SII-SWORD/CoKE huggingface dataset:
U3 small nucleolar RNA-associated protein 4 (UTP4)
Type: Family

This family includes U3 small nucleolar RNA-associated protein 4 (UTP4), a ribosome biogenesis factor that is involved in nucleolar processing of pre-18S ribosomal RNA. In yeast, it is required for optimal pre-ribosomal RNA transcription by RNA polymerase I , while in human is required for pre-rRNA processing .
MTMR3, protein tyrosine phosphatase domain (MTMR3_PTP)
Type: Domain

This entry represents the protein tyrosine phosphatase domain of Myotubularin-related protein 3 (MTMR3). MTMR3 specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate . It may also de-phosphorylate proteins phosphorylated on Ser, Thr, and Tyr residues . This enzyme has shown to play a regulatory role in the regulation of abscission, the final step of mitosis , and innate immune responses to viral DNA through the modulation of STING trafficking .
Cystathionine beta-synthase, C-terminal domain (CBS_C)
Type: Domain

This entry represents the C-terminal region of Cystathionine beta-synthase (CBS), which includes two tandem repeats of the CBS domain. CBS is an hydro-lyase that catalyses the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine. This catabolic route allows the elimination of L-methionine and the toxic metabolite L-homocysteine . This protein is also involved in the production of hydrogen sulphide, a gasotransmitter with signalling and cytoprotective effects on neurons .

CBS domains are evolutionarily conserved structural domains found in a variety of non functionally-related proteins from all kingdoms of life. These domains pair together to form a intramolecular dimeric structure (CBS pair), termed Bateman domain . CBS domains have been shown to bind mainly ligands with an adenosyl group such as AMP, ATP and S-AdoMet, but may also bind metal ions, or nucleic acids . Hence, they play an essential role in the regulation of the activities of numerous proteins, and mutations in them are associated with several hereditary diseases . CBS domains are found attached to a wide range of other protein domains suggesting that CBS domains may play a regulatory role making proteins sensitive to adenosyl-carrying ligands. The region containing the CBS domains in cystathionine-beta synthase is involved in regulation by S-AdoMet . CBS domain pairs from AMPK bind AMP or ATP . The CBS domains from IMPDH, which bind ATP, have shown to have a role in the regulation of adenylate nucleotide synthesis .
Sperm acrosome membrane-associated protein 4/Protein Bouncer (SPACA4/Bouncer)
Type: Family

This entry includes proteins from chordates that contain a UPAR/Ly6 domain, including Sperm acrosome membrane-associated protein 4 (SPACA4) from humans and Protein Bouncer (Bncr) from Danio rerio (Zebrafish).

SPACA4 (also known as Sperm acrosomal membrane-associated protein 14) is a sperm surface membrane protein that may be involved in sperm-egg plasma membrane adhesion and fusion during fertilization .

Bncr is an oocyte-expressed fertilization factor that mediates sperm-egg binding and is essential for sperm entry into the egg and to mediate species-specific gamete recognition and fertilization, which is vital for vertebrate species performing external fertilization .
GRB2-associated-binding protein 1-4-like (Gab1-4-like)
Type: Family

This entry represents GRB2-associated-binding proteins 1-4 (Gab1-4) and similar proteins from animals. Proteins in this family contain one PH domain. GAB1 from humans and its orthologues dos and soc-1 from Drosophila and C. elegans , respectively, function as adapter proteins that modulate intracellular signalling cascades triggered by activated receptor-type kinases. Gab1 from human plays a role in FGFR1 signalling, is involved in the MET/HGF-signalling pathway and functions as an important upstream regulator in EGF-mediated activation of mTORCs .
E3 ubiquitin-protein ligase MARCHF4/9/11 (MARCHF4/9/11)
Type: Family

This entry represents E3 ubiquitin-protein ligases MARCHF4, 9 and 11 predominantly found in chordates. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Members of this small protein family contain a RING-CH-type zinc finger domain and are integrated into the cellular membrane .

MARCHF4 and 9 are closely related. These proteins reduce the surface expression of major histocompatibility complex class I (MHC I), and downregulate CD4. They promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. MARCHF4 appears to be mainly expressed in the brain. MARCHF9 controls the expression of the critical cell adhesion molecule ICAM-1 .

MARCHF11, identified later, is also involved in the regulation of the poly-ubiquitination of CD4. This protein seems to be specifically expressed in the early developmental stages of spermatids . SAMT family proteins have been identified as substrates of MARCH11 in mouse spermatids, suggesting that MARCH11 plays a role in mammalian spermatogenesis .
Peptidyl-prolyl cis-trans isomerase domain superfamily (PPIase_dom_sf)
Type: Homologous_superfamily

This superfamily represents the peptidyl-prolyl cis-trans isomerase domain found in a wide range of proteins, including trigger factor , FK506-binding proteins , proteins from the parvulin family such as Par10 from E.coli, Pin1 and Par14 from human or Pin from plants , chaperone SurA and foldase protein PrsA . This domain catalyses cis/trans isomerization of peptidyl-prolyl bonds, which is often rate-limiting for protein folding.

This domain consists of a flattened β-barrel of four/six-stranded, antiparallel sheets, surrounded by four/six α-helices.
Flagellin, C-terminal domain (Flagellin_C)
Type: Domain

Bacterial flagella are responsible for motility and chemotaxis . They comprise a basal body, a hook and a filament, the latter accounting for 98% of the mass . Flagellin is the subunit protein that polymerises to form the flagella , the subunits being transported through the centre of the filament to the tip, where they then polymerise . Both the N- and C- termini of the subunit protein, which are α-helical in structure , are required to mediate polymerisation. Although no export or assembly, consensus sequences have been identified: Ala, Val, Leu, Ile, Gly, Ser, Thr, Asn, Gln and Asp tend to make up around 90% of the sequence, Cys and Trp being absent .

Flagellin plays a role in the activation of innate and adaptive immunity. It is an specific ligand for Toll-like receptor 5 (TLR5) in the host, which has lead to great interest to use it as adjuvant for vaccines . The protein is also recognised by the intracellular NAIP5/NLRC4 inflammasome receptor .

This entry represents the C-terminal domain of Flagellin and similar bacterial proteins. This domain comes together with the N-terminal domain (

) to form the D0 and D1 structural domains . These domains are responsible for the activation of TLR5, with the C-terminal D0 region playing a key role .
Aftiphilin-like (Aftin-like)
Type: Family

This entry represents Aftiphilin and related proteins from animals, including Uncharacterised protein CLBA1 (Clathrin-binding box of aftiphilin-containing protein 1). Aftin forms a stable complex with p200 and gamma-synergin . It may play a role in membrane trafficking. Aftiphilin contains a clathrin box, with two identified clathrin-binding motifs .
T-box transcription factor, DNA-binding domain (T-box_DNA-bd)
Type: Domain

This is the highly conserved DNA-binding domain of T-box transcription factors.

Transcription factors of the T-box family are required both for early cell-fate decisions, such as those necessary for formation of the basic vertebrate body plan, for differentiation and organogenesis and also have been associated to multiple aspects of development and in adult terminal cell-type differentiation in different animal lineages . The T-box is defined as the minimal region within the T-box protein that is both necessary and sufficient for sequence-specific DNA binding, all members of the family so far examined bind to the DNA consensus sequence TCACACCT and function as transcriptional repressors and/or activators . The T-box is a relatively large DNA-binding domain, generally comprising about a third of the entire protein (17-26kDa) .

These genes were uncovered on the basis of similarity to the DNA binding domain of Mus musculus (Mouse) Brachyury (T) gene product, which similarity is the defining feature of the family. The Brachyury gene is named for its phenotype, which was identified 70 years ago as a mutant mouse strain with a short blunted tail. The gene, and its paralogues, have become a well-studied model for the family, and hence much of what is known about the T-box family is derived from the murine Brachyury gene.

Consistent with its nuclear location, Brachyury protein has a sequence-specific DNA-binding activity and can act as a transcriptional regulator . Homozygous mutants for the gene undergo extensive developmental anomalies, thus rendering the mutation lethal . The postulated role of Brachyury is as a transcription factor, regulating the specification and differentiation of posterior mesoderm during gastrulation in a dose-dependent manner .

T-box proteins tend to be expressed in specific organs or cell types, especially during development, and they are generally required for the development of those tissues, for example, Brachyury is expressed in posterior mesoderm and in the developing notochord, and it is required for the formation of these cells in mice .
Exocyst complex subunit EXOC6/Sec15, C-terminal (EXOC6/Sec15_C)
Type: Domain

This entry represents the C-terminal domain of Sec15 subunit, which has the conserved CATCHR fold consisting of α-helical bundles .

Sec15 is a component of the exocyst complex involved in the the tethering of post-Golgi Golgi secretory vesicles to the plasma membrane during exocytosis and plays a role in several cellular functions such as cell polarisation, cytokinesis, ciliogenesis and tumour invasion. The exocyst is one of the members of the complexes associated with tethering containing helical rods (CATCHR), together with COG, GARP, and Dsl1 complexes, which share a fold consisting of α-helical bundles forming a rod structure . Its C-terminal domain mediates Rab GTPases binding which occurs in a GTP-dependent manner .
Zw10/DSL1, C-terminal (Zw10/DSL1_C_sf)
Type: Homologous_superfamily

Zeste white 10 (ZW10) was initially identified as a mitotic checkpoint protein involved in chromosome segregation as part of the RZZ (Rod-Zwilch-Zw10) complex, and then implicated in targeting cytoplasmic dynein and dynactin to mitotic kinetochores, but it is also important in non-dividing cells. These include cytoplasmic dynein targeting to Golgi and other membranes, and SNARE-mediated ER-Golgi trafficking in the context of Zw10-Rint1-Nag complex which are DSL11, Tip20, and Sec39 orthologues, respectively . Yeast DSL1, is a peripheral membrane protein required for transport between the Golgi and the endoplasmic reticulum, part of the Dsl1p complex (Dsl1Tip20-Sec20-Sec39) . These proteins are members of the CATCHR (complexes associated with tethering containing helical rods) family which includes subunits of evolutionarily related complex, such as conserved oligomeric Golgi (COG), Golgi-associated retrograde protein (GARP) and exocyst .
Malate synthase, N-terminal and TIM-barrel domains (MS_N_TIM-barrel_dom)
Type: Homologous_superfamily

Malate synthase (MS) (

) catalyses the aldol condensation of glyoxylate with acetyl-CoA to form malate as part of the second step of the glyoxylate bypass and an alternative to the tricarboxylic acid cycle in bacteria, fungi and plants. There have been identified two isoforms, A and G (MSA and MSG, respectively) that differ in size and is attributed to an inserted α/β domain in MSG that may have regulatory function . MSA and MSG consist of an N-terminal α-helical clasp domain, a central TIM-barrel domain and a C-terminal helical plug domain. In malate synthases, the TIM β/α-barrel fold and the C-terminal helical domain are well conserved and the cleft between them forms the active site .

This entry covers the N-terminal clasp and the TIM-barrel domains of malate synthases.
Exocyst complex subunit Exo70, C-terminal (Exo70_C)
Type: Domain

This is the C-terminal domain of Exo70, which consists of α-helical bundles involved in binding the small GTPase Rho3 and is important for localization to the membrane as it directly interacts with phosphatidylinositol 4,5-bisphosphate . The interaction with phospholipids is essential for the membrane association of the exocyst complex.

The Exo70 protein forms one subunit of the exocyst complex (consist of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84 in budding yeast). First discovered in Saccharomyces cerevisiae , it is evolutionarily conserved in eukaryotes. It mediates the tethering of post-Golgi secretory vesicles to the plasma membrane and promotes the assembly of the SNARE complex for membrane fusion. It also plays a role in cell polarisation, primary ciliogenesis, cytokinesis, pathogen invasion, tumourigenesis and metastasis . It is a member of the the Complex Associated with Tethering Containing Helical Rods (CATCHRs) family which also includes Conserved Oligomeric Golgi complex (COG) and Golgi-Associated Retrograde Protein complex (GARP) and DSL1 complexes, all evolutionarily related and share structural features consisting of α-helical bundles at the C terminus and coiled-coil region at the N terminus . Exo70 interacts with phospholipids the Rho3 GTPase . This interaction with Rho3 mediates one of the three known functions of Rho3 in cell polarity: vesicle docking and fusion with the plasma membrane (the other two functions are regulation of actin polarity and transport of exocytic vesicles from the mother cell to the bud) .
FAM124 domain (FAM124_dom)
Type: Domain

The FAM124 domain belongs to the Vicnial oxygen chelatase (VOC) superfamily of proteins and is comprised of two tandem α/β domains. Residue conservation suggests that it might be enzymatic. Certain FAM124 domains fused to the TRADD-N domain are predicted to have secondarily lost their enzymatic activity and might be involved in protein-protein interactions .
ER-bound oxygenase mpaB/B' (MPAB)
Type: Family

This entry includes the endoplasmic reticulum (ER)-bound oxygenases mpaB' (MPAB2) and mpaB (MPAB) from Penicillium brevicompactum and Penicillium roqueforti, respectively, which are part of the gene cluster that mediates the biosynthesis of mycophenolic acid (MPA) and mediates the oxidative cleavage the C19-C20 double bond in farnesyl-DHMP (FDHMP) to yield FDHMP-3C via a mycophenolic aldehyde intermediate . This entry also includes uncharacterised sequences from bacteria.
GapR-like, DNA-binding domain (GapR-like_DNA-bd)
Type: Domain

GapR is a nucleoid-associated protein (NAP) critical for cellular function in Caulobacter crescentus (also known as Caulobacter vibrioides). Loss of GapR causes severe defects in growth, cell division, DNA replication, and chromosome segregation . This is a DNA-binding protein which has mainly an α-helical secondary structure. In the absence of DNA, GapR is a dimer, with each monomer folded into two extended α-helices, while in the presence of DNA, GapR forms a tetramer, with the C-terminal α-helix of each monomer reorganised into two shorter helices, which allows GapR to encircle the DNA .

This the DNA-binding domain of GapR from Caulobacter crescentus and related sequences. This domain is not only highly conserved in alphaproteobacteria, it is also present in cyanobacteria, firmicutes, planctomycetes, actinobacteria, and even archaea and eukaryotes, possibly through horizontal gene transfer. This domain is also found in phages, in which is associated to DNA-related processes .
Tag1 (Tag1)
Type: Family

This fungal family includes Tag1 (also known as YLR173W), a vacuolar membrane protein involved in termination of autophagy. It regulates autophagy termination during persistent nitrogen starvation through Atg1p-mediated re-phosphorylation of Atg13p and PAS disassembly . This is a type II membrane protein containing a hydrophobic transmembrane region, with the N-terminal region oriented toward the cytosol and the C-terminal inside the lumen, which is glycosylated. Tag1, together with Vac7 from yeast and TMEM106B from humans, has homology with LEA-2 domain. It has three tandemly repeated LEA-2 domains .
Mastermind-like 1-3 (MAML1-3)
Type: Family

This family includes the neurogenic mastermind-like proteins 1-3 (MAML1-3) from chordates, which act as critical transcriptional co-activators for Notch signalling . Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) , tumour suppressor pathway (p53) and colon carcinoma survival (beta-catenin) . MAML proteins could mediate cross-talk among the various signalling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.

They consist of an N-terminal domain which adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors . This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 , NOTCH2 , NOTCH3 and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP and CDK8 . The C-terminal region is required for transcriptional activation.
Neurogenic mastermind-like, N-terminal domain superfamily (MAML_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain found in a family of neurogenic mastermind-like proteins (MAMLs), which act as critical transcriptional co-activators for Notch signaling . Notch receptors are cleaved upon ligand engagement and the intracellular domain of Notch shuttles to the nucleus. MAMLs form a functional DNA-binding complex with the cleaved Notch receptor and the transcription factor CSL, thereby regulating transcriptional events that are specific to the Notch pathway. MAML proteins may also play roles as key transcriptional co-activators in other signal transduction pathways as well, including: muscle differentiation and myopathies (MEF2C) , tumour suppressor pathway (p53) and colon carcinoma survival (beta-catenin) . MAML proteins could mediate cross-talk among the various signaling pathways and the diverse activities of the MAML proteins converge to impact normal biological processes and human diseases, including cancers.

The N-terminal domain of MAML proteins adopt an elongated kinked helix that wraps around ANK and CSL forming one of the complexes in the build-up of the Notch transcriptional complex for recruiting general transcription factors . This N-terminal domain is responsible for its interaction with the ankyrin repeat region of the Notch proteins NOTCH1 , NOTCH2 , NOTCH3 and NOTCH4. It forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1, and also binds CREBBP/CBP and CDK8 . The C-terminal region is required for transcriptional activation.
Bcl-2, Bcl-2 homology region 1-3 (Bcl-2_BH1-3)
Type: Domain

B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes . Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways .

Bcl-2 and its relatives are functionally classified as either antiapoptotic or proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins .

The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif . Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins .

This entry covers the Bcl-2 homology regions 1, 2 and 3 (BH1-3).
Poly (ADP-ribose) glycohydrolase (PARG), catalytic domain (PARG_cat_C)
Type: Domain

This entry represents the Macro domain fold localised in the C-terminal end of PARG catalytic domain from animals, plants and some fungal species .

Poly(ADP-ribose) glycohydrolase (PARG) (

) is a ubiquitously expressed exo- and endoglycohydrolase which catalyses the hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, reversing the effects of poly(ADP-ribose) . It generates mono-ADP-ribosylated proteins in cells, due to its ability of degrading poly(ADP-ribose) without cleaving the terminal protein-ribose bond . PARG is also involved in the synthesis of nuclear ATP, which is required for extensive chromatin remodeling events . This protein mediates oxidative and excitotoxic neuronal death .

Arabidopsis thaliana PARG1 is involved in abiotic stress responses and DNA repair .
Acyl-CoA oxidase/dehydrogenase, middle domain superfamily (Acyl-CoA_Oxase/DH_mid-dom_sf)
Type: Homologous_superfamily

Acyl-CoA dehydrogenases (

) are a family of flavoproteins that catalyse the alpha,beta-dehydrogenation of acyl-CoA thioesters to the corresponding trans 2,3-enoyl CoA-products with the concomitant reduction of enzyme-bound FAD. Different family members share a high sequence identity, catalytic mechanisms, and structural properties, but differ in the position of their catalytic bases and in their substrate binding specificity. Butyryl-CoA dehydrogenase prefers short chain substrates, medium chain-and long-chain acyl-CoA dehydrogenases prefer medium and long chain substrates, respectively, and Isovaleryl-CoA dehydrogenase prefers branched-chain substrates.

The monomeric enzyme is folded into three domains of approximately equal size, where the N-terminal domain is all-α, the middle domain is an open (5,8) barrel, and the C-terminal domain is a four-helical bundle. The constituent families differ in the numbers of C-terminal domains. This entry represents the middle β-barrel domain found in medium chain acyl-CoA dehydrogenases, as well as in the related peroxisomal acyl-CoA oxidase-II enzymes. Acyl-CoA oxidase (ACO;

) catalyses the first and rate-determining step of the peroxisomal beta-oxidation of fatty acids .