SII-SWORD/CoKE huggingface dataset:
Twist-related protein 2, basic helix-loop-helix domain (Twist2_bHLH)
Type: Domain

This entry represents the basic helix-loop-helix (bHLH) domain found in Twist2 and related proteins from vertebrates.

Twist-related protein 2 (Twist2) is a bHLH transcriptional factor that regulates the development of mesenchymal tissues and plays a critical role in embryogenesis. It binds to the E-box consensus sequence 5'-CANNTG-3' as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C . Twist2 is also involved in cancer progression and is a valuable biomarker for certain cancer types . Mutations in this protein are associated with other human disorders such as ectodermal dysplasias .
Midline-1, B-box-type 1 zinc finger (MID1_Bbox1_Zfn)
Type: Domain

This entry represents the B-box-type 1 (Bbox1) zinc finger of MID1, which is characterised by a C6H2 zinc-binding consensus motif .

The microtubule-associated E3 ligase MID1 (

) contains a type 1 B-box zinc finger domain. MID1 specifically binds Alpha-4, which in turn recruits the catalytic subunit of phosphatase 2A (PP2Ac). This complex is required for targeting of PP2Ac for proteasome-mediated degradation. The MID1 B-box coordinates two zinc ions and adopts a β/β/α cross-brace structure similar to that of ZZ, PHD, RING and FYVE zinc fingers .

MID1 is associated with microtubules throughout the cell cycle, co-localising with cytoplasmic fibres in interphase and with the mitotic spindle and midbodies during mitosis and cytokinesis . It has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination .
Nuclear factor NF-kappa-B p105 subunit, death domain (NF-kB_p105_DD)
Type: Domain

This entry represents the Death Domain (DD) of NF-kappaB subunit precursor p105, which can undergo cotranslational processing by the 26S proteasome to produce a 50kDa protein (p50). p50 is a DNA binding subunit of the NF-kappaB (NF-kappaB) protein complex .

NF-kappaB is a pleiotropic transcription factor present in almost all cell types. It is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappaB is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RelA/p65, RelB, NFKB1/p50, c-Rel and NFKB2/p52 . Each individual NF-kappaB subunit, and perhaps each dimer, carries out unique functions in regulating transcription. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins .

NF-kB1 and NF-kB2 are synthesised as large precursors, called p105 and p100, which undergo processing to generate the NF-kB subunits p50 and p52, respectively . The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway, and involves selective degradation of their C-terminal regions containing ankyrin repeats . Unlike RelA, RelB and c-Rel, p50 and p52 do not contain transactivation domains in their C-termini. Nevertheless, they play critical roles in modulating the specificity of NF-kB function .
Ectoderm-neural cortex protein 1, BACK domain (ENC1_BACK)
Type: Domain

This entry represents the BACK (BTB and C-terminal Kelch) domain of ENC1.

Ectoderm-neural cortex protein 1 (ENC1), also known as kelch-like protein 37 (KLHL37), is expressed in the central nervous system (CNS), where it interacts with actin and contributes to the organisation of the cytoskeleton during the specification of neural fate . ENC1 functions as a negative regulator of transcription factor Nrf2 (a regulator of a cellular defense mechanism against environmental insults) through suppressing Nrf2 protein translation . It plays a pivotal role in neuronal and adipocyte differentiation .

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .
Kelch-like ECH-associated protein 1, BACK domain (KEAP1_BACK)
Type: Domain

This entry represents the BACK (BTB and C-terminal Kelch) domain of KEAP1 and similar animal proteins.

Kelch-like ECH-associated protein 1 (KEAP1, also known as KLHL19) is a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress. It targets NFE2L2/NRF2 (a transcription factor) for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression . Another KEAP1 substrate, PGAM5, a Bcl-XL-interacting protein, has also been identified .

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .
Nop5, N-terminal domain superfamily (Nop5_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of Nop56/58 homologue from archaea Nop5, whose structure is very well conserved . This domain mediates a stable interaction with fibrillarin, playing a role in both ribonucleoprotein (RNP) assembly and methyltransferase activity.
Contactin-1, Ig-like domain 3 (Contactin-1_Ig-like_3)
Type: Domain

This entry represents the third immunoglobulin (Ig) domain of contactin-1.

Contactin-1 (CNTN1) is expressed by a diversity of neurons and contributes to the formation and function of neuronal connections . Contactin-1 regulates both myelin formation and organisation of nodal and paranodal domains in the central and peripheral nervous system . It plays a relevant role in cerebellar ontogenesis and cerebral cortex development . Contactin-1 contributes to the invasion and metastasis of several tumours . It is comprised of six immunoglobulin domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol.

Contactins are cell adhesion molecules that belong to the immunoglobulin superfamily and are involved in neural development . They usually consist of six N-terminal Ig domains, four fibronectin type III domains, and a C-terminal glycophosphatidylinositol (GPI)-anchor to the extracellular part of the cell membrane .
Contactin-1, immunoglobulin domain 6 (Contactin-1_Ig6)
Type: Domain

This entry represents the sixth immunoglobulin (Ig) domain of contactin-1.

Contactin-1 (CNTN1) is expressed by a diversity of neurons and contributes to the formation and function of neuronal connections . Contactin-1 regulates both myelin formation and organisation of nodal and paranodal domains in the central and peripheral nervous system . It plays a relevant role in cerebellar ontogenesis and cerebral cortex development . Contactin-1 contributes to the invasion and metastasis of several tumours . It is comprised of six immunoglobulin domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol.

Contactins are cell adhesion molecules that belong to the immunoglobulin superfamily and are involved in neural development . They usually consist of six N-terminal Ig domains, four fibronectin type III domains, and a C-terminal glycophosphatidylinositol (GPI)-anchor to the extracellular part of the cell membrane .
Contactin-1/2, immunoglobulin domain 2 (Contactin-1_2_Ig1)
Type: Domain

This entry represents the second immunoglobulin (Ig) domain of contactin-1/2 and similar proteins from vertebrates.

Contactin-1 (CNTN1) is expressed by a diversity of neurons and contributes to the formation and function of neuronal connections . Contactin-1 regulates both myelin formation and organisation of nodal and paranodal domains in the central and peripheral nervous system . It plays a relevant role in cerebellar ontogenesis and cerebral cortex development . Contactin-1 contributes to the invasion and metastasis of several tumours .

Contactins are cell adhesion molecules that belong to the immunoglobulin superfamily and are involved in neural development . They usually consist of six N-terminal Ig domains, four fibronectin type III domains, and a C-terminal glycophosphatidylinositol (GPI)-anchor to the extracellular part of the cell membrane .
Maltose transport system permease protein MalF, P2 domain superfamily (MalF_P2_sf)
Type: Homologous_superfamily

The maltose transport system is composed of a periplasmic maltose-binding protein (MBP), two integral membrane proteins, MalF and MalG, and two copies of the cytoplasmic ATP-binding cassette MalK . The structures of the two transmembrane (TM) subunits, MalF and MalG, are composed of eight and six TM helices, respectively. The TM helices of MalF and MalG assemble into two crescent shaped structures with their concave surfaces facing each other and enclosing the maltose. MalF consists of four periplasmic domains. This entry represents the second periplasmic loop of MalF (P2), which binds to MalE and is involved in activation of the MalFGK2-E complex by inducing structural changes in maltose-bound MalE . P2 is also responsible for substrate recognition .
Bridge-like lipid transfer protein family member 1, N-terminal (BLTP1_N)
Type: Domain

This entry represents the N-terminal domain of BLTP1 from animals .

Bridge-like lipid transfer protein family member 1 (BLTP1, formerly known as Tweek/KIAA1109/FSA in human) is a tube-forming lipid transport protein which provides phosphatidylethanolamine for glycosylphosphatidylinositol (GPI) anchor synthesis in the endoplasmic reticulum. It plays a role in endosomal trafficking and endosome recycling and it is also involved in the actin cytoskeleton and cilia structural dynamics . BLTP1 also acts as a regulator of phagocytosis . In humans, it has been associated with rheumatoid arthritis . Mutations of the BLTP1 gene has been associated with Alkuraya-Kucinskas syndrome (MIM 617822), a severe disorder of brain development and arthrogryposis .

Members of this entry belong to the repeating β-groove (RBG) superfamily together with VPS13, ATG2, SHIP164, BLTP2/FMP27, which are all conserved lipid transfer proteins containing long hydrophobic grooves . They all share the same structure comprising multiple repeating modules consisting of five β-sheets followed by a loop.
Frizzled-4/Mom-5, 7TM (Frizzled-4/Mom-5_7TM)
Type: Domain

This entry represents the C-terminal transmembrane domain of Frizzled-4 from arthropods and Mom-5 from nematodes.

Frizzleds are seven transmembrane-spanning proteins that constitute an unconventional class of G protein-coupled receptors . They have important regulatory roles during embryonic development .

Frizzleds expose their large N terminus on the extracellular side. The N-terminal, extracellular cysteine-rich domain (CRD) has been implicated as the Wnt binding domain and its structure has been solved . The cysteine-rich domain of Frizzled (Fz) is shared with other receptor tyrosine kinases that have roles in development including the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. The cytoplasmic side of many Fz proteins has been shown to interact with the PDZ domains of PSD-95 family members and is thought to have a role in the assembly of signalling complexes. The conserved cytoplasmic motif of Fz, Lys-Thr-X-X-X-Trp, is required for activation of the beta-catenin pathway, and for membrane localisation and phosphorylation of Dsh.

In Drosophila melanogaster, the frizzled locus is involved in planar cell polarity, which is the coordination of the cytoskeleton of epidermal cells to produce a parallel array of cuticular hairs and bristles . In the wild-type wing, all hairs point towards the distal tip , whereas in Fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the developing wing, Fz function is required for cells to respond to the extracellular polarity signal as well as the proximal-distal transmission of an intracellular polarity signal.

In Caenorhabditis elegans, protein mom-5 is the equivalent of frizzled .

Three main signalling pathways are activated by agonist-activated Frizzled proteins: the Fz/beta-catenin pathway, the Fz/Ca2 pathway and the Fz/PCP (planar cell polarity) pathway . The Wnt/beta-catenin pathway is the best studied signalling pathway involving Fz receptors. In the Wnt/beta-catenin pathway the first downstream cytoplasmic components activated by Fz signalling include Dishevelled (Dsh) and/or its regulatory kinases.
Nuclear factor interleukin-3-regulated protein-like , bZIP domain (NFIL3-like_bZIP)
Type: Domain

This entry represents the Basic leucine zipper (bZIP) domain of NFIL3. The bZIP structural motif contains a basic region and a leucine zipper, composed of α-helices with leucine residues 7 amino acids apart, which stabilise dimerisation with a parallel leucine zipper domain. Dimerisation of leucine zippers creates a pair of the adjacent basic regions that bind DNA and undergo conformational change. Dimerisation occurs in a specific and predictable manner resulting in hundreds of dimers having unique effects on transcription.

Nuclear factor interleukin-3-regulated protein (NFIL3, also known as E4BP4) was first identified as a transcriptional repressor capable of binding an activating transcription factor (ATF) DNA consensus sequence site in the adenovirus E4 promoter . Later, it was independently identified as a transactivator of the IL3 promoter in human T cells .

E4BP4 is involved in a several biological processes, including transcriptional control of the circadian clock, neuron growth and survival, osteoblast function, and regulation of ovulation . It is essential for the development of NK cells and CD8alpha(+) conventional dendritic cells, and is also involved in macrophage activation, polarisation of CD4(+) T cell responses and B cell class switching to IgE .

This group of proteins also includes the orthologue of human NFIL3 in Caenorhabditis elegans transcription factor atf-2 .
DNA-directed RNA pol I, largest subunit, C-terminal domain (DNA-dir_RNA_pol1_lsu_C)
Type: Domain

This entry represents the C-terminal domain of the largest subunit of DNA-directed RNA polymerase I, also known as subunit RPA1, which constitutes the catalytic core component of RNA Pol I . The yeast member of this family is known as Rpb190 .

DNA-dependent RNA polymerases (

) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-dependent RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

1. RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

2. RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

3. RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (greater than 100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.
Plk4-like, second cryptic polo-box domain superfamily (Plk4-like_POLO_box_2_sf)
Type: Homologous_superfamily

This entry represents the second (cryptic) polo-box domain of Plk4 and similar proteins mainly found in animals.

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 .
Cinnamyl alcohol dehydrogenase-like (CAD-like)
Type: Family

This entry includes the cinnamyl alcohol dehydrogenases (CADs) and closely related sequences which are members of the medium chain dehydrogenase/reductase (MDR)/zinc-dependent alcohol dehydrogenase-like family and contain two domains: a C-terminal NAD(P) binding-Rossmann fold domain and an N-terminal catalytic domain with distant homology to GroES. CADs reduce cinnamaldehydes to cinnamyl alcohols in the last step of monolignal metabolism in plant cells walls in a NADPH dependent manner and bind two zinc ions . This family also includes geissoschizine synthase from Madagascar periwinkle, a protein involved in monoterpenoid indole alkaloids (MIAs) biosynthesis pathway. MIAs, such as catharanthine, tabersonine, vincadifformine, vindoline or vincristine, are important anticancer drugs . CAD family members are also found in non-plant species , such as ADH6/ADH7 from yeast where they have an aldehyde reductase activity and may be involved in fusel alcohol synthesis or in aldehyde tolerance, and YahK/YjgB from bacteria . ADH-like proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria).
Succinate-semialdehyde dehydrogenase [NADP(+)] GABD/Sad-like (GABD/Sad-like)
Type: Family

This family represents a group of succinate semialdehyde dehydrogenases mainly found in bacteria, including SSADH1 from Mycobacterium tuberculosis and Sad from Escherichia coli. Succinate-semialdehyde dehydrogenase 1 (SSADH1 or GabD1) catalyses the NADP-dependent oxidation of succinate semialdehyde (SSA) to succinate. SSADH activity in Mycobacterium tuberculosis (Mtb) is encoded by both gabD1 (Rv0234c) and gabD2 (Rv1731). The Mtb GabD1 SSADH1 reportedly is an enzyme of the gamma-aminobutyrate shunt, which forms a functional link between two TCA half-cycles by converting alpha-ketoglutarate to succinate . Sad catalyses the NAD-dependent oxidation of succinate semialdehyde to succinate. It acts preferentially with NAD as cosubstrate but can also use NADP . This family also includes Aldh from Paenarthrobacter nicotinovorans which has sequence similarity to Sad. It does not display succinate semialdehyde dehydrogenase activity. Instead, it acts as an aldehyde dehydrogenase involved in the oxidative D-xylose degradation pathway. It is able to use both NAD and NADP; however, it shows a preference for NADP .
Uncharacterized protein YbaP-like (YbaP-like)
Type: Family

This family represents a group on uncharacterised bacterial proteins, including YbaP from E.coli and	Shigella flexneri and TP_0675 from Treponema pallidum.
ATP-dependent DNA helicase RecG/Transcription-repair-coupling factor (RecG/Mfd)
Type: Family

This entry represents a family of proteins from plants and bacteria that belong to the helicase superfamily 2 (SF2), including ATP-dependent DNA helicase RecG and Transcription-repair-coupling factor (Mfd) .

RecG plays a critical role in recombination and DNA repair both in plants and bacteria. It helps to process Holliday junction intermediates to mature products by catalysing branch migration. It has a DNA unwinding activity characteristic of a DNA helicase with a 3'- to 5'- polarity . RecG unwind branched duplex DNA (Y-DNA) and has a role in constitutive stable DNA replication (CsdR) and R-loop formation . It is genetically synergistic to RadA and RuvABC . The structure of the Thermatoga maritima RecG protein shows three distinct domains with an α-β configuration, the largest N-terminal Domain 1 which interacts with DNA junctions, and Domains 2 and 3 at the C-terminal which contain the characteristic motifs that identify RecG as an SF2 helicase .
Proliferation-associated protein 2G4/ARX1 (PA2G4/ARX1)
Type: Family

This family includes proliferation-associated protein 2G4 (PA2G4, also known as ErbB3-binding protein 1) and its homologues such as ARX1 from yeast . PA2G4 is a RNA-binding protein involved in growth regulation. This protein is present in pre-ribosomal ribonucleoprotein complexes and may be involved in ribosome assembly and the regulation of intermediate and late steps of rRNA processing . This protein can interact with the cytoplasmic domain of the ErbB3 receptor and may contribute to transducing growth regulatory signals . This protein is also a transcriptional co-repressor of androgen receptor-regulated genes and other cell cycle regulatory genes through its interactions with histone deacetylases . ARX1 from yeast is involved in proper assembly of pre-ribosomal particles during the biogenesis of the 60S ribosomal subunit . Although these proteins belong to the peptidase M24 family, they do not contain metal cofactors and lack aminopeptidase activity.
Protein YciF (YciF)
Type: Family

This family includes poorly characterised bacterial proteins, such as YciF from Escherichia coli. This protein is produced by bacteria in response to stress conditions. It adopts a dimeric configuration in which each monomer shows five α-helices. Its function is still unknown .
Arylsulfatase B (ARSB)
Type: Family

This family represents Arylsulfatase B (ARSB) and its paralogues, ARSI and ARSJ. ARSB removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation . It is involved in the regulation of cell adhesion, cell migration and invasion in colonic epithelium . ARSI displays arylsulfatase activity at neutral pH, when co-expressed with SUMF1. Arylsulfatase activity has been detected in the secretion medium of retinal cell line, but no activity has been recorded when measured in cell extracts .