SII-SWORD/CoKE huggingface dataset:
Cullin-9, BRcat domain (BRcat_RBR_CUL9)
Type: Domain

This entry represents the BRcat (benign-catalytic) domain of Cullin-9 and similar proteins from vertebrates. It adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity. This domain coordinates two zinc atoms that are essential for its folding.

Cullin-9 (CUL-9), also called UbcH7-associated protein 1 (H7-AP1), p53-associated parkin-like cytoplasmic protein, or PARC, is a cytoplasmic RBR-type E3 ubiquitin-protein ligase that function as a tumour suppressor and promotes p53-dependent apoptosis. It mediates the ubiquitination and degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. It is also a critical downstream effector of the 3M complex in the maintenance of microtubules and genome integrity. Moreover, CUL-9, together with CUL-7, forms homodimers and heterodimers, as well as some atypical Cullin RING ligase complexes, which may exhibit ubiquitin ligase activity. CUL-9 contains a CPH domain (conserved in Cul7, PARC, and HERC2 proteins), a DOC (DOC1/APC10) domain, cullin homology domains linked with E3 ligase function, and a C-terminal RBR domain previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction .
Cullin-9, RING finger, HC subclass (RING-HC_RBR_CUL9)
Type: Domain

This entry represents the RING domain of Cullin-9 and similar proteins from vertebrates. It is a C3HC4-type RING-HC finger required for RBR-mediated ubiquitination.

Cullin-9 (CUL-9), also called UbcH7-associated protein 1 (H7-AP1), p53-associated parkin-like cytoplasmic protein, or PARC, is a cytoplasmic RBR-type E3 ubiquitin-protein ligase that function as a tumour suppressor and promotes p53-dependent apoptosis. It mediates the ubiquitination and degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. It is also a critical downstream effector of the 3M complex in the maintenance of microtubules and genome integrity. Moreover, CUL-9, together with CUL-7, forms homodimers and heterodimers, as well as some atypical Cullin RING ligase complexes, which may exhibit ubiquitin ligase activity. CUL-9 contains a CPH domain (conserved in Cul7, PARC, and HERC2 proteins), a DOC (DOC1/APC10) domain, cullin homology domains linked with E3 ligase function, and a C-terminal RBR domain previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction .
Ankyrin repeat and IBR domain-containing protein 1, RING finger, HC subclass (RING-HC_RBR_ANKIB1)
Type: Domain

This entry represents the RING domain of ANKIB1 and similar proteins predominantly found in vertebrates. It isa C3HC4-type RING-HC finger required for RBR-mediated ubiquitination.

Ankyrin repeat and IBR domain-containing protein 1 (ANKIB1) is an RBR-type E3 ubiquitin-protein ligase that may function as part of an E3 complex, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfers it to substrates. It contains an N-terminal ankyrin repeat domain and an RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD (two RING fingers and a DRIL (double RING finger linked)) domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction .
Ankyrin repeat and IBR domain-containing protein 1, Rcat domain (Rcat_RBR_ANKIB1)
Type: Domain

This entry represents the Rcat domain of ANKIB1 and similar proteins predominantly found in vertebrates. It is essential for RBR E3 ligase activity and adopts the same fold as the BRcat domain.

Ankyrin repeat and IBR domain-containing protein 1 (ANKIB1) is an RBR-type E3 ubiquitin-protein ligase that may function as part of an E3 complex, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes and then transfers it to substrates. It contains an N-terminal ankyrin repeat domain and an RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD (two RING fingers and a DRIL (double RING finger linked)) domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction .
Alpha-macroglobulin-like, thiol-ester bond-forming region (Alpha-macroglob_thiol-ester_cl)
Type: Conserved_site

This short highly conserved region, containing the GCGEQ motif, is found in protease inhibitors and complement factors, members of A2MF family. These proteins utilise a unique trapping mechanism that pseudo-inhibits proteases regardless of their catalytic class . With a few exceptions (e.g., complement C5), A2MF proteins contain an internal thioester formed between the cysteine and a glutamine side chain in the conserved GCGEQ motif. After bait region cleavage, this thioester is exposed and can react with nucleophilic amine and hydroxyl groups on proteins and carbohydrates. As a result, the nascent activated A2MF protein may become covalently linked to the bait region-cleaving protease. The trapped protease remains catalytically active but is prevented from cleaving protein substrates through steric hindrance imposed by the inhibitor following a proteolytically triggered conformational change.
Coronavirus replicase NSP3, Y domain (CoV_NSP3_Y)
Type: Domain

This entry represents the Y domain of NSP3 from coronaviruses, which possesses a well-ordered globular α/β fold consisting of two ββααβ structural repeats

.

Non-structural protein NSP3 is a multi-domain protein, the largest product of coronavirus ORF1a which encodes the poyprotein 1a/1ab (pp1a/1ab). NSP3 is released from pp1a/1ab by the papain-like protease domain(s), which is (are) part of NSP3 itself. NSP3 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 the formation of the the replication/ transcription complex (RTC). The RTC associates with host ER membranes producing convoluted membranes and double-membrane vesicles. It is also involved in post-translational modifications of host proteins to antagonise its innate immune response .

NSP3 comprises up to 16 different domains and regions, their organisation differs between coronaviruses (CoV). However, eight domains and two transmembrane regions are conserved in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (hypervariable region), a macrodomain (X domain), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro, depending on the CoV there are one or two PLpro), the NSP3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1, Y2 and Y3 of unknown functions. The Y1 domain is conserved in all viruses of the order Nidovirales, while Y2 and Y3 are conserved in all coronaviruses. The three domains from the Y region (Y1 to Y3) are located at the cytosolic side of the ER. The level of their conservation is close to that for the enzymatic domains of Nsp3 and exceeds nonenzymatic ones. From the consistently high conservation of Y1, Y2, and Y3, it has been hypothesize that Y1 to Y3 may form a single functional unit with a conserved enzymatic function .
Non-structural protein NSP3, group 2-specific marker domain, betacoronavirus (NSP3_G2M_bCoV)
Type: Domain

This entry represents the group 2-specific marker (G2M) domain, also known as betacoronavirus-specific marker (bCoV-SM), that is found in the nonstructural protein NSP3 from betacoronavirus. This domain is absent in alpha- and deltacoronaviruses . NSP3 is the largest protein encoded by the coronavirus genome and plays various roles in the viral life cycle . It is an essential component of the replication/transcription complex. It consists of several distinct domains, the organisation of which differs between coronavirus genera, due to duplication or absence of some domains .

The G2M domain adopts a globular structure with segregated α-helices and β-strands

.
Anthrax toxin lethal factor-like domain (ATLF-like_dom)
Type: Domain

This entry represents a domain mainly found in proteins from firmicutes, including Lethal factor from Bacillus anthracis (LF), the endopeptidase component of the anthrax toxin, which is able to trigger rapid cell death in macrophages . This domain is composed of a four-stranded β-sheet and a helical bundle backing the β-sheet (

). All catalytically active ATLF-like domains contain conserved sequence motif HEXXH, where the two histidines ligate the catalytic zinc ion, and the glutamic acid acts as catalytic base activating a zinc-bound water molecule for nucleophilic attack on the scissile peptide bond .

It is also found in Edema factor from B. anthracis (EF), also called Calmodulin-sensitive adenylate cyclase ; in Toxin Certhrax from Bacillus cereus, a putative ADP-ribosyltransferase ; and in Pro-Pro endopeptidase from Clostridioides difficile (PPEP-1) .
Carbohydrate binding module family 56 (CBM56)
Type: Domain

Carbohydrate binding modules (CBMs) are independent domains existing in carbohydrate active enzymes. The majority of such domains exhibit carbohydrate binding activity. They target the enzyme to a particular carbohydrate, maintain its association with the substrate and by this proximity effect enhance the enzyme catalytic efficiency. The CBM family 56 (CBM56) domain is an ~95-amino acid module, which selectively binds insoluble beta-1,3-glucans, probably by binding domains in the polysaccharide with triple-helical quaternary structure .

The CBM56 domain folds into a β-sandwich with a Fibronectin type III topology and is structurally similar to CBM39 domain . This module is likely to use a binding interface and mechanisms of recognition of the quaternary structure of beta-1,3-glucans similar to CBM39.
NSP12, interface domain, coronavirus (NSP12_IF_CoV)
Type: Domain

RNA-directed RNA Polymerase corresponds to the nonstructural protein 12 (NSP12) produced by cleavage of ORF1b. NSP12 contains a polymerase domain that assumes a structure resembling a cupped 'right hand', similar to other polymerases, containing a fingers domain, a palm domain and a thumb domain. Coronavirus (CoV) NSP12 also contains a nidovirus-unique N-terminal extension (nidovirus RdRp-associated nucleotidyltransferase (NiRAN)) that possesses a kinase-like fold allowing the binding of NSP12 to NSP7 and NSP8 which is followed by an interface domain (IF). NSP12 possesses some minimal activity on its own, but the addition of the NSP7 and NSP8 co-factors greatly stimulates polymerase activity .

This entry represents the CoV NSP12 interface domain.
OCA domain (OCA)
Type: Domain

The OCA domain spans ~23 amino acids and is found near the N terminus of the POU2AF family of coactivators. It comprises the minimal non-globular region that has been shown to bind to the binary complex of class II POU domain-containing transcription factors (TFs) and a DNA octamer motif . The structure of the ternary complex of OCA domain bound to POU domain/octamer DNA has been determined, in which the OCA adopts mainly an extended conformation and a short α-helix near the C terminus. The disordered part of OCA interacts with the major DNA grove while residues from the ordered helical part make contacts with the POU domain .

The OCA domain is also found in another family of cofactors, the nuclear factor (NF)-kappaB inhibitor zeta (IkappaBzeta) proteins, NF-kappaB regulators which function not only as repressors but also as activators of a selective subset of NF-kappaB target genes .
Non-structural protein 2, middle domain, coronavirus (CoV_NSP2_M)
Type: Domain

Coronavirus non-structural protein 2 (NSP2) is encoded by ORF1a/1ab and proteolytically released from the pp1a/1ab polyprotein. This protein has been implicated in processes ranging from translation repression to endosomal transport, ribosome biogenesis, and actin filament binding. NSP2 in SARS-CoV-2 and other coronaviruses have been observed to localise to endosomes and replication-transcription complexes (RTC). It may be involved in binding nucleic acids and regulating intracellular signalling pathways. Viral-host protein interaction studies in SARS-CoV and SARS-CoV-2 found that this protein could interact with several host proteins, including prohibitin 1 (PHB1) and PHB2, which are implicated in a number of cellular functions, including cellular migration, differentiation and apoptosis . NSP2 structure from SARS-CoV-2 has been recently solved and revealed that it consists of an N-terminal, middle and C-terminal domains . NSP2 has been pointed as an interesting target to develop anti-SARS-CoV-2 therapies as it may play important roles during viral infection .

This entry represents the middle domain of NSP2 from alpha and betacoronaviruses.
AD domain (AD)
Type: Domain

This entry represents the AD domain found in a group of eukaryotic proteins that belong to the Lsm12 family, including human Gem-associated protein 6 (Gemin-6) and Protein LSM12. Gemin-6 is a component of the survival of motor neurons (SMN) protein complex, which plays a key role in the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs) . LSM12 binds nicotinic acid adenine dinucleotide phosphate (NAADP) that confers NAADP sensitivity to the two pore channel complex (TPCs) by acting as TPC accessory protein necessary for NAADP-evoked Ca2 release .

Members of this group consist of an N-terminal Sm domain (

) followed by an AD domain and are involved in RNA metabolism
. The AD domain is likely to possess an RNA-binding function given the similarity of its predicted structure to anticodon-binding domains.
Sm domain (Sm)
Type: Domain

This entry represents a domain found in Sm, Lsm (like-Sm) and Hfq proteins that belong to a large family of proteins from all cellular organisms and are involved in numerous processes associated with RNA processing and gene expression regulation. The Sm and Lsm proteins are found in archaea and eukaryotes, whereas Hfq proteins exist in bacteria and in the archaea Methanocaldococcus jannaschii. The eukaryotic Sm and Lsm proteins form heteroheptameric complexes and play essential roles in splicing and mRNA decapping. In contrast, prokaryotic Hfq proteins associate in homohexamers and are involved in post-transcriptional regulation of gene expression. Lsm archaeal proteins (SmAPs) form homoheptamers and interact with polynucleotide phosphorylase P and uridine-rich RNA sequences and are probably involved in the processing of tRNAs .

All these proteins contain the Sm domain that spans ~60-70 residues in length and folds into an open five-stranded β-barrel capped on one side with an α-helix . This domain contains two conserved sequence motifs, Sm1 and Sm2 . The Sm domain is responsible for both protein oligomerisation and specific RNA binding.
Colipase, chordates (CLPS_chr)
Type: Family

This entry represents colipase (CLPS), a protein that acts as a cofactor required for the activity of pancreatic lipase. CLPS is secreted by the pancreas in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Its function is to prevent the inhibitory effect of bile salts on the lipase-catalysed hydrolysis of long-chain triglycerides. Bile salts, at concentrations near their critical micellar concentration, desorb lipase from emulsified triacylglycerol and, thereby, inhibit lipolysis. Colipase functions by anchoring pancreatic lipase to the lipid-water interface through the formation of the stoichiometric colipase-lipase complex . Members of this protein family are specific to vertebrates.
OBERON1-like, PHD finger (OBE1-like_PHD)
Type: Domain

This entry represents the plant homeodomain (PHD) finger domain of Protein OBERON 1 (OBE1, or potyvirus VPg-interacting protein 2) from Arabidopsis thaliana and similar sequences from streptophytes. OBE1, which acts together with Protein OBERON 2, is involved in the maintenance and/or establishment of the meristems. They interact with potyvirus VPg-interacting proteins (PVIP1 and 2) and act as central regulators in auxin-mediated control of development. PHD fingers can recognise the unmodified and modified histone H3 tail, and some have been found to interact with non-histone proteins .
CABYR/SP17, dimerization domain (DD_CABYR_SP17)
Type: Domain

This entry represents the N-terminal domain of dimerization/docking (D/D) domain of Calcium-binding tyrosine phosphorylation-regulated protein (CABYR), Sperm surface protein Sp17 (SP17) and similar animal proteins. This domain shows similarity to the D/D domain of the R subunit of cAMP-dependent protein kinase (PKA), which dimerises to form a four-helix bundle that serves as a docking site for A-kinase-anchoring proteins (AKAPs). This facilitates the localisation of PKA to specific sites in the cell. The D/D domain of CABYR and SP17 have been shown to bind to AKAP3, a protein that is also associated to the FS of mammalian spermatozoa .

CABYR and SP17 are naturally located in the human sperm fibrous sheath (FS). CABYR was originally isolated from spermatoza and was thought to be testis-specific, but has recently been observed in lung and brain tumours. It is a polymorphic calcium binding protein that is phosphorylated during capacitation . SP17 plays an important role in the interaction of sperm with the zona pellucida during fertilization. It also promotes cell-cell adhesion. SP17 is found in various human tumours of unrelated histological origin including metastatic squamous cell carcinoma, multiple myeloma, ovarian cancer, and primary nervous system tumours, among others .
DNA polymerase gamma, palm domain (POLG_palm_dom)
Type: Domain

This entry represents the palm domain of human DNA polymerase gammaA (Pol gammaA), the catalytic subunit of the mitochondrial DNA polymerase, and similar proteins from animals and fungi. This subunit possesses both polymerase and proofreading exonuclease activities, and together with the accessory subunit, Pol gammaB, constitute the Pol gamma holoenzyme. This protein is important for mitochondrial DNA maintenance and mutation of the catalytic subunit of Pol gamma is implicated in more than 30 human diseases. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit. The Pol gammaA belongs to classA polymerases and its palm domain adopts a canonical polymerase configuration

.

DNA-dependent DNA polymerases can be classified into six main groups based upon phylogenetic relationships with E. coli polymerase I (classA), E. coli polymerase II (class B), E.coli polymerase III (class C), euryarchaeota polymerase II (class D), human polymerase beta (class X), E. coli UmuC/DinB and eukaryotic RAP 30/Xeroderma pigmentosum variant (class Y). The structure of these polymerases resembles in overall morphology a cupped human right hand, with fingers (which bind an incoming nucleotide and interact with the single-stranded template), palm (which harbors the catalytic amino acid residues and also binds an incoming dNTP) and thumb (which binds double-stranded DNA) subdomains .
D-lyxose isomerase EcSI-like (EcSI_cupin)
Type: Family

This family represents sugar isomerases comprising group I of D-lyxose isomerases homologous to pathogenic Escherichia coli O157 z5688 (EcSI or Z5688) which has an active site highly similar to YdaE from the sigma B regulon of Bacillus subtilis . Substrate screening has revealed that EcSI is capable of acting on D-lyxose (E.C:

) and D-mannose (EC:

). Studies show that overexpression of EcSI enables cell growth on D-lyxose as the sole carbon source. Proteins in this family belong to the cupin superfamily with a conserved 'jelly roll-like' double-stranded β-helix fold .
CRISPR-associated protein Cas5fv (Cas5fv)
Type: Family

This entry represents Cas5fv that is one of the CRISPR-associated (Cas) proteins of type I-F variant CRISPR-Cas system. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas modules are adaptive immune systems found in archaea and bacteria against foreign nucleic acids such as phages and plasmids via RNA-guided endonucleases. CRISPR-Cas systems are classified based on Cas protein content and arrangement in CRISPR-Cas loci into two main classes (1 and 2) and at least six types (I, II, III, IV, V, VI). Class 1 systems utilize multiple Cas proteins and CRISPR RNA (crRNA) to form an effector complex while class 2 systems employ a large, single effector with crRNA to mediate interference .

Type I CRISPR-Cas systems are most widespread in nature and the Cas protein composition of the employed Cascade interference complexes differ between seven subtypes (A-F, U). Type I-F variant (I-Fv) is a subtype that rely on a minimal set of five Cas proteins and has structural differences with I-F and I-E Cascades. Double strand DNA recruitment and recognition in the type I-Fv Cascade is facilitated from the major groove side by Cas5fv instead of the large subunit Cas8 and the finger domain of Cas7fv

. Type I-F and I-Fv cascades differ substantially in their DNA interaction sites, which are also a prime target of anti-CRISPR proteins .
Iron-sulfur cluster assembly protein CyaY (CyaY)
Type: Family

This entry represents Iron-sulfur cluster assembly protein CyaY and similar proteins from proteobacteria. CyaY, the bacterial homologous to eukaryotic protein Frataxin, is involved in iron-sulfur (Fe-S) cluster assembly. Partial Phylogenetic Profiling suggests that CyaY most likely functions as part of the ISC system for FeS cluster biosynthesis, and is supported by experimental data in some species .
o-succinylbenzoate synthase MenC (MenC)
Type: Family

This family represents o-succinylbenzoate synthase MenC (also known as OSB synthase and N-succinylamino acid racemase NAAAR). MenC converts 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC) to 2-succinylbenzoate (OSB) that also acts as a N-succinylamino acid racemase (NSAR/NAAAR) that catalyses the racemisation of various N-succinylamino acids, including N-succinyl-L-valine, N-succinyl-L-alanine, N-succinyl-L-methionine, N-succinyl-L-tyrosine, N-succinyl-L-serine, N-succinyl-L-isoleucine, N-succinyl-L-phenylalanine and N-succinyl-L-leucine .
L-cysteine desulfhydrase Cds1 (Cds1)
Type: Family

This entry represents a group of proteins from proteobacteria and actinomycetes, including L-cysteine desulfhydrase Cds1 from Mycobacterium tuberculosis. Cds1 is a cysteine desulfhydrase that generates hydrogen sulfide, H2S, which modulates the balance between respiration and glycolysis, and also contributes to redox homeostasis in this organism . Members of this protein family have a PALP domain (

).