in the Parvoviridae family of viruses.

The PV NS1-Nuc domain consists of a central five-stranded antiparallel β-sheet surrounded by clusters of α-helices (see

). The central β-sheet forms a cleft that embraces the endonuclease active site. The NS1-Nuc domain structure reveals an overall fold that is canonical to the HUH superfamily of endonucleases that are involved in rolling-circle replication, which contain signature motif HUH, also known as motif 2, and motif YUxxYx(2-3)K, also known as motif 3 (where Y is tyrosine, U is hydrophobic residue, x is any residue, and K is lysine). Divalent metal ions are required for DNA cleavage activities for the HUH-superfamily of endonucleases. The catalytic centre of HUH-endonucleases is composed of four residues. Unlike the two characteristic histidine residues, the third catalytic residue is changeable (either Glu or His). The fourth residue is a tyrosine, which is highly conserved in HUH-endonucleases .

The family Parvoviridae is a group of small (18-26nm diameter), non-enveloped, and autonomously replicating icosahedral viruses containing a single-stranded linear DNA genome ranging from 4-6 kb in length, with terminal hairpins [E1]. The parvoviral single-stranded DNA genome contains two open reading frames (ORFs), one encoding nonstructural (NS) proteins, the other capsid proteins. All parvoviruses encode a nonstructural protein NS1 (termed Rep in adeno-associated virus [AAV]) that is essential for viral DNA replication and packaging of viral DNA into capsid. It may play other versatile roles, for example, in the transactivation of viral and cellular gene expression, DNA damage response, cell cycle arrest, apoptosis, and/or the modulation of innate immunity.

The N terminus of the parvoviral NS1 protein contains an origin of replication binding (OBD) domain, also known as a DNA-specific binding domain or nuclease (NS1-Nuc) domain. Its central region contains a helicase domain, which includes an NTP-binding site, and its C terminus includes a transactivation domain (TAD). The PV NS1-Nuc domain plays an important role in the "rolling hairpin" replication of the single-stranded parvoviral DNA genome: after cellular enzymes have converted the viral genome into double-stranded DNA, it recognizes origin of replication sequences and cleaves (i.e., nicks) one strand DNA at a nearby site known as the terminal resolution site (trs). Since the DNA encountered by NS1 is double-stranded, it is assumed that binding of NS1 to its target sequences induces strand separation, allowing for the endonuclease activity of NS1 to cleave at the trs
site . A homologue of parvoviral NS1, U94, is found in human herpesvirus 6 variants A and B (HHV-6A and HHV-6B, respectively) which do not replicate by "rolling hairpin" mecanism. U94 has key functions in the virus life cycle and associated diseases, having demonstrated or putative roles in virus replication, integration, and reactivation .
Fusexin 1 (Fsx1)
Type: Family

This entry represents a small group of archaeal proteins, including Fusexin 1 from Haloferax sp. (Fsx1), which exhibits fusogenic activity and mediates cell-cell fusion in mammalian cells (bilateral fusion) .
Potassium channel tetramerization domain-containing protein 16, H1 domain (H1_KCTD16)
Type: Domain

Potassium channel tetramerisation domain-containing protein 16 (KCTD16) is a BTB/POZ domain-containing protein that is an auxiliary subunit of gamma-aminobutyric acid type B (GABA-) receptors associated with mood disorders. It interacts with amyloid beta precursor protein (APP), a type I transmembrane protein involved in a variety of cellular processes such as cell adhesion and axon guidance . KCTD16 generates largely non-desensitising receptor responses. KCTD16 consists of an N-terminal BTB domain followed by a region called the H1 domain. The BTB domain mediates interaction with the receptor. The H1 domain, found at the C terminus, which possesses a β-propeller-like fold, engages in interactions with G-protein β and γ subunits. In the related protein KCTD12, the H1 domain is also responsible for desensitisation.

This entry corresponds to the H1 domain of KCTD16, which may not be involved in desensitisation .
Potassium channel tetramerization domain-containing protein 8, H1 domain (H1_KCTD8)
Type: Domain

Potassium channel tetramerization domain-containing protein 8 (KCTD8), a BTB/POZ domain-containing protein, is an auxiliary subunit of gamma-aminobutyric acid type B (GABA-B) receptors that determine the pharmacology and kinetics of the receptor response . It generates largely non-desensitising receptor responses. KCTD8 consists of an N-terminal BTB domain followed by a region called the H1 domain. The BTB domain mediates interaction with the receptor. The H1 domain, which possesses a β-propeller-like fold, engages in interactions with G-protein β and γ subunits. In the related protein KCTD12, the H1 domain is also responsible for desensitisation.

This entry corresponds to the H1 domain of KCTD8, which may not be involved in desensitisation .
Potassium channel tetramerization domain-containing protein 12, H1 domain (H1_KCTD12)
Type: Domain

Potassium channel tetramerization domain-containing protein 12 (KCTD12), also called predominantly fetal expressed T1 domain (Pfetin), is a BTB/POZ domain-containing protein that is an auxiliary subunit of gamma-aminobutyric acid type B (GABA-B) receptors associated with mood disorders . It regulates agonist potency and kinetics of GABA-B receptor signalling . It promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition . It also regulates colorectal cancer cell stemness through the ERK pathway . KCTD12 consists of an N-terminal BTB domain followed by a region called the H1 domain. The BTB domain mediates interaction with the receptor. The H1 domain, which possesses a β-propeller-like fold, engages in interactions with G-protein β and γ subunits and is responsible for desensitisation .

This entry corresponds to the H1 domain.
LxmA-like, leader domain (LxmA-like_leader)
Type: Domain

This entry represents the N-terminal leader domain found in a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) mainly from actinomycetes whose lanthionine moiety is created by a novel class of enzyme, including LxmA. This group also includes a number of other RiPPs that much lower sequence similarity outside the leader peptide region .
Phe operon leader peptide (PheL)
Type: Family

This entry represents a family of proteins specific to enterobacterales, including Phe operon leader peptide from Escherichia coli (

, PheL), which is involved in control of the biosynthesis of phenylalanine .
Multiple cyclophane triceptide AmcA, group 3a (AmcA_3a)
Type: Family

This entry represents a family of proteins from actinomycetes that belong to one of several classes of peptide natural product synthesized on the ribosome and then post-translationally modified (RiPP), where the modification begins with the actinobacterial multiple cyclophane-forming radical SAM peptide maturase AmcB .
Rtel1, harmonin homology domain (Rtel1_HHD)
Type: Domain

This entry represents a domain which appears to be similar to the N-terminal domain of the scaffolding protein harmonin, and therefore, it has been named as the harmonin homology domain (HHD), found C-terminal of these proteins. In human and some other mammals as well as in some fish species, this domain is found as two tandem ones, referred to as HHD1 and HHD2 (or HNL1/2) , while in plants and arthropods it is found as a single domain. HHD1/2 may mediate protein-protein interactions. It has been shown that the HHD1 domain from the human protein mediates interaction of RTEL1 with SLX4, which prevents replication-transcription collision through R-loop dissolution. Mutations in these domain are associateδ with Hoyeraal-Hreidarsson syndrome and pulmonary fibrosis .

Regulator of telomere elongation helicase 1 (Rtel1) is the animal functional analogue of yeast Srs2, which is a DNA helicase and DNA-dependent ATPase involved in DNA repair and checkpoint recovery . Rtel1 is an essential DNA helicase that disassembles a variety of DNA secondary structures to facilitate DNA replication, repair, and recombination processes, and to maintain both telomeric and genomic stability . It is recruited by Trf2 to telomeres in S phase to promote T-Loop unwinding . It is also required for the export and the correct cytoplasmic trafficking of the small nuclear (sn) RNA pre-U2, a component of the major spliceosome complex . Human Rtel1 is implicated in the etiology of Dyskeratosis congenital (DC, is an inherited bone marrow failure and cancer predisposition syndrome) . Point mutations in its helicase domains, and truncations which result in loss of its C terminus have been discovered in DC families. It acts as anti-recombinase and antagonises homologous recombination by promoting the disassembly of D loop recombination intermediates in a reaction dependent upon ATP hydrolysis . Rtel1 is also a candidate gene influencing glioma susceptibility .
HetZ-related (HetZ-rel)
Type: Family

This entry represents a family of proteins from cyanobacteria. Members of this group are paralogs of the heterocyst differentiation protein HetZ and occur in largely the same set of genomes.
Host nuclease inhibitor GamL-like (GamL-like)
Type: Family

This entry represents a family of proteins mainly found in tailed bacteriophages and prophages from Enterobacterales, including Host nuclease inhibitor GamL from the Enterobacteria phage phi80. Members of this family are phage inhibitors of host nucleases such as RecBCD and SbcCD. This family has a distant relationship to Gam (see

), which inhibits RecBCD.
Hepatitis C virus, p7 channel (HCV_p7)
Type: Domain

This entry represents the p7 channel from hepatitis C virus.

Hepatitis C virus (HCV) p7 protein is a viroporin essential for virus production. The p7 monomer is comprised of 2 trans-membrane helices connected by a cytosolic loop, and oligomerises to form cation-specific ion channels. These ion channels dissipate pH gradients in secretory vesicles potentially protecting acid-labile intracellular virions during egress (the rupturing of the infected cell and release of viral contents). p7 protein has at least two different functions in culture, one via the formation of these ion channels, the other through its specific interaction with the non-structural viral protein NS2. Several compounds targeting p7 have been investigated as anti-HCV drugs .
PHD finger-containing protein 1-3/5-6 (PHD1-3/5-6)
Type: Family

This family includes PHD-containing proteins 1-3/5/6 from plants (PHD1-3/5-6), such as ASI1-immunoprecipitated protein 2 (AIPP2, also known as PHD3), protein PARALOG OF AIPP2 (PAIPP2, also known as PHD2) . Members of this entry together with AIPP3/BDT1, cooperate to form a BAH-PHD bivalent histone reader complex able to read histone H3 lysine 27 trimethylation (H3K27me3) and low-methylated H3K4 histone marks in order to regulate transcription, especially to prevent early flowering. It promotes AIPP3/BDT1 binding to H3K27me3 . Plants missing all PHD finger-containing proteins (e.g. PHD1, PAIPP2/PHD2, AIPP2/PHD3, PHD4, PHD5 and PHD6) exhibit an increased expression of flowering genes leading to an early flowering phenotype under long-day conditions as well as growth retardation .