SII-SWORD/CoKE huggingface dataset:
G2 nidogen/fibulin G2F (G2_nidogen/fibulin_G2F)
Type: Domain

Basement membranes are sheet-like extracellular matrices found at the basal surfaces of epithelia and condensed mesenchyma. By preventing cell mixing and providing a cell-adhesive substrate, they play crucial roles in tissue development and function. Basement membranes are composed of an evolutionarily ancient set of large glycoproteins, which includes members of the laminin family, collagen IV, perlecan and nidogen/entactin . Nidogen/entactin is an important basement membrane component, which promotes cell attachment, neutrophil chemotaxis, trophoblast outgrowth, and angiogenesis and interacts with many other basement membrane proteins, like collagen, perlecan, lamin, and has a potential role in the assembly and connection of networks. It consists of three globular regions, G1-G3. G1 and G2 are connected by a thread-like structure, whereas that between G2 and G3 is rod-like .

The nidogen G2 region binds to collagen IV and perlecan. The nidogen G2
structure is composed of two domains, an N-terminal EGF-like domain and a much larger β-barrel domain of ~230 residues. The nidogen G2 β-barrel consists of an 11-stranded β-barrel of complex topology, the interior of which is traversed by the hydrophobic, predominantly α helical segment connecting strands C and D. The N-terminal half of the barrel comprises two β-meanders (strands A-C and D-F) linked by the buried α-helical segment. The polypeptide chain then crosses the bottom of the barrel and forms a five-stranded Greek key motif in the C-terminal half of the domain. Helix alpha3 caps the top of the barrel and forms the interface to the EGF-like domain. The nidogen G2 β-barrel domain has unexpected structural similarity to green fluorescent proteins of Cnidaria, suggesting that they derive from a common ancestor. A large surface patch on the barrel surface is strikingly conserved in all metazoan nidogens. Site-directed mutagenesis demonstrates that the conserved residues in the conserved patch are involved in the binding of perlecan, and possibly also of collagen IV .

A similar domain is also found in hemicentin, a protein which functions at various cell-cell and cell-matrix junctions and might assist in refining broad regions of cell contact into oriented, line-shaped junctions .
BBSome complex member BBS5 (BBL5)
Type: Family

BBSome complex member BBS5 is part of the BBSome complex that may function as a coat complex required for sorting of specific membrane proteins to the primary cilia . Mutations in the BBS5 gene cause Bardet-Biedl syndrome 5, which is a syndrome characterised by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation .
LARP1-like, DM15 repeat (DM15)
Type: Repeat

This repeat is found in a highly conserved C-terminal region of La-related protein 1 (LARP1). LARP1 is implicated in the stability, localisation, and translational efficiency of mRNAs required for cell development, migration, division, and general translation . Upregulation of this protein occurs in several cancers and is correlated with tumor progression and adverse clinical outcome . LARP1 is found in eukaryotes and has been shown to play conserved roles in regulating the stability of mRNAs across the animal and plant kingdoms.

In all eukaryotes, except for Ascomycota fungi, LARP1 possesses three related, well-conserved, DM15 repeats. The structure of the LARP1 region that spans these repeats has been solved and it folds into a typical α-α superhelix. Each of the DM15 repeats adopts an α-helical hairpin and these pack against each other to form an elongated globular domain . LARP1 DM15 domain directly binds to the cap of TOP mRNA. Residues from each of the conserved DM15 repeats participate in the recognition of the invariant cytidine in the first position of TOP mRNAs .
Coiled-coil and C2 domain-containing protein 1, DM14 domain (CC2D1A/B_DM14)
Type: Domain

This is a short helical domain found in multiple copies in most members of this entry. In CC2D1A/B proteins is present four times. Its function is not yet known .

This entry includes coiled-coil and C2 domain-containing protein 1A/B (CC2D1A/B, also known as Freud-1/2). CC2D1A is involved in many pathways, including nuclear factor kappaB, PDK1/Akt, cAMP/PKA, Notch and bone morphogenetic protein . It is a calcium-regulated repressor of serotonine receptor 5-HT1A and dopamine-D2 receptor expression . CC2D1B binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons .

CC2D1A and CC2D1B have also been shown to interact with the CHMP4 family of proteins, the major subunit of the ESCRT-III complex. They may regulate degradation and signaling of EGFR and TLR4 .

CC2D1A and CC2D1B share conserved domains, including several DM14 domains that are specific to this protein family, a C-terminal helix-loop-helix domain, and a C2 domain. The CC2D1A C2 domain is thought to be calcium insensitive and it lacks several acidic residues that mediate calcium binding of the PKC C2 domain. In addition, it contains a poly-basic insert that is not present in calcium-dependent C2 domains and may function as a nuclear localization signal . The CC2D1B C2 domain appears to be essential for its DNA binding and repressor function; it may mediate protein-protein interactions .
Domain of unknown function DM7 (DM7)
Type: Domain

This domain of unknown function has been found in a number of Drosophila proteins that belong to DM7 family.
Protein of unknown function DUF1431, cysteine-rich, Drosophila (DUF1431_DROsp)
Type: Family

This cysteine-rich family of proteins has currently only been identified in Drosophila species.
THAP-type zinc finger (THAP_Znf)
Type: Domain

The THAP-type zinc finger (consensus: C-x(2,4)-C-x(35,50)-C-x(2)-H) is an ~90-residue domain restricted to animals, which is shared between the THAP family of cellular DNA-binding proteins, and transposases from mobile genomic parasites . THAP1, the prototype of the THAP family, possesses zinc-dependent sequence-specific DNA binding activity and recognizes a consensus DNA target sequence of 11 nucleotides . The THAP-type zinc finger can be found in one or more copies and can be associated with other domains, such as the C2H2-type zinc finger.

The structure of the THAP-type zinc finger reveals the presence between the C2CH zinc coordinating residues of a short antiparallel β-sheet interspersed by a long loop-helix-loop insertion. This loop-helix-loop motif has been shown to be essential for the identification of a number of critical residues for DNA recognition .
Peroxin/Ferlin domain (Peroxin/Ferlin)
Type: Domain

These two closely linked domains are found in ferlin gene family members and in peroxisomal membrane proteins (peroxins). The function of the domains is unknown.
Peptidase C19, ubiquitin-specific peptidase, DUSP domain (Pept_C19_DUSP)
Type: Domain

Deubiquitinating enzymes (DUB) form a large family of cysteine protease that can deconjugate ubiquitin or ubiquitin-like proteins (see

) from ubiquitin-conjugated proteins. All DUBs contain a catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. The ~120-residue DUSP (domain present in ubiquitin-specific proteases) domain is one of these specific subdomains. Single or tandem DUSP domains are located both N- and C-terminal to the ubiquitin carboxyl-terminal hydrolase catalytic core domain (see

) .
DM9 repeat (DM9_repeat)
Type: Repeat

This repeat of unknown function was identified in Diptera proteins; later on, it was also found in a wide range of invertebrates and vertebrates , such as natterin . It is often present in proteins comprising only two or four DM9 repeats and occasionally is linked to other domains at its N-or C-terminal. In the mannose-specific lectin CGL1 from Crassostrea gigas, DM9 exhibit high binding specificity and avidity toward D-mannose residue and served as a pattern recognition receptor (PRR) with a broad range of recognition spectrum to various pathogen-associated molecular patterns . It also mediates immune recognition and cellular encapsulation .
Peptidoglycan recognition protein family domain, metazoa/bacteria (PGRP_domain_met/bac)
Type: Domain

This domain is found in a family of animal peptidoglycan recognition proteins homologous to Bacteriophage T3 lysozyme , and some bacterial homologues. The bacteriophage molecule, but not its moth homologue, has been shown to have N-acetylmuramoyl-L-alanine amidase activity. One member of this family, Tag7, is a cytokine .
Prolyl 4-hydroxylase, alpha subunit (Pro_4_hyd_alph)
Type: Domain

Mammalian prolyl 4-hydroxylase alpha catalyses the posttranslational formation of 4-hydroxyproline in -xaa-pro-gly-sequences in collagens and other proteins. Prokaryotic enzymes might catalyse hydroxylation of antibiotic peptides. These are 2-oxoglutarate-dependent dioxygenases, requiring 2-oxoglutarate and dioxygen as cosubstrates and ferrous iron as a cofactor .
Nose resistant-to-fluoxetine protein, N-terminal (Nose-resist-to-fluoxetine_N)
Type: Domain

This is the N-terminal domain of Caenorhabditis elegans NRF-6 (Nose Resistant to Fluoxetine-4) and NDG-4 (resistant to nordihydroguaiaretic acid-4) proteins; the domain is also present in several other worm and fly proteins. NRF-6 and NDG-4 are multipass transmembrane proteins which may act together in a complex to function to transport fluoxetine across the hypodermal barrier to the inside of the animal, where it can then act on neuromuscular targets to induce muscle contraction.The complex may more generally play a role in regulation of membrane transport in C. elegans .
Testicular haploid expressed repeat (THEG)
Type: Repeat

Repeats found in the Mus musculus (Mouse) and Homo sapiens (Human) THEG (testicular haploid expressed gene) proteins and several Drosophila melanogaster (Fruit fly) proteins .

This repeat is the only conserved part of the THEG proteins from vertebrate spermatids. Both human and mouse THEG are specifically expressed in the nucleus of haploid male germ cells and are involved in the regulation of nuclear functions . Although the differential gene expression of THEG in spermatid-Sertoli cell co-culture supports the relevance of germ cell-Sertoli cell interaction for gene regulation during spermatogenesis, THEG was not found to be essential for spermatogenesis in mice .
Beta-propeller repeat TECPR (Beta-propeller_rpt_TECPR)
Type: Repeat

Tectonins I and II are two dominant proteins in the nuclei and nuclear matrix from plasmodia of Physarum polycephalum (Slime mold) which encode 217 and 353 amino acids, respectively. Tectonin I is homologous to the C-terminal two-thirds of tectonin II. Both proteins contain six tandem repeats that are each 33-37 amino acids in length and define a new consensus sequence. Homologous repeats are found in L-6, a bacterial lipopolysaccharide-binding lectin from horseshoe crab hemocytes. The repetitive sequences of the tectonins and L-6 are reminiscent of the WD repeats of the beta-subunit of G proteins, suggesting that they form β-propeller domains. The tectonins may be lectins that function as part of a transmembrane signalling complex during phagocytosis . It has been demonstrated that tectonin β-propeller repeat-containing protein 1 (TECPR1) has a critical function during autophagosome maturation and autophagosome-lysosome fusion .
Parallel beta-helix repeat (PbH1)
Type: Repeat

The tertiary structures of pectate lyases and rhamnogalacturonase A show a stack of parallel β-strands that are coiled into a large helix. Each coil of the helix represents a structural repeat that, in some homologues, can be recognised from sequence information alone. Conservation of asparagines might be connected with asparagine-ladders that contribute to the stability of the fold. Proteins containing these repeats most often are enzymes with polysaccharide substrates .
TDU repeat (TDU_repeat)
Type: Repeat

The mammalian TEF and the Drosophila scalloped genes belong to a conserved family of transcriptional factors that possesses a TEA/ATTS DNA-binding domain. Transcriptional activation by these proteins likely requires interactions with specific coactivators. In Drosophila, Scalloped (Sd) interacts with Vestigial (Vg) to form a complex, which binds DNA through the Sd TEA/ATTS domain. The Sd-Vg heterodimer is a key regulator of wing development, which directly controls several target genes and is able to induce wing outgrowth when ectopically expressed. The human protein, TONDU, contains a short domain homologous to the domain of Vg required for interaction with Sd. TONDU specifically interacts with a domain conserved in all the mammalian TEF factors .
Purine-rich element binding protein family (PUR-bd_fam)
Type: Family

The purine-rich element binding (Pur) protein family protein consists of DNA-binding proteins from animals, plants and bacteria, including PURalpha/beta/gamma from humans, Pur-alpha 1 from Arabidopsis thaliana and Transcriptional/translational repressor BpuR from Borreliella burgdorferi. Human Pur-alpha is a highly conserved, sequence-specific DNA-and RNA-binding protein involved in diverse cellular and viral functions including transcription, replication, and cell growth. It has a modular structure with alternating three basic aromatic class I and two acidic leucine-rich class II repeats in the central region of the protein . BpuR binds DNA adjacent to the erp transcriptional promoter. It inhibits transcription from the promoter in combination with BpbA .
LPS-induced tumour necrosis factor alpha factor (LITAF)
Type: Domain

LITAF (LPS-induced TNF-activating factor) (also known as SIMPLE; small integral membrane protein of the late endosome) is an endosome-associated integral membrane protein important for multivesicular body (MVB) sorting. It is a monotypic membrane protein with both termini exposed to the cytoplasm and is anchored to membranes via an in-plane helical membrane anchor, present within the highly conserved C-terminal region known as the 'LITAF domain' or 'SIMPLE-like domain'. The LITAF domain consists of conserved cysteines separated by a 22 residue hydrophobic region. LITAF domains are found throughout the eukaryotes, suggesting ancient conserved functions, with multiple instances of expansion, especially in the metazoa .

The LITAF domain consists of five β-sheets, three N-terminal and two C- terminal to the predicted hydrophobic anchor region and is stabilized by the coordination of a zinc atom by two pairs of evolutionarily conserved cysteine residues. Consistent with a protein domain that resides in close proximity to membranes, specific residues within the LITAF domain interact with phosphoethanolamine (PE) head groups. The anchoring-region of the LITAF domain is likely to embed into the cytosolic-facing monolayer of the membrane bilayer by adopting an amphipathic character .
La-type HTH domain (La_HTH)
Type: Domain

This domain is found at the N terminus of La RNA-binding proteins as well as other proteins .

Human Ro ribonucleoproteins (RNPs) are composed of one of the four small Y RNAs and at least two proteins, Ro60 and La. The La protein is a 47kDa polypeptide that frequently acts as an autoantigen in systemic lupus erythematosus and Sjogren's syndrome . In the nucleus, La acts as a RNA polymerase III (RNAP III) transcription factor, while in the cytoplasm, La acts as a translation factor . In the nucleus, La binds to the 3'UTR of nascent RNAP III transcripts to assist in folding and maturation . In the cytoplasm, La recognises specific classes of mRNAs that contain a 5'-terminal oligopyrimidine (5'TOP) motif known to control protein synthesis . The specific recognition is mediated by the N-terminal domain of La, which comprises a La motif and a RNA recognition motif (RRM). The La motif adopts an α/β fold that comprises a winged-helix motif .

Homologous La domain-containing proteins have been identified in a wide range of organisms except Archaea, bacteria and viruses .
Protein of unknown function DM4/12 (DM4_12)
Type: Family

This domain of unknown function is found in primarily in Drosophila melanogaster (Fruit fly) proteins of unknown function.
Carbohydrate-binding/sugar hydrolysis domain (Carb-bd_sugar_hydrolysis-dom)
Type: Domain

The CASH domain is shared by many carbohydrate-binding proteins and sugar hydrolases. The CASH domain is characterised by internal repetitions of glycines and hydrophobic residues that correspond to the repetitive units of a predicted or observed right-handed β-helix structure of the pectate lyase superfamily. The basic structural unit of this family consists of three β-strands that form a single turn of the β-helix. Each turn contains ~20 amino acids, and is normally repeated between 7 and 11 times to form the elongated helix structure. The repeats show a low degree of sequence identity when compared with each other. The region of homology with the CASH domain corresponds to the core region of the β-helix, covering from the second to the sixth repeat .
TRAM/LAG1/CLN8 homology domain (TLC-dom)
Type: Domain

TLC is a protein domain with at least 5 transmembrane α-helices. Lag1p and Lac1p are essential for acyl-CoA-dependent ceramide synthesis , TRAM is a subunit of the translocon and the CLN8 gene is mutated in Northern epilepsy syndrome. Proteins containing this domain may possess multiple functions such as lipid trafficking, metabolism, or sensing. Trh homologues possess additional homeobox domains .
NEAT domain (NEAT_dom)
Type: Domain

This domain identifies a group of iron-regulated surface determinant proteins found exclusively in bacteria. Among them, the iron-regulated surface determinant protein H (isdH, also known as harA) binds human plasma haptoglobin-hemoglobin complexes, haptoglobin and hemoglobin. It binds haptoglobin-hemoglobin complexes with significantly higher affinity than haptoglobin alone . In Staphylococcus aureus, isdH protein contains three NEAT (NEAr Transporter) domains: IsdH(N1), IsdH(N2), and IsdH(N3). These three domains have different functions, IsdH(N1) binds hemoglobin and haptoglobin, whereas IsdH(N3) captures heme that is released from hemoglobin .
Heat shock chaperonin-binding (STI1_HS-bd)
Type: Domain

This entry represents a heat shock chaperonin-binding domain found in human Stress-inducible phosphoprotein STI1 and similar sequences found in eukaryotes. STI1 acts as a co-chaperone for HSP90AA1 . Both N- and C-terminal ends of STI1 are capable of binding heat shock proteins . This domain is found both singly and duplicated in different proteins. This domain shows an α-helical structure .
Clostridial hydrophobic repeat (ChW)
Type: Repeat

This hydrophobic repeat is found in a number of proteins from Clostridium and other bacteria. It contains a conserved tryptophan residue.
Elp3/MiaA/NifB-like, radical SAM core domain (Elp3/MiaA/NifB-like_rSAM)
Type: Domain

This domain is found in FeMo cofactor biosynthesis protein NifB, PqqA peptide cyclase, Oxygen-independent coproporphyrinogen III oxidase (HemN), biotin synthase (BioB), Lipoyl synthase (LipA), Ribosomal protein S12 methylthiotransferase RimO, GTP 3',8-cyclase (MoaA) and tRNA-2-methylthio-N(6)-dimethylallyladenosine synthase (MiaB), and similar proteins found in cellular organisms. This group includes a representative in the eukaryotic elongator
subunit, Elp-3. Some members of this entry are methyltransferases .
Presenilin/signal peptide peptidase (Preselin/SPP)
Type: Family

Presenilin 1 (PSN1) and presenilin 2 (PSN2) are membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. They undergo tightly regulated endolytic processing to generate stable PSN C-terminal and N-terminal fragments that form the catalytic core of the gamma-secretase complex, an endoprotease complex that catalyses the intramembrane cleavage of integral membrane proteins such as Notch receptors .

Presenelins are related to the signal peptide peptidase (SPP) family of aspartic proteases that promote intramembrane proteolysis to release biologically important peptides. However, the SPPs work as single polypeptides. SPP catalyses intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. In humans, SPP activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognised by the immune system, and are required in the processing of the hepatitis C virus core protein .

This group of aspartic peptidases belong to MEROPS peptidase family A22 (presenilin family, clan AD).
SprT-like (SprT-like_domain)
Type: Domain

This entry represents a domain found in SprT (

), which is a regulator of bolA gene in stationary phase . The majority of members contain the metallopeptidase zinc binding signature which has a HExxH motif, however there is no evidence for them being metallopeptidases.
YqgF/RNase H-like domain (YqgF/RNaseH-like_dom)
Type: Domain

The YqgF domain family is described as RNase H-like and typified by the Escherichia coli protein YqgF .YqgF domain-containing proteins are predicted to be ribonucleases or resolvases based on homology to RuvC Holliday junction resolvases.

The group of proteins containing this domain are found primarily in the low-GC Gram-positive bacteria Holliday junction resolvases (HJRs) and in eukaryote orthologs. The RuvC HJRs are conspicuously absent in the low-GC Gram-positive bacterial lineage, with the exception of Ureaplasma urealyticum(

, ). Furthermore, loss of function ruvC mutants of Escherichia coli show a residual HJR activity that cannot be ascribed to the prophage-encoded RusA resolvase . This suggests that the YqgF family proteins could be alternative HJRs whose function partially overlaps with that of RuvC .

The functions of eukaryotic proteins having this domain are less well described. In Saccharomyces cerevisiae (Baker's yeast) Spt6p and its orthologues, the catalytic residues are substituted indicating that they lack the enzymatic function of resolvases . Spt6p has been implicated in transcription initiation and in maintaining normal chromatin structure during transcription elongation .

Horizontal gene transfer, lineage-specific gene loss and gene family expansion, and non-orthologous gene displacement seem to have been major forces in the evolution of HJRs and related nucleases. The diversity of HJRs and related nucleases in bacteria and archaea contrasts with their near absence in eukaryotes. The few detected eukaryotic representatives of the endonuclease fold and the RNase H fold have probably been acquired from bacteria via horizontal gene transfer. The identity of the principal HJR(s) involved in recombination in eukaryotes remains uncertain; this function could be performed by topoisomerase IB or by a novel, so far undetected, class of enzymes. Likely HJRs and related nucleases were identified in the genomes of numerous bacterial and eukaryotic DNA viruses. Gene flow between viral and cellular genomes has probably played a major role in the evolution of this class of enzymes.

The YqgF domain is also found in Tex proteins, where maintains the core structural elements and aligns especially well with RuvC nucleases, although Tex does not appear to possess nuclease activity . Tex (toxin expression) is a highly conserved bacterial protein involved in expression of critical toxin genes .