SII-SWORD/CoKE huggingface dataset:
Programmed cell death protein 10, dimerisation domain superfamily (PDC10_dimerisation_sf)
Type: Homologous_superfamily

Programmed cell death 10 protein (PDCD10/CCM3) is part of the CCM complex and is required for neuronal migration . Outside of this complex, it is crucial in vascularization and in angiogenesis as it functions in vessel permeability and stability . This protein plays an essential role in early embryonic angiogenesis and cardiovascular development. PDCD10/CCM3 interacts with a variety of proteins, including paxillin, membrane receptor vascular epidermal growth factor receptor 2, CCM complex component CCM2 and germinal centre kinase III proteins (GCKIII). PDCD10/CCM3 contains an N-terminal dimerisation domain and a C-terminal focal adhesion targeting-homology (FAT-H) domain .

This entry represents the N-terminal dimerisation domain of PDC10/CCM3, consisting of four α-helices. This domain is also found at the C-terminal of GCKIIIs (STK24/MST3, STK25, STK26/MST4), which adopts a closely related fold. GCKIIIs are involved in the regulation of apoptosis, cell proliferation, polarity, migration, and cytoskeleton remodelling. This domain mediates homo and heterodimerization. PDCD10/CCM3 forms a heterodimer with GCKIIIs analogous to CCM3 homodimer .
Clp protease, ATP-binding subunit ClpX, bacteria (ClpX_bact)
Type: Family

ClpX is a member of the HSP (heat-shock protein) 100 family. Gel filtration and electron microscopy showed that ClpX subunits associate to form a six-membered ring that is stabilised by binding of ATP or nonhydrolysable analogs of ATP . It functions as an ATP-dependent molecular chaperone and is the regulatory subunit of the ClpXP protease .

ClpXP is involved in DNA damage repair, stationary-phase gene expression, and ssrA-mediated protein quality control. To date more than 50 proteins include transcription factors, metabolic enzymes, and proteins involved in the starvation and oxidative stress responses have been identified as substrates .

The N-terminal domain of ClpX is a C4-type zinc binding domain (ZBD) involved in substrate recognition. ZBD forms a very stable dimer that is essential for promoting the degradation of some typical ClpXP substrates such as lO and MuA .

This entry represents ClpX subunit from bacteria.
Daxx, histone-binding domain superfamily (DAXX_histone-bd_sf)
Type: Homologous_superfamily

Daxx (also known as death domain-associated protein 6) is a nuclear protein that modulates transcription of various genes and is involved in cell death and/or the suppression of growth. Daxx is also a histone chaperone conserved in metazoa that acts specifically on histone H3.3. This entry represents the histone-binding domain of Daxx that interacts with the histone H3.3-H4 dimer, and in doing so competes with DNA binding and interactions between the histone chaperone ASF1/CIA and the H3-H4 dimer .
Legumain prodomain superfamily (Legumain_prodom_sf)
Type: Homologous_superfamily

Asparaginyl endopeptidase, also known as legumain, is a family of cysteine proteases found in many organisms. This group of cysteine peptidases belong to the MEROPS peptidase family C13 (legumain family, clan CD). A type example is legumain from Canavalia ensiformis (Jack bean, Horse bean) . Although legumains were first described from beans (also known as Vacuolar Processing Enzymes), homologues have been identified in plants, protozoa, vertebrates, and helminths . In blood-feeding helminths, asparaginyl endopeptidases (sometimes described as hemoglobinases) have been located in the gut and are considered to be involved in host hemoglobin digestion .

This domain is found in the proenzyme form legumain (also known of Vacuolar-processing enzyme). The mature active form of these proteins is generated by autoproteolytic maturation at acidic pH. In the 3D structure of the proenzyme, this prodomain is located on top of the protease domain, blocking access to the active site, conferring enzymatic latency and conformational stability. It shows an entirely α-helical fold, with an activation peptide and a region that assemblies into a death domain-like fold at the C-terminal (also referred to as as legumain stabilization and activity modulation (LSAM) domain) .
mRNA-capping enzyme catalytic subunit, OB fold domain superfamily (MCEL_OB_dom_sf)
Type: Homologous_superfamily

mRNA-capping enzyme catalytic subunit from Vaccinia virus (MCEL, also known as mRNA-capping enzyme D1 subunit) catalyses three enzymatic reactions: the 5' triphosphate end of the pre-mRNA is hydrolysed to a diphosphate by RNA 5' triphosphatase; the diphosphate RNA end is capped with GMP by RNA guanylyltransferase and the GpppN cap is methylated by RNA (guanine-N7) methyltransferase. It consists of an N-terminal RNA triphosphatase (TPase)-guanylyltransferase (GTase) module and a C-terminal guanine-N7-methyltransferase (MTase) module . The N-terminal module comprises a TPase domain at the very N-terminal, followed by the GTase at the C-terminal, which consists of the nucleotidyltransferase (NTPase) and OB fold domains.

This superfamily represents the OB fold of poxviral mRNA-capping enzyme catalytic subunit which is at the C-terminal of the guanylyltransferase (GTase) module.
mRNA-capping enzyme catalytic subunit, nucleotidyltransferase domain superfamily (MCEL_NTPase_sf)
Type: Homologous_superfamily

mRNA-capping enzyme catalytic subunit from Vaccinia virus (MCEL, also known as mRNA-capping enzyme D1 subunit) catalyses three enzymatic reactions: the 5' triphosphate end of the pre-mRNA is hydrolysed to a diphosphate by RNA 5' triphosphatase; the diphosphate RNA end is capped with GMP by RNA guanylyltransferase and the GpppN cap is methylated by RNA (guanine-N7) methyltransferase. It consists of an N-terminal RNA triphosphatase (TPase)-guanylyltransferase (GTase) module and a C-terminal guanine-N7-methyltransferase (MTase) module . The N-terminal module comprises a TPase domain at the very N-terminal, followed by the GTase at the C-terminal, which consists of the nucleotidyltransferase (NTPase) and OB fold domains.

This superfamily represents the NTPase domain from poxviral mRNA-capping enzyme catalytic subunit, which is at the N-terminal of the guanylyltransferase (GTase) module. It consists of a central six-stranded antiparallel β-sheet, a four-stranded mixed β-sheet and three α-helices.
mRNA-capping enzyme catalytic subunit, RNA triphosphatase domain superfamily (MCEL_TPase_sf)
Type: Homologous_superfamily

mRNA-capping enzyme catalytic subunit from Vaccinia virus (MCEL, also known as mRNA-capping enzyme D1 subunit) catalyses three enzymatic reactions: the 5' triphosphate end of the pre-mRNA is hydrolysed to a diphosphate by RNA 5' triphosphatase; the diphosphate RNA end is capped with GMP by RNA guanylyltransferase and the GpppN cap is methylated by RNA (guanine-N7) methyltransferase. It consists of an N-terminal RNA triphosphatase (TPase)-guanylyltransferase (GTase) module and a C-terminal guanine-N7-methyltransferase (MTase) module . The N-terminal module comprises a TPase domain at the very N-terminal, followed by the GTase at the C-terminal, which consists of the nucleotidyltransferase (NTPase) and OB fold domains.

This superfamily represents the TPase domain from poxviral mRNA-capping enzyme catalytic subunit, which adopts and α/β barrel structure. The central core consists of an anti-parallel eight-stranded β-barrel which forms closed hydrophilic tunnel.
Fantastic Four domain (FAF_dom)
Type: Domain

This entry represents a plant specific domain called "fantastic four" (FAF). Members in this family include FAF1/2/3/4 from Arabidopsis thaliana. They may be modulators of the genetic circuit that regulates the meristem . This family also includes Protein SUGARY ENHANCER 1 from maize, which has a FAF domain and is involved in starch metabolism in endosperm .
TASOR (TASOR)
Type: Family

TASOR is a key component of the HUSH complex, a vertebrate-specific multiprotein complex that mediates epigenetic repression of both exogenous and endogenous genetic elements . The HUSH complex regulates H3K9me3 deposition by promoting recruitment of SETDB1 and also recruits MORC2 to compact chromatin . The HUSH complex represses L1 retrotransposons and is also involved in the silencing of unintegrated retroviral DNA by being recruited by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed . TASOR is crucial in early embryonic development , and contains a catalytically-inactive PARP domain, necessary for epigenetic regulation of target elements.
Acetyl-CoA hydrolase/transferase (ActCoA_hydro)
Type: Family

This family contains several enzymes which take part in pathways involving acetyl-CoA. Acetyl-CoA hydrolase

from yeast is localized in mitochondria and cytosol and has CoA transferase activity, in particular for CoASH transfer from succinyl-CoA to acetate with minor acetyl-CoA hydrolase activity . It catalyses the formation of acetate from acetyl-CoA . Succinyl-CoA:coenzyme A transferase (CAT1)

produces succinyl-CoA, and acetate-CoA transferases

utilises acyl-CoA and acetate to form acetyl-CoA.
NSP14, guanine-N7-methyltransferase domain, coronavirus (N7_MTase_CoV)
Type: Domain

The unique coronavirus (CoV) transcription/replication machinery comprised of multiple virus-encoded non structural proteins (NSP) plays a vital role during initial and intermediate phases of the viral life cycle. This entry represents NSP14, encoded as part of polyprotein pp1ab and excised by NSP5. Its N-terminal exoribonuclease (ExoN) domain plays a proofreading role for prevention of lethal mutagenesis, and the C-terminal domain functions as an S-adenosyl methionine (SAM)-dependent (guanine-N7) methyl transferase (N7-MTase) for mRNA capping . NSP14 forms the nsp14-nsp10 complex involved in RNA viral proofreading .

This is the NSP14 N7-MTase domain, which comprises a total of twelve β-strands and five α-helices and exhibits a noncanonical MTase fold with a rare β-sheet insertion and a peripheral zinc finger. The fold presents a central five-stranded β-sheet made up of four parallel strands and one antiparallel strand. The central β-sheet is sandwiched between a single α-helix and three long loops punctuated by two small helices. A zinc finger (ZF) motif is located between strand β11 and helix α4 and is important for the proper folding of this region. The cap-precursor guanosine-P3-adenosine-5',5'-triphosphate (GpppA) and SAM bind in proximity in a highly constricted pocket between two β-sheets to accomplish methyl transfer. In comparison with the conventional SAM-binding motif [DEY]-x-G-x-G-x-G, the corresponding conserved motif in CoV N7-MTase is D-x-G-x-P-x-[GA] [

, [:29279395],

,

,

,

].
Nidovirus 3'-5' exoribonuclease domain (NIV_EXON)
Type: Domain

The largest RNA virus genomes currently known are found in the order Nidovirales, an order of positive-stranded RNA (RNA) viruses, which includes the family Coronaviridae. One of the postulated drivers of the expansion of nidovirus genomes is the presence of a proofreading 3'-5' exoribonuclease (ExoN) belonging to the DEDDh family, which also includes the proofreading domains of many DNA polymerases as well as other eukaryotic and prokaryotic exonucleases. ExoN may enhance the fidelity of RNA synthesis by correcting nucleotide incorporation errors made by the RNA-dependent RNA polymerase. Among nidoviruses, 3'-5' ExoN activity is found in all large genome nidoviruses (coronaviruses, CoVs), toroviruses. and roniviruses), as well as in mesoniviruses. Short genome nidoviruses (arteriviruses) lack such ExoN activity. Acquisition of such ExoN activity might have allowed nidoviruses to evolve larger genomes. In CoVs, ExoN resides in a bifunctional replicase subunit (NSP14) whose C-terminal has (N7-guanine)-methyltransferase (N7-MTase) activity. NSP14 is a modular protein composed of the two functional domains, bordered on their N terminus by two other structural domains. These four regions are organized as follows: (i) a flexible N terminus forming the major bifunctional part of contacts with the Nsp10 ExoN/MTase coactivator domain, followed by (ii) the ExoN domain, (iii) a flexible hinge region formed by a loop and three strands, and (iv) the C terminus N-MTase domain. The bifunctional ExoN/N7-MTase organisation is conserved in most nidovirus families but the N7-MTase domain is lacking in, e.g., toroviruses, bafiniviruses and several recently discovered nidoviruses .

The ExoN domain is an α/β fold constituted of six α-helices and nine strands, organized into three distinct β-sheets. The core of the domain is formed by a central β-sheet made up of five antiparallel strands and surrounded by five helices. In the presence of Nsp10, residues of the ExoN active site are correctly positioned and form a highly active ExoN. It contains a first zinc finger motif (ZF1) that contributes to the structural stability, while a second zinc finger motif (ZF2) is important for catalysis. Although the overall structure of the nidovirus ExoN domain has diverged significantly from other proteins, the architecture of the catalytic core and active sites resembles those used by DEDD-type exonuclease, suggesting a conserved mechanism for catalysis. Five conserved active-site residues arranged in three canonical motifs (I, II, and III) orchestrate ExoN activity. A His categorizes the nidovirus ExoN domain as a DEDDh-type exoribonuclease .
Serine/threonine-protein kinase, first cryptic polo-box domain superfamily (Ser_Thr-PK_POLO_box_1_sf)
Type: Homologous_superfamily

The polo-like Ser/Thr kinases (Plk1, Plk2/Snk, Plk3/Prk/Fnk, Plk4/Sak, and the inactive kinase Plk5) play various roles in cytokinesis and mitosis. At their C terminus, they contain a tandemly repeated polo-box domain (PBD) (in the case of Plk4, a tandem repeat of cryptic PBDs is found in the middle of the protein followed by a C-terminal single repeat), which appears to be involved in autoinhibition and in mediating the subcellular localization. The latter may be controlled via interactions between the polo-box domain and phospho-peptide motifs. The phosphopeptide binding site is formed at the interface between the two tandemly repeated PBDs. The PBDs of Plk4/Sak appear unique in participating in homodimer interactions, though it is not clear whether and how they interact with phosphopeptides .

In metazoans, Plk4 kinases control daughter centriole assembly. Plk4 homologues have an N-terminal kinase domain, a C-terminal polo box, and a central domain termed the 'cryptic polo box' (CPB) that has been shown to dimerize, to be sufficient for centriole localization and to be required for Plk4 to promote centriole assembly. Probable serine/threonine-protein kinase zyg-1 (

) (ZYG-1) is a Plk4 homologue found in C. elegans. Crystal structure for the CPB of C. elegans ZYG-1, reveals that it forms a Z-shaped dimer containing an intermolecular β-sheet with an extended basic surface patch. Electrostatic interactions between the basic patch on the ZYG-1 CPB dimer and the SPD-2 acidic region dock ZYG-1 onto centrioles to promote new centriole assembly. ZYG-1 CPB contains two tandem polo boxes (PB1 and PB2), each containing a six-stranded β-sheet with an α-helix packed against one side .

This entry represents the first (cryptic) polo-box domain of Plk4 and homologues.
Nidovirus 2-O-methyltransferase (NIV_2_O_MTASE)
Type: Domain

Positive-stranded RNA (RNA) viruses that belong to the order Nidovirales infect a wide range of vertebrates (families Arteriviridae and Coronaviridae) or invertebrates (Mesoniviridae and Roniviridae). Examples of nidoviruses with high economic and societal impact are the arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) and the zoonotic coronaviruses (CoVs) causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Covid-19 (SARS-CoV-2) in humans.

The 3'-terminal region of the most conserved ORF1b in three of the four families of the order Nidovirales (except for the family Arteriviridae) encodes a 2'-O-methyltransferase (2'-O-MTase), known as non structural protein (NSP) 16 in CoV and implicated in methylation of the 5' cap structure of nidoviral mRNAs. Assembly of a cap1 structure at the 5' end of viral mRNA assists in translation and evading host defense. The cap structure consists of a 7-methylguanosine (m7G) linked to the first nucleotide of the RNA transcript through a 5'-5' triphosphate bridge. The CoV NSP16 methyltransferase forms an obligatory complex with NSP10 to efficiently convert client mRNA species from the cap-0 ((me7)G(0)pppA(1)) to the cap-1 form ((me7)G(0)pppA(1m)) by methylating the ribose 2'-O of the first nucleotide of the nascent mRNA using S-adenosyl methionine (SAM) as the methyl donor .

The nidovirus 2'-O-MTase domain exhibits the characteristic fold of the class I MTase family, comprising a β-sheet flanked by α-helices and loops. The nidovirus 2'-O-MTase domain harbors a catalytic K-D-K-E tetrad that is conserved among 2'-O-MTases .
Zinc finger, RZ-type (ZF_RZ_dom)
Type: Domain

This entry represents the RZ type zinc finger domain, found in NFX1-type zinc finger-containing protein 1 (ZNFX1) and E3 ubiquitin-protein ligase RNF213 from humans and other eukaryotic proteins. It contains two conserved histidine residues and four conserved cysteine residues in a CHC3H motif. It can bind divalent transition metals, with a preference for Zn2+.

ZNFX1 is an RNA-binding protein that initiates the antiviral response and is required to restrict the replication of RNA viruses .

RNF213 is a giant E3 ubiquitin ligase that can catalyse ubiquitination of both proteins and lipids, which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity. This protein functions as a key immune sensor by catalysing ubiquitination of the lipid A moiety of bacterial lipopolysaccharide (LPS) via its RZ-type zinc-finger: restricts the proliferation of cytosolic bacteria, such as Salmonella, by generating the bacterial ubiquitin coat through the ubiquitination of LPS. It is a major susceptibility factor of Moyamoya disease, a cerebrovascular disorder that can result in stroke or death .
Arterivirus Nsp11 N-terminal/Coronavirus NSP15 middle domain (AV_NSP11N_COV_NSP15M)
Type: Domain

Positive-stranded RNA (+RNA) viruses that belong to the order Nidovirales infect a wide range of vertebrates (families Arteriviridae and Coronaviridae) or invertebrates (Mesoniviridae and Roniviridae). Examples of nidoviruses with high economic and societal impact are the arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) and the zoonotic coronaviruses (CoVs) causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Covid-19 (SARS-CoV-2) in humans. The replicase gene encodes two polyproteins, pp1a and pp1ab, which are proteolytically processed to nonstructural proteins (NSPs). Among the NSPs found in Nidovirales, nonstructural protein 15 (NSP15) from coronaviruses (CoV) and NSP11 from arteriviruses (AV) participate in the viral replication process and in the evasion of the host immune system. They contain in their C-terminal region a conserved endoribonuclease domain called nidoviral uridylate-specific endoribonuclease (NendoU) with cleavage specificity for single- and double-stranded RNA 5' of uridine nucleotides to produce a 2'-3'-cyclic phosphate end product. Arterivirus Nsp11 contains two conserved compact domains: the N-terminal domain (NTD) and C-terminal domain (NendoU), whereas CoV NSP15 folds into three domains: N-terminal, middle domain, and C-terminal catalytic NendoU domain. No counterpart corresponding to the NTD of CoV NSP15 exists in AV NSP11. The NTD of AV NSP11 is small and related to NSP15 middle domain, which may serve as an interaction hub with other proteins and RNA .

This domain contains a central β-sheet flanked by two small α-helices on either side .
RNA-dependent RNA polymerase, coronavirus (RdRp_CoV)
Type: Domain

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. CoVs 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.

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 them, the NSP12 RNA-dependent RNA polymerase, that includes an RdRp catalytic domain conserved in all RNA viruses, possesses some minimal activity on its own, but the addition of the NSP7 and NSP8 cofactors greatly stimulates polymerase activity. The NSP12-NSP7-NSP8 subcomplex is thus defined as the minimal core
component for mediating coronavirus RNA synthesis .

The NSP12 subunit contains an N-terminal NiRAN domain, an interface domain and a C-terminal polymerase domain, represented in this entry, which resembles a right hand, comprising the fingers, palm and thumb subdomains. The active site is located on the palm subdomain and is formed by five conserved NSP12 elements known as motifs A-E .
NSP1, C-terminal domain, betacoronavirus (bCoV_NSP1_C)
Type: Domain

Nonstructural protein 1 (NSP1) is a critical virulence factor of coronaviruses (CoV) and plays key roles in suppressing host gene expression, which facilitates viral replication and immune evasion. NSP1 is a characteristic feature of alpha and betacoronavirus, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses . NSP1 binds to the 40S ribosomal subunit and inhibits host translation, and it also induces a template-dependent endonucleolytic cleavage of host mRNAs , while viral mRNAs are less susceptible to NSP1-mediated inhibition of translation, because of their 5'-end leader sequence . NSP1 also suppresses the host innate immune functions by inhibiting type I interferon expression and host antiviral signalling pathways. The C-terminal domain binds to the mRNA entry tunnel interfering with mRNA binding (

) . NSP1 consists of a globular domain arranged in a mixed parallel/antiparallel 6-stranded β-barrel with an α-helix covering one end of the barrel and another helix alongside the barrel . In addition to the globular domain, bCoV NSP1s have a C-terminal domain .

This entry represents the C-terminal domain of bCoV NSP1, which binds to the mRNA channel of the 40S ribosome, where it interferes with mRNA binding and inhibits host protein translation. . This domain comprises two α-helices and two short loops .