SII-SWORD/CoKE huggingface dataset:
Non-structural protein NSP3, SUD-N (Mac2) domain, betacoronavirus (NSP3_SUD-N_bCoV)
Type: Domain

This entry represents the N-terminal region of the SUD domain (SUD-N or Mac2) found in non-structural protein NSP3, the product of ORF1a in group 2 (beta) coronaviruses. It is found in human SARS-CoV and SARS-CoV-2 polyprotein 1a and 1ab, and in related coronavirus polyproteins .

SUD consists of three globular domains separated by short linker peptide segments: SUD-N, SUD-M, and SUD-C . Among these, SUD-N and SUD-M are macrodomains. The SUD-N domain is a related macrodomain which also binds G-quadruplexes . While SUD-N is specific to the NSP3 of SARS and betacoronaviruses of the sarbecovirus subgenera (B lineage), SUD-M is present in most NSP3 proteins except the NSP3 from betacoronaviruses of the embecovirus subgenera (A lineage). SUD-M, despite its name, is not specific to SARS. SUD-C adopts a frataxin-like fold, has structural similarity to DNA-binding domains of DNA-modifying enzymes, binds single-stranded RNA, and regulates the RNA binding behavior of the SUD-M macrodomain. SARS-CoV Nsp3 contains a third macrodomain (the X-domain). The X-domain may function as a module binding poly(ADP-ribose); however, SUD-N and SUD-M do not bind ADP-ribose, as the triple glycine sequence involved in its binding is not conserved in these .

Nsp3c-N and Nsp3c-M each display a typical α/β/α Macro domain fold, in spite of the complete absence of sequence similarities. The central β-sheet with six β-strands in the order β1-β6-β5-β2-β4-β3 is flanked by two (or three) helices on either side. Only the last strand, β3, is antiparallel to the other strands. Currently, most known functions of Nsp3c-N/M are connected with RNA binding. All the residues important for binding ADP-ribose and for de-MARylation/de-PARylation activity are not conserved in Nsp3c-N/M; therefore Nsp3c-N/M cannot bind ADP-ribose. Both Nsp3c-N and Nsp3c-M domains bind unusual nucleic acid structures formed by consecutives guanosine nucleotides, where four strands of nucleic acid are forming a superhelix (so-called G-quadruplexes) .
MRH domain (MRH_dom)
Type: Domain

The mannose 6-phosphate (Man-6-P) receptor homology (MRH) domain is present in recycling receptors (mannose 6-phosphate receptors, MRPs), resident endoplasmic reticulum (ER) proteins (glucosidase 2 beta subunit, Endoplasmic reticulum lectin 1 XTP3-B, OS-9), and in Golgi glycosyltransferase (GlcNAc-phosphotransferase gamma-subunit), which are characterised by the presence of one or more MRH domains. Many MRH domains act as lectins and bind specific phosphorylated (MPRs) or non phosphorylated (glycosidase 2 beta subunit, XTP3-B and OS-9) high mannose-type N-glycans. The MPRs are the only proteins known to bind Man-6-P residues via their MRH domains. The MRH domain can function in protein-carbohydrate and protein-protein interactions .

This domain has a β-barrel structure formed by nine β-strands organised into two orthogonally oriented antiparallel β-sheet .
HNF-1, dimerization domain (HNF_P1)
Type: Domain

The homeodomain proteins hepatocyte nuclear factor (HNF)-1alpha and HNF-1beta comprise a functionally important family in which dimerization is essential for DNA binding. HNF-1alpha and HNF-1beta regulate tissue-specific genes in liver, kidney, intestine, and pancreas. These proteins form homo- and heterodimers through an autonomously folded domain encompassing the 32 N-terminal amino acids (HNF-p1). The dimerization domain also binds the transcriptional coactivator DCoH, which stimulates HNF-1alpha activity . The HNF-p1 dimer folds into an X-type, antiparallel, four-helix bundle (4HB). Each monomer consists of two helices: a longer N-terminal helix and a shorter C-terminal helix, connected by a tight turn unrelated to classical β- or γ-turn families. The dimer contains a rigid element, the N-terminal anti-parallel mini-zipper comprising α-helices 1 and 1', and a plastic element, the C-terminal coiled-coil comprising α-helices 2 and 2' .
DEUBAD domain (DEUBAD_dom)
Type: Domain

Protein ubiquitination is a fundamental mechanism that affects nearly all aspects of cellular life. Deubiquitinating enzymes (DUBs) play important roles in ubiquitin (Ub) signalling by Ub cleavage from adducts. The Ub C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) contains four members including UCH37 (also called ubiquitin carboxy-terminal hydrolase isozyme L5, UCHL-5) and BAP1 which share high similarity in the catalytic domain (UCH) and the C-terminal region, termed the UCH37-like domain (ULD) which is responsible for binding interaction partners and is also involved in the regulation of DUB activity. ULD from BAP1 and UCH-L5 binds the DEUBiquitinase ADaptor (DEUBAD) domain present in their interacting partners, e.g., ASXL1 for BAP1, and RPN13 (ADRM1) and INO80G (NFRKB) for UCH-L5 .

This entry represents the DEUBAD domain which consists of eight α-helices that form a helical bundle surrounding a compact hydrophobic core . It has a modular architecture with the core formed by helices 1-4, primarily responsible for binding to ULD, and accessory elements that lead to full activation, or inhibition, of the UCH activity .
Rpn13/ADRM1, Pru domain (Rpn13/ADRM1_Pru)
Type: Domain

This entry represents the Pru (pleckstrin-like receptor for the Ub) domain.

This entry includes Rpn13 from budding yeasts and its homologue, ADRM1 from animals.

Rpn13 is a subunit and an ubiquitin receptor of the 19S regulatory particle of the 26S proteasome lid. The 26S proteasome is a huge macromolecular protein-degradation machine consisting of a proteolytically active 20S core, in the form of four disc-like proteins, and one or two 19S regulatory particles. The regulatory particle(s) sit on the top and or bottom of the core, de-ubiquitinate the substrate peptides, unfold them and guide them into the narrow channel through the centre of the core. Rpn13 and its homologues dock onto the regulatory particle through the N-terminal region which binds Rpn2. The C-terminal part of the domain binds de-ubiquitinating enzyme Uch37/UCHL5 and enhances its isopeptidase activity. Rpn13 binds ubiquitin via a conserved amino-terminal region called the pleckstrin-like receptor for ubiquitin, termed Pru, domain . The domain forms two contiguous anti-parallel β-sheets with a configuration similar to the pleckstrin-homology domain (PHD) fold . Rpn13's ability to bind ubiquitin and the proteasome subunit Rpn2/S1 simultaneously supports evidence of its role as a ubiquitin receptor. Finally, when complexed to di-ubiquitin, via the Pru, and Uch37 via the C-terminal part, it frees up the distal ubiquitin for de-ubiquitination by the Uch37 .
HNF-1, POU-specific (POUs) atypical domain (HNF-1_POU)
Type: Domain

This entry represents the atypical POU-specific domain found in hepatocyte nuclear factor (HNF)-1alpha and HNF-1beta.

The POU (pronounced 'pow') domain [1 to 7] is a highly charged 155-162-amino acid region of sequence similarity which has been identified in the three mammalian transcription factors Pit-1, Oct-1, and Oct-2 and in the product of the nematode gene unc-86. The POU domain is a bipartite DNA binding protein module that binds selectively to the DNA octamer motif ATGCAAAT and a subset of derivatives. It consists of two subdomains, a C-terminal homeodomain (POUh) and an N-terminal 75- to 82-residue POU-specific (POUs) region separated by a short non-conserved linker. The POU-specific region or 'box' can be subdivided further into two highly conserved regions, A and B, separated by a less highly conserved segment. The POUs domain is always found in association with a POUh domain, and both are required for high affinity and sequence-specific DNA binding. The POUs domain consists of four α helices packed to enclose an extensive hydrophobic core. The POUs domain contains an unusual HTH structure, which differs from the canonical HTH motif in the length of the first α helix and the turn. The region of hypervariability located between subdomains A and B lies within the sequence corresponding to the C-terminal end of helix 2 and the linker between helices 2 and 3. In the model of the POUs-DNA complex, the C terminus of helix 2 and the turn of the HTH motif project away from the DNA such that sequence variability in this region can be accommodated without adversely affecting DNA binding .

HNF1alpha (MODY3 gene product, the most commonly mutated MODY protein) and HNF1beta (hepatocyte nuclear factor 1beta; also known as vHNF1 or TCF2) (MODY5 gene product) are atypical members of the POU transcription factors. Their atypical POUs domains have at least one additional α-helix at the N terminus, and the second helix and adjacent loop of their POUh domains are much longer, creating a more extensive interface between the POUs and POUh domains. This extended interface fixes the relative orientations of the two domains and provides rigidity for DNA recognition as opposed to the flexibility seen in another POU transcription factor, Pit-1 .
Bacterial microcompartment (BMC) circularly permuted domain (BMC_CP)
Type: Domain

Bacterial microcompartments (BMCs) are large proteinaceous structures comprised of a roughly icosahedral shell and a series of encapsulated enzymes. They are found across bacteria where they play functionally diverse roles including CO(2) fixation and the catabolism of a range of organic compounds. They function as organelles by sequestering particular metabolic processes within the cell. A shell or capsid, which is composed of a few thousand protein subunits, surrounds a series of sequentially acting enzymes and controls the diffusion of substrates and products (including toxic or volatile intermediates) into and out of the lumen. Although functionally distinct BMCs vary in their encapsulated enzymes, all are defined by homologous shell proteins. The shells of BMCs are made primarily of a family of proteins whose structural core is the BMC domain, and variations upon this core provide functional diversity .

There are three classes of constituent proteins that form a shell with icosahedral symmetry: hexamer-forming proteins containing a single BMC domain (BMC-H); trimer/pseudohexamer-forming proteins consisting of a fusion of two BMC domains (BMC-T), and pentamer-forming proteins containing a bacterial microcompartment vertex (or BMV) domain (BMC-P). The BMC-H and BMC-T proteins form the facets, and the BMC-P proteins form the vertices of the icosahedron. These three protein types form cyclic homooligomers with pores at the centre of symmetry that enable metabolite transport across the shell .

The BMC domain fold consists of three α-helices (designated A, B, and C) and four β-strands (designated β1, β2, β3, and β4). Some instances of the BMC shell protein reveal a circular permutation in which a highly similar tertiary structure is built from secondary structure elements occurring in a different order. The secondary structure elements contributed by the C-terminal region of the typical BMC fold are instead contributed by the N-terminal region of the BMC circularly permuted domain .

This entry represent the circularly permuted BMC domain found in ethanolamine utilization protein EutS/ EutL and related proteins.
Structural accessory protein ORF7a, SARS-CoV-like, X4e domain (ORF7a_SARS-CoV-like_X4e)
Type: Domain

This entry includes the structural accessory protein ORF7a, also called NS7a, X4 and U122, of Severe Acute Respiratory Syndrome Coronaviruses (SARS-CoV) from betacoronavirus subgenera Sarbecovirus (lineage B), including SARS-CoV-2. ORF7a/NS7a from betacoronavirus in the subgenera Sarbecovirus (B lineage) are not related to NS7a proteins from other coronavirus lineages. The structure of the structural accessory protein ORF7a, shows similarities to the immunoglobulin-like fold with some features resembling those of the Dl domain of ICAM-1 and suggests a binding activity to integrin I domains . In SARS-CoV-infected cells, ORF7a is expressed and retained intracellularly within the Golgi network . ORF7a is thought to play an important role during the SARS-CoV replication cycle . Expression studies of ORF7a have shown that biological functions include induction of apoptosis through a caspase-dependent pathway, activation of the p38 mitogen-activated protein kinase signaling pathway, inhibition of host protein translation, and suppression of cell growth progression. These results collectively suggested that ORF7a protein may be involved in virus-host interactions . Studies in SARS-CoV-2 revealed that ORF7a plays a role as antagonist of host tetherin (BST2), disrupting its antiviral effect. ORF7a binds to BST2 and sequesters it to the perinuclear region, thereby preventing its antiviral function at cell membrane .

This entry represents the X4 ectodomain from ORF7a (X4e), which forms a well defined β-sandwich fold. It is built up from seven β-strands, four strands form one β-sheet and the other three strands form a second sheet. The sheets are closely packed or 'sandwiched' against each other. Each sheet is amphipathic with the hydrophobic side facing inward. Two disulfide bonds link both sheets on opposite edges therefore stabilizing the β-sandwich structure .
CcmK/CsoS1, bacterial microcompartment domain (CcmK/CsoS1_BMC)
Type: Domain

Bacterial microcompartments (BMCs) are large proteinaceous structures comprised of a roughly icosahedral shell and a series of encapsulated enzymes. They are found across bacteria where they play functionally diverse roles including CO(2) fixation and the catabolism of a range of organic compounds. They function as organelles by sequestering particular metabolic processes within the cell. A shell or capsid, which is composed of a few thousand protein subunits, surrounds a series of sequentially acting enzymes and controls the diffusion of substrates and products (including toxic or volatile intermediates) into and out of the lumen. Although functionally distinct BMCs vary in their encapsulated enzymes, all are defined by homologous shell proteins. The shells of BMCs are made primarily of a family of proteins whose structural core is the BMC domain, and variations upon this core provide functional diversity .

There are three classes of constituent proteins that form a shell with icosahedral symmetry: hexamer-forming proteins containing a single BMC domain (BMC-H); trimer/pseudohexamer-forming proteins consisting of a fusion of two BMC domains (BMC-T), and pentamer-forming proteins containing a bacterial microcompartment vertex (or BMV) domain (BMC-P). The BMC-H and BMC-T proteins form the facets, and the BMC-P proteins form the vertices of the icosahedron. These three protein types form cyclic homooligomers with pores at the centre of symmetry that enable metabolite transport across the shell .

The BMC domain fold consists of three α-helices (designated A, B, and C) and four β-strands (designated β1, β2, β3, and β4). Some instances of the BMC shell protein reveal a circular permutation in which a highly similar tertiary structure is built from secondary structure elements occurring in a different order. The secondary structure elements contributed by the C-terminal region of the typical BMC fold are instead contributed by the N-terminal region of the BMC circularly permuted domain .

This entry represents the BMC domain found in CsoS1/CcmK and related proteins. CsoS1 and CcmK are the shell proteins of the carboxysome, a polyhedral inclusion where RuBisCO (ribulose bisphosphate carboxylase, ccbL-ccbS) is sequestered .
ToxT, HTH1 motif superfamily (ToxT_HTH1)
Type: Homologous_superfamily

ToxT, a member of the AraC-family of transcriptional regulators, is the master virulence regulator that controls the expression of two virulence factors in Vibrio cholerae - toxin-coregulated pilus (TCP) and cholera toxin (CT), that lead to intestinal infection. This superfamily represents the HTH1 motif, which is located in close proximity to the C terminus and plays a role in the stability and folding of the protein .
HRDC domain superfamily (HRDC_dom_sf)
Type: Homologous_superfamily

The HRDC (helicase and RNaseD C-terminal) domain is comprised of two orthogonally packed α-hairpin subdomains, and is involved in interactions with DNA and protein. It has been suggested that this domain plays a role dissolving double Holliday junctions efficiently .

HRDC domains are found at the C terminus of many RecQ helicases, including the human Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN and RecQ-like DNA helicase BLM . RecQ helicases have been shown to unwind DNA in an ATP-dependent manner. The structure of the HRDC domain consists of a 4-5 helical bundle of two orthogonally packed α-hairpins, and as such it resembles auxiliary domains in bacterial DNA helicases and other proteins that interact with nucleic acids. A positively charged region on the surface of the HRDC domain is able to interact with DNA.

The HRDC domain is also present in eukaryotic and archaeal RNA polymerase II subunit RBP4, the N-terminal of which forms a heterodimerisation α-hairpin .

The HRDC domain has a putative role in nucleic acid binding. Mutations in the HRDC domain associated with the human BLM gene result in Bloom Syndrome (BS), an autosomal recessive disorder characterised by proportionate pre- and postnatal growth deficiency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin; predisposition to malignancy; and chromosomal instability .
Sulfolobus spindle-shape virus 1 F-112 protein-like superfamily (F-112-like_sf)
Type: Homologous_superfamily

This entry is represented by Sulfolobus spindle-shape virus 1 (SSV1), F112 protein . This protein adopts a winged helix DNA binding fold containing an intrachain disulfide bond . The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.
UbiA prenyltransferase superfamily (UbiA_sf)
Type: Homologous_superfamily

The UbiA superfamily of prenyltransferases includes bacterial 4-hydroxybenzoate octaprenyltransferase (gene ubiA); yeast mitochondrial para-hydroxybenzoate--polyprenyltransferase (gene COQ2); protoheme IX farnesyltransferase (heme O synthase) from yeast and mammals (gene COX10), and from bacteria (genes cyoE or ctaB) ; and 2-acylphloroglucinol 4-prenyltransferase and 2-acyl-4-prenylphloroglucinol 6-prenyltransferase from plant chloroplasts which catalyse prenylation steps in the beta-bitter acid pathway . These are integral membrane proteins, which probably contain seven transmembrane segments. Archaeal family members include lycopene elongase/hydratase - this type of enzyme has been shown to be involved in bacterioruberin synthesis in Halobacterium salinarum and Haloferax volcanii .
NCX, central ion-binding domain superfamily (NCX_ion-bd_dom_sf)
Type: Homologous_superfamily

Na/Ca2 exchangers (NCX) are membrane transporters that play an essential role in maintaining the homeostasis of cytosolic Ca2 for cell signalling. Ca2 is moved into or out of the cytosol depending on Na concentration. NCX has a symmetrical structure containing ten transmembrane helices, divided in two halves with a similar structure but opposite orientation. Based on its symmetry, NCX is able to catalyse bidirectional ion-exchange reactions. Four ion-binding sites cluster at the centre of the protein: one specific for Ca2 and three that likely bind Na. Two passageways allow for Na and Ca2 access to the central ion-binding sites from the extracellular side .

This superfamily entry represents the large central ion-binding region made up of 8 transmembrane helices, also known as the intracellular regulatory domain.
RecQ-mediated genome instability protein 1, N-terminal helical domain superfamily (RMI1_N_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal helical domain of RMI 1 (RecQ-mediated genome instability protein) proteins from metazoa . This domain is found at the N-terminal of an oligo-nucleotide-binding domain or OB-fold, and forms a stable complex with Bloom syndrome protein BLM and DNA topoisomerase 3-alpha .
Interferon regulatory factor 2-binding protein 1/2, C3HC4-type RING finger superfamily (I2BP1/2_C3HC4-RING_sf)
Type: Homologous_superfamily

Interferon regulatory factor 2-binding protein 1 and 2 (IRF-2BP1/2) and their homologue IRF-2BP-like (also known as IRF-2BPL or C14orf4) (

) are nuclear transcriptional repressor proteins that bind to the C-terminal repression domain of IRF-2 and can inhibit both enhancer-activated and basal transcription. They contain N-terminal zinc finger and C-terminal RING finger domains . Mutations in IRF2BP2 are responsible for a Familial Form of Common Variable Immunodeficiency Disorder (CVID), one of the most frequently diagnosed forms of primary immunodeficiency characterised by low quantity of IgG and IgA and poor specific antibody production . IRF2BPL may play a role in the development of the central nervous system and in neuronal maintenance .

This superfamily represents the C-terminal C3HC4-type RING finger of IRF2BP1/2 and IRF2BPL .
Hemolysin, pre-stem domain (Hemolysin_pre-stem_dom_sf)
Type: Homologous_superfamily

This superfamily represents the pre-stem domain found in bacterial virulence factor - hemolysin - which forms pores in erythrocytes and causes them to lyse. The structure of the pre-stem domain of Vibrio cholerae Cytolysin (VCC,

) consists of extended two-strand β-sheet that makes contacts with a unique loop (VCC bracket) from the β-sandwich .
Large ribosomal subunit protein mL55 superfamily (Ribosomal_mL55_sf)
Type: Homologous_superfamily

Members of this superfamily are involved in mitochondrial biogenesis and G2/M phase cell cycle progression. They form a component of the mitochondrial ribosome large subunit (39S) which comprises a 16S rRNA and about 50 distinct proteins .
Plasmodium RESA, N-terminal helical domain superfamily (PRESA_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of RESA (ring-infected erythrocyte surface antigen) from Plasmodium falciparum, the apicomplexan parasite that causes the most severe form of malaria in humans.

The short, four-helical domain first identified in the Plasmodium export proteins PHISTa and PHISTc has been identified in the P. falciparum-specific RESA-type (Ring-infected erythrocyte surface antigen) proteins in association with the DnaJ domain. Overall, at least 67 proteins have been detected in P. falciparum with complete copies of the PRESAN domain. No versions of this domain were detected in other apicomplexan genera, suggesting that the domain was 'invented' after the divergence of the lineage leading to the genus Plasmodium undergoing a dramatic proliferation only in P. falciparum. The structure of this domain has been solved. It contains a short initial helix (α1) followed by an antiparallel bundle of 3 long helices (α2-α4) .
Folliculin, DENN domain, C-terminal superfamily (FLCN_DENN_C_sf)
Type: Homologous_superfamily

Folliculin (FLCN) is a tumor suppressor that enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) Activating Protein (GAP) activity. It belong to the DENN module family of proteins and contains a divergent DENN module comprised of a N-terminal longin domain (also known as upstream DENN domain, u-DENN), followed by a DENN domain. It forms a complex with its partners, FNIP1 or FNIP2 (Folliculin interacting protein 1 or 2), which directly contacts the Rag GTPases RagC/D to stimulate GTP hydrolysis and thus promote the conversion to the GDP-bound state. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. They contain longin domains that heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, and C-terminal DENN domains which interact at the distal end of the structure .

This is a subdomain found at the C terminus in the DENN domain of folliculin.
Putative substrate of the Dot/Icm secretion system superfamily (SoDot-IcmSS_sf)
Type: Homologous_superfamily

This superfamily includes the putative substrates of the Dot/Icm type IVA secretion system from Legionella species.