SII-SWORD/CoKE huggingface dataset:
ZN598/HEL22, RING finger (RING-HC_ZNF598/HEL2)
Type: Domain

This entry represents the RING-HC finger domain in ZNF598 from animals and HEL2 from yeasts .

ZNF598 plays a key role in the ribosome quality control (RQC), a pathway that takes place when the ribosome has stalled during translation, leading to degradation of nascent peptide chains. ZNF598 is activated when ribosomes are stalled following translation of prematurely polyadenylated mRNAs . Independently of its role in RQC, this protein may also act as a negative regulator of interferon-stimulated gene expression . ZNF598 is associates with eukaryotic initiation factor 4E (eIF4E) homologous protein from mammalian (m4EHP) through binding to Grb10-interacting GYF protein 2 (GIGYF2). The m4EHP-GIGYF2 complex functions as a translational repressor and is essential for normal embryonic development of mammalian .

HEL2 in addition to its role in the ribosome quality control, also acts as an activator of the No-Go decay (NGD) pathway by mediating polyubiquitination of monoubiquitinated RPS3/uS3 and RPS7/es7. RPS3/uS3 and RPS7/es7 are first monoubiquitinated by MAG2 and MOT2/NOT4, respectively, and HEL2 mediates formation of 'Lys-63'-linked polyubiquitin chains on monoubiquitin, leading to activation of the NGD pathway in a CUE2-mediated endonucleolytic cleavage . Hel2 is involved ubiquitination and degradation of excess histones .
Ecdysone receptor, ligand-binding domain (NR_LBD_EcR)
Type: Domain

The ecdysone receptor (EcR) belongs to the superfamily of nuclear receptors (NRs) of ligand-dependent transcription factors . Ecdysone receptor is present only in invertebrates and regulates the expression of a large number of genes during development and reproduction. EcR functions as a heterodimer by partnering with ultraspiracle protein (USP), the orthologue of the vertebrate retinoid X receptor (RXR) . The natural ligands of ecdysone receptor are ecdysteroids, the endogenous steroidal hormones found in invertebrates . In addition, insecticide bisacylhydrazine, used against pests, has shown to act on EcR. EcR must be dimerised with a USP for high-affinity ligand binding to occur. The ligand binding triggers a conformational change in the C-terminal part of the EcR ligand-binding domain that leads to transcriptional activation of genes controlled by EcR .

Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, ecdysone receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a non-conserved hinge and a C-terminal ligand binding domain (LBD) . This entry represent the LBD domain of the ecdysone receptor.
Carbonic anhydrase VII (Alpha_CA_VII)
Type: Family

Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidines . This vertebrate subgroup comprises isozyme VII. CA VII is the most active cytosolic enzyme after CA II, and may be highly expressed in the brain. Human CA VII may be a target of antiepileptic sulfonamides/sulfamates .
Carbonic anhydrase, prokaryotic-like (Alpha_CA_prokaryot-like)
Type: Family

Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyse the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidines .

This subfamily includes bacterial carbonic anhydrase alpha , as well as plant enzymes such as tobacco nectarin III and yam dioscorin and, carbonic anhydrases from molluscs, such as nacrein, which are part of the organic matrix layer in shells. Other members of this family may be involved in maintaining pH balance, in facilitating transport of carbon dioxide or carbonic acid, or in sensing carbon dioxide levels in the environment. Dioscorin is the major storage protein of yam tubers and may play a role as an antioxidant . Tobacco Nectarin may play a role in the maintenance of pH and oxidative balance in nectar . Mollusc nacrein may participate in calcium carbonate crystal formation of the nacreous layer . This subfamily also includes three alpha carbonic anhydrases from Chlamydomonas reinhardtii (CAH 1-3). CAH1/2 are localized in the periplasmic space. CAH1 facilitates the movement of carbon dioxide across the plasma membrane when the medium is alkaline. CAH3 is localized to the thylakoid lumen and provides CO2 to Rubisco .
Antirestriction protein ArdA, domain 3 (ArdA_dom3)
Type: Homologous_superfamily

ArdA functions in bacterial conjugation to allow an unmodified plasmid to evade restriction in the recipient bacterium and yet acquire cognate modification . ArdA forms a dimer and each monomer is comprised of three small α-β domains, each with a different fold, arranged in a row in each monomer.

This superfamily represents the bacterial antirestriction (ArdA) protein C-terminal domain 3. Structurally, this domain consists of three-stranded β-sheet and three α-helices packed together in a manner that creates a groove in the structure. The helical arrangement in the C-terminal domain contains a component of the winged helix-turn-helix motif. The evolution of ArdA is curious as domains 2 (

) and 3 (

) show a similar fold to that of nucleotide binding proteins but the opposite charge to the characteristic positive charge of oligonucleotide binding proteins. This reversal in surface potential suggests that ArdA is not a DNA- (or RNA)-binding protein .
ProX-like, substrate-binding domain (PBP2_ProX-like)
Type: Domain

This entry represents the substrate-binding domain found in ProX from the hyperthermophilic archaeon Archaeoglobus fulgidus and its related proteins. AfProX is involved in uptake of compatible solutes such as the trimethylammonium compound glycine betaine and the dimethylammonium compound proline betaine, but the relative substrate preference is not known. To counteract the efflux of water, many microorganisms accumulate the compatible solutes for a sustained adjustment to high osmolarity surroundings . AfProX belongs to the type 2 periplasmic binding fold protein superfamily (PBP2). The PBP2 proteins are typically comprised of two globular subdomains connected by a flexible hinge and bind their ligand in the cleft between these domains in a manner resembling a Venus flytrap .
Antirestriction protein ArdA, domain 1 (ArdA_dom1)
Type: Homologous_superfamily

ArdA functions in bacterial conjugation to allow an unmodified plasmid to evade restriction in the recipient bacterium and yet acquire cognate modification . ArdA forms a dimer and each monomer is comprised of three small α-β domains, each with a different fold, arranged in a row in each monomer.

This superfamily represents the bacterial antirestriction (ArdA) protein N-terminal domain 1. Structurally, it consists of a three-stranded anti-parallel β-sheet and one short α-helix interspersed with three large loops of 10 or more residues. Domain 1 is not essential for anti-restriction as it can be deleted, indicating that the key aspect of anti-restriction by ArdA is the binding to the MTase core using domains 2 (

) and 3 (

) .
Antirestriction protein ArdA, domain 2 (ArdA_dom2)
Type: Homologous_superfamily

ArdA functions in bacterial conjugation to allow an unmodified plasmid to evade restriction in the recipient bacterium and yet acquire cognate modification . ArdA forms a dimer and each monomer is comprised of three small α-β domains, each with a different fold, arranged in a row in each monomer.

This superfamily represents the antirestriction protein (ArdA) domain 2. Domains 2 and 3 (

) have folds similar to those of nucleotide binding proteins, but which present a negative potential, opposite to the positive potential characteristic of nucleotide binding proteins. This reversal in surface potential suggests that ArdA is not a DNA- (or RNA)-binding protein .
Integrator complex subunit 11, MBL-fold (INTS11-like_MBL-fold)
Type: Domain

This entry represents the MBL-fold found in integrator complex subunit 11 (INTS11 or Int11, also known as RC-68). Integrator (INT) is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1-Int14 (Integrator subunits). Integrator complex has been implicated in a variety of Pol II transcription events including 3' end processing of snRNA, transcription initiation, promoter-proximal pausing, termination of protein-coding transcripts, and in HVS pre-miRNA 3' end processing . INTS11 is the endonuclease subunit for INT, responsible for the cleavage reaction at the 3' end of target RNAs . INTS11 belongs to the MBL-fold metallo-hydrolase superfamily which is comprised mainly of hydrolytic enzymes which carry out a variety of biological functions .
MAGE homology domain, winged helix WH1 motif (MAGE_WH1)
Type: Homologous_superfamily

This superfamily includes MAGE (melanoma antigen-encoding gene) proteins, which are expressed in a wide variety of tumours but not in normal cells, with the exception of the male germ cells, placenta, and, possibly, cells of the developing embryo. The cellular function is currently unknown. This superfamily also contains the yeast protein, Nse3. The Nse3 protein is part of the Smc5-6 complex and interacts with NSE4/EID family proteins . Nse3 has been demonstrated to be important in meiosis .

MAGE proteins share a conserved domain known as the MAGE homology domain (MHD). This superfamily entry represents the domain that contains a winged helix motif WH1.
MAGE homology domain, winged helix WH2 motif (MAGE_WH2)
Type: Homologous_superfamily

This superfamily includes MAGE (melanoma antigen-encoding gene) proteins, which are expressed in a wide variety of tumours but not in normal cells, with the exception of the male germ cells, placenta, and, possibly, cells of the developing embryo. The cellular function is currently unknown. This superfamily also contains the yeast protein, Nse3. The Nse3 protein is part of the Smc5-6 complex and interacts with NSE4/EID family proteins . Nse3 has been demonstrated to be important in meiosis .

MAGE proteins share a conserved domain known as the MAGE homology domain (MHD). This superfamily entry represents the domain that contains a winged helix motif WH2.
Collagen alpha-3(VI) chain, vWA domain (vWA_collagen_alpha3-VI-like)
Type: Domain

This entry represents the vWA domain found in collagen alpha 3(VI). The extracellular matrix represents a complex alloy of variable members of diverse protein families defining structural integrity and various physiological functions. The most abundant family is the collagens with more than 20 different collagen types identified thus far. Collagens are centrally involved in the formation of fibrillar and microfibrillar networks of the extracellular matrix, basement membranes as well as other structures of the extracellular matrix. Some collagens have about 15-18 vWA domains in them. The VWA domains present in these collagens mediate protein-protein interactions .
Rpa43, N-terminal ribonucleoprotein (RNP) domain (RNAP_I_Rpa43_N)
Type: Domain

This entry represents the N-terminal ribonucleoprotein (RNP) domain of Rpa43, which is a subunit of eukaryotic RNA polymerase (RNAP) I that is homologous to Rpb7 of eukaryotic RNAP II, Rpc25 of eukaryotic RNP III, and RpoE of archaeal RNAP. Rpa43 has two domains, an N-terminal RNP domain and a C-terminal oligonucleotide-binding (OB) domain. Rpa43 heterodimerizes with Rpa14 and this heterodimer has genetic and biochemical characteristics similar to those of the Rpb7/Rpb4 heterodimer of RNAP II. In addition, the Rpa43/Rpa14 heterodimer binds single-stranded RNA, as is the case for the Rpb7/Rpb4 and the archaeal E/F complexes. The position of Rpa43/Rpa14 in the three-dimensional structure of RNAP I is similar to that of Rpb4/Rpb7, which forms an upstream interface between the C-terminal domain of Rpb1 and the transcription factor IIB (TFIIB), recruiting pol II to the pol II promoter. Rpb43 binds Rrn3, an rDNA-specific transcription factor, functionally equivalent to TFIIB, involved in recruiting RNAP I to the pol I promoter .
CtsR, N-terminal domain superfamily (CtsR_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal winged HTH domain of CtsR, a dimeric repressor. The members include several Firmicute transcriptional repressor of class III stress genes (CtsR) proteins. CtsR of L. monocytogenes negatively regulates the clpC, clpP and clpE genes belonging to the CtsR regulon .

CtsR consists of an N-terminal domain, a DNA binding domain with a helix-turn-helix motif (HTH) and a C-terminal dimerisation domain organised in a four helix bundle, with an unknown function. CtsR has a role in forming a complex with DNA, binding to promoter regions of heat-shock genes. It is mainly involved in the regulatory network of the bacterial heat-shock response. The phosphorylation sites reside in the winged HTH domain .
Tyrosine 3-monooxygenase, catalytic domain (Eu_TyrOH_cat)
Type: Domain

Tyrosine 3-monooxygenase (TH) or eukaryotic tyrosine hydroxylase (TyrOH) is a member of the biopterin-dependent aromatic amino acid hydroxylase family of non-heme, iron(II)-dependent enzymes that also includes prokaryotic and eukaryotic phenylalanine-4-hydroxylase (PheOH) and eukaryotic tryptophan hydroxylase (TrpOH) . TyrOH catalyzes the conversion of tyrosine to L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of the catecholamines dopamine, noradrenaline, and adrenaline .

All three of the aromatic amino acid hydroxylases from eukaryotic sources share a three domain structure. There is an N-terminal regulatory domain of 100-170 residues, followed by the catalytic domain and a C-terminal 40 residues tetramerization domain .
Tryptophan 5-hydroxylase, catalytic domain (TrpOH_cat)
Type: Domain

Tryptophan 5-hydroxylase (TPH) or eukaryotic tryptophan hydroxylase (TrpOH) is a member of the biopterin-dependent aromatic amino acid hydroxylase family of non-heme, iron(II)-dependent enzymes that also includes prokaryotic and eukaryotic phenylalanine-4-hydroxylase (PheOH) and eukaryotic tyrosine hydroxylase (TyrOH) . The catalytic domains of all three enzymes have a very similar fold with a mixture of α and β structures .

TPH oxidizes L-tryptophan to 5-hydroxy-L-tryptophan, the rate-limiting step in the biosynthesis of serotonin (5-hydroxytryptamine), a widely distributed hormone and neurotransmitter . Two forms of TPH have been identified in mammals: TPH1, expressed highly in the gastrointestinal tract and the pineal gland, and TPH2, expressed in neuronal cells and the myenteric plexus of the gut and responsible for the vast majority of 5-HT synthesis in the central nervous system .
Ribosomal protein S6 kinase alpha-3, C-terminal catalytic domain (RPS6KA3_C)
Type: Domain

This entry represents the C-terminal catalytic domain of ribosomal protein S6 kinase alpha-3.

RPS6KA3 (also called RSK2) is expressed highly in the regions of the brain with high synaptic activity and plays a role in the maintenance and consolidation of excitatory synapses. It is a specific modulator of phospholipase D in calcium-regulated exocytosis . Mutations in the RPS6KA3 gene cause Coffin-Lowry syndrome (CLS), a rare syndromic form of X-linked mental retardation characterised by growth and psychomotor retardation and skeletal abnormalities . RSK2 is one of four RSK isoforms (RSK1-4) from distinct genes present in vertebrates.

The most striking feature of RSKs is the presence of two functional and non-identical phosphotransferase domains . RSKs contain an N-terminal kinase domain (NTD) that is characteristics of the AGC family and a C-terminal kinase domain (CTD) that is characteristics of the CAMK family. They are activated by signaling inputs from extracellular regulated kinase (ERK) and phosphoinositide dependent kinase 1 (PDK1). ERK phosphorylates and activates the CTD of RSK, serving as a docking site for PDK1, which phosphorylates and activates the NTD, which in turn phosphorylates all known RSK substrates. RSKs act as downstream effectors of mitogen-activated protein kinase (MAPK) and play key roles in mitogen-activated cell growth, differentiation, and survival .
Ribosomal S6 kinase, N-terminal catalytic domain (RSK_N)
Type: Domain

This entry represents the N-terminal catalytic domain of Ribosomal S6 kinase (RSK). There are four RSK isoforms (RSK1-4) from distinct genes present in vertebrates . Their most striking feature is the presence of two functional and non-identical phosphotransferase domains . RSKs contain an N-terminal kinase domain (NTD) that is characteristics of the AGC family and a C-terminal kinase domain (CTD) that is characteristics of the CAMK family. They are activated by signaling inputs from extracellular regulated kinase (ERK) and phosphoinositide dependent kinase 1 (PDK1). ERK phosphorylates and activates the CTD of RSK, serving as a docking site for PDK1, which phosphorylates and activates the NTD, which in turn phosphorylates all known RSK substrates. RSKs act as downstream effectors of mitogen-activated protein kinase (MAPK) and play key roles in mitogen-activated cell growth, differentiation, and survival .
NAC-alpha domain-containing protein 1, UBA-like domain (NACAD_UBA)
Type: Domain

The biological function of NACAD remains unknown, but it shows high sequence similarity to the nascent polypeptide-associated complex (NAC) subunit alpha (NACA) that exists as part of several protein complexes playing a role in proliferation, apoptosis, or degradation. Like NACA, NACAD contains an NAC domain and a C-terminal ubiquitin-associated (UBA)-like domain. This entry represents the UBA-like domain of NACAD.
CtsR, C-terminal domain superfamily (CtsR_C_sf)
Type: Homologous_superfamily

This superfamily correspond to the CtsR C-terminal dimerisation domain. CtsR is an important repressor that modulates the transcription of class III stress genes in Gram-positive bacteria, mainly from Firmicute species.

CtsR consists of an N-terminal domain, a DNA binding domain with a helix-turn-helix motif (HTH) and a C-terminal dimerisation domain organised in a four helix bundle, with an unknown function. CtsR has a role in forming a complex with DNA, binding to promoter regions of heat-shock genes. It is mainly involved in the regulatory network of the bacterial heat-shock response. The phosphorylation sites reside in the winged HTH domain .
Sbi, C3 binding domain IV (Sbi_C3_db_domIV)
Type: Homologous_superfamily

This superfamily includes the immunoglobulin-binding protein Sbi domain IV (Sbi-IV) which binds the central complement protein C3. Sbi-IV interacts with Sbi-III to induce a consumption of complement via alternative pathway activation . When not interacting with Sbi-III, Sbi-IV inhibits the alternative pathway without complement consumption. Sbi-IV structurally comprises a three-helix bundle .

Sbi-IV is similar to Efb-C and Ehp . Sbi-IV binds to the thioester-containing domain of native C3. The interaction between Sbi-IV and C3, in the presence of domain III, results in the formation of a covalent Sbi-III-IV-C3 adduct followed by futile fluid phase consumption of C3 .
Alpha-helical PorB/PorC (Alpha_h_PorB/PorC)
Type: Homologous_superfamily

This superfamily represents the putative cell wall channel-forming proteins porin B (PorB) and porin C (PorC) from Corynebacterium sp. Porin B from Corynebacterium glutamicum (Brevibacterium flavum) allows the exchange of material across the mycolic acid layer, which is the protective nonpolar barrier. Porin B has an α helical core structure consisting of four α-helices surrounding a nonpolar interior. There is a disulphide bridge between helices 1 and 4 to form a stable covalently bound ring . The channel of PorB is oligomeric .
TAB2/3, CUE domain (TAB2/3_CUE)
Type: Domain

TAB2 (TGF-beta-activated kinase 1 and MAP3K7-binding protein 2) is an adaptor protein that regulates activation of TAK1, a MAP kinase kinase kinase (MAPKKK), through linking TAK1 to TRAF6 in the Interleukin-1 (IL-1) induced NF-kappaB activation pathway . TAB3 is a TAB2-like TAK1-binding protein that activates NF-kappaB similar to TAB2 . It activates TAK1 and regulates its association with TRAF2 and TRAF6. Moreover, TAB3 interacts with TRAF6 and TRAF2 in an IL-1- and a TNF-dependent manner, respectively. TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction . Both of them contain an N-terminal CUE domain, a coiled-coil (CC) region, a TAK1-binding domain and a C-terminal Npl4 zinc finger (NZF) ubiquitin-binding domain (UBD) .

This entry represents the CUE domain found in TAB2 and TAB3.
Eukaryotic phenylalanine-4-hydroxylase, catalytic domain (Euk_PheOH_cat)
Type: Domain

Eukaryotic phenylalanine-4-hydroxylase (eu_PheOH) is a member of the biopterin-dependent aromatic amino acid hydroxylase family of non-heme, iron(II)-dependent enzymes that also includes prokaryotic phenylalanine-4-hydroxylase (pro_PheOH), eukaryotic tyrosine hydroxylase (TyrOH) and eukaryotic tryptophan hydroxylase (TrpOH) . The three enzymes have a three-domain structure, with an N-terminal regulatory domain (humanPheOH residues 1-142), a central catalytic domain (hPheOH residues 143-410), and a C-terminal tetramerization domain (hPheOH residues 411-452) .

PheOH catalyzes the first and rate-limiting step in the metabolism of the amino acid L-phenylalanine (L-Phe), the hydroxylation of L-Phe to L-tyrosine (L-Tyr). It uses (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) as the physiological electron donor. The catalytic activity of the tetrameric enzyme is tightly regulated by the binding of L-Phe and BH4 as well as by phosphorylation. Mutations in the human enzyme are linked to a severe variant of phenylketonuria .
DNA polymerase delta subunit 3 superfamily (POLD3_sf)
Type: Homologous_superfamily

DNA polymerase delta (Pol delta), one of the major eukaryote replicases, consists of 4 subunits in humans: p125, p55, p66 and p12. The interaction between the non-catalytic subunits p55 and p66 is crucial for Pol delta regulation .

This superfamily entry represents the p66 subunit (also known as POLD3) which contains a winged helix-turn-helix domain (wHTH).
ATP-dependent 6-phosphofructokinase, vertebrate-type (PFK_vert-type)
Type: Family

Phosphofructokinase (PFK), a key regulatory enzyme in glycolysis, catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-biphosphate. Eukaryotic ATP-dependent phosphofructokinases have evolved from the bacterial PFKs by gene duplication and fusion events and exhibit complex allosteric behavior . In mammalian cells, PFK exists in three types of isozymes: muscle, liver and platelet . This entry includes PFKs from vertebrates, and also PFK1 and PFK2 from the yeast Kluyveromyces lactis .
Tudor domain-containing protein 3, UBA domain (UBA_TDRD3)
Type: Domain

This entry represents the UBA domain of TDRD3.

TDRD3 is a modular protein containing a Tudor domain, a DUF/OB-fold motif and a ubiquitin-associated (UBA) domain . It shows both nucleic acid- and methyl-binding properties and can interact with methylated RNA-binding proteins, such as fragile X messenger ribonucleoprotein 1 (FMRP) and DEAD/H box-3 (also known as DDX3X/Y, DBX/Y, HLP2 and DDX14) which is implicated in human genetic diseases . At this point, TDRD3 may play a central role in RNA processing regulatory pathways involving arginine methylation. TDRD3 localizes predominantly to the cytoplasm stress granules (SGs) . The Tudor domain is essential and sufficient for its recruitment to SGs .