SII-SWORD/CoKE huggingface dataset:
CDP-glycerol glycerophosphotransferase, N-terminal domain (TagF_N)
Type: Homologous_superfamily

Wall-associated teichoic acids are a heterogeneous class of phosphate-rich polymers that are covalently linked to the cell wall peptidoglycan of Gram-positive bacteria. They consist of a main chain of phosphodiester-linked polyols and/or sugar moieties attached to peptidoglycan via a linkage unit. CDP-glycerol:poly(glycerophosphate) glycerophosphotransferase TagF is responsible for the polymerisation of the main chain of the teichoic acid by sequential transfer of glycerol-phosphate units from CDP-glycerol to the linkage unit lipid . The TagF-like family of enzymes has been shown to be responsible for wall teichoic acid priming and polymerization events .

This entry represents the N-terminal domain of TagF which exhibits a Rossmann-fold and includes a small two α-helix region .
Phytochrome, PHY domain superfamily (Phytochrome_PHY_sf)
Type: Homologous_superfamily

Phytochromes form a major family of photoreceptors responsible for red light perception in plants, fungi and bacteria . They undergo reversible photoconversion between red-absorbing (Pr) and far-red-absorbing (Pfr) states, thereby ultimately converting a light signal into a distinct biological signal that mediates subsequent cellular responses . This entry represents the PHY domain of phytochrome which connects the chromophore binding domains PAS-GAF with the output kinase .
Bromo adjacent homology (BAH) domain superfamily (BAH_sf)
Type: Homologous_superfamily

This entry represents the BAH (bromo-adjacent homology) domain which is commonly found in chromatin-associated proteins . The BAH domain appears to act as a protein-protein interaction module specialised in gene silencing, as suggested for example by its interaction within yeast Orc1p with the silent information regulator Sir1p. The BAH module might therefore play an important role by linking DNA methylation, replication and transcriptional regulation .
DENN domain, C-terminal lobe (DENN_C)
Type: Homologous_superfamily

This entry represents the C-terminal lobe of the DENN domain, which consists of a 5-stranded β sheet surrounded by helices . It includes DENN domain found in MAP kinases, myotubularin, and DENN-containing proteins from eukaryotic organisms. It also includes the elicitor of plant defence protein 1 found in fungi.

The tripartite DENN (Differentially Expressed in Normal and Neoplastic Cells) domain is an evolutionarily conserved protein module found in several proteins involved in Rab-mediated processes and, in some cases, regulation of MAPK (Mitogen-Activated Protein Kinase) signalling pathways and related proteins in eukaryotic organisms. The DENN domain consists of three subdomains: uDENN (upstream DENN)

, the core DENN domain

, and dDENN (downstream DENN)

, which are structurally distinct but functionally interconnected due to their roles in Rab GTPase activation. Recent studies have confirmed the DENN domain's function as a guanine nucleotide exchange factor (GEF) for Rab GTPases, facilitating the exchange of GDP for GTP to activate Rabs. This activity has been demonstrated for various DENN proteins, such as DENND1A and DENND1B, which specifically activate Rab35, and DENND2B, which serves as a GEF for Rab10 and Rab13, influencing processes like primary ciliogenesis and epithelial cancer development .

The tripartite structure of the DENN domain, comprising uDENN, DENN itself, and dDENN, features distinct patterns of sequence conservation and variable interdomain lengths that suggest functional specialisation. Structural studies have revealed conserved residues critical for Rab binding and catalytic activity, emphasising the role of DENN domains in spatially and temporally regulating membrane trafficking events . Additionally, DENN domains are often associated with other domains such as RUN

, PLAT

, which may further enhance their functional versatility in cellular signalling pathways .

Some proteins known to contain a tripartite DENN domain include:

Human mitogen-activated protein kinase activating protein containing death domain (MADD)

, orthologous to Rab3GEP

Human SET domain-binding factor 1 (SBF1)

Human DENN domain-containing protein 2B

Human C-myc promoter-binding protein

In Arabidopsis, SCD1 is a unique gene encoding for the only protein containing a complete DENN domain. SCD1 is part of a protein complex that interacts with the exocyst complex and the RabE1 family of GTPases. It is also involved in activating innate immune responses against bacteria .

Recent findings highlight the broader target spectrum of DENN domains than previously appreciated. For example, DENND2B interacts with Rab35 as both an effector and a GEF at intercellular bridges during cytokinesis. These discoveries underscore the importance of DENN domain proteins in regulating diverse cellular processes such as vesicle trafficking, signal transduction, ciliogenesis, and cancer progression .
Sec1-like, domain 1 (Sec-1-like_dom1)
Type: Homologous_superfamily

This superfamily represents the domain 1 of Sec1 and related proteins.

Sec1-like molecules have been implicated in a variety of eukaryotic vesicle transport processes including neurotransmitter release by exocytosis . They regulate vesicle transport by binding to a t-SNARE from the syntaxin family. This process is thought to prevent SNARE complex formation, a protein complex required for membrane fusion. Whereas Sec1 molecules are essential for neurotransmitter release and other secretory events, their interaction with syntaxin molecules seems to represent a negative regulatory step in secretion .

The nSec1 polypeptide chain can be divided into three domains. The first domain, consists of a five-stranded parallel β-sheet flanked by five α-helices. The second domain, like the first one, has an α-β-α fold, however the β-sheet of domain 2 features five parallel strands with an additional antiparallel strand on one edge. The third domain is a large insertion between the third and fourth parallel strands of domain 2, and can be subdivided in two .

Members of the Sec1 family include Sec1, Sly1, Slp1/Vps33, Vps45/Stt10 (yeast), Unc-18 (nematode), Munc-18b/muSec1, Munc-18c (mouse), Rop (Drosophila), Munc-18/n-Sec1/rbSec1A and rbSec1B (rat) .
Vacuolar protein sorting-associated protein 33, domain 3b (VPS33_dom3b)
Type: Homologous_superfamily

Members of the Sec1 family include Sec1, Sly1, Slp1/Vps33, Vps45/Stt10 (yeast), Unc-18 (nematode), Munc-18b/muSec1, Munc-18c (mouse), Rop (Drosophila), Munc-18/n-Sec1/rbSec1A and rbSec1B (rat) .

The nSec1 polypeptide chain can be divided into three domains. The first domain, consists of a five-stranded parallel β-sheet flanked by five α-helices. The second domain, like the first one, has an α-β-α fold, however the β-sheet of domain 2 features five parallel strands with an additional antiparallel strand on one edge. The third domain is a large insertion between the third and fourth parallel strands of domain 2, and can be subdivided in two .

Vacuolar protein sorting-associated protein 33 (Vps33) is essential for vacuolar biogenesis, maturation and function. It is involved in the sorting of vacuolar proteins from the Golgi apparatus and their targeting to the vacuole . In worm, fly, zebrafish and mammals two homologues of yeast Vps33p have been detected (termed VPS33A and VPS33B in humans). These homologues may reflect the evolution of organelle/tissue-specific functions in multicellular organisms. It is thought that VPS33B may be required for transport to conventional lysosomes, while VPS33A is mainly involved in biogenesis of melanosomes and related lysosomal compartments .

This superfamily entry represents the C-terminal region of domain 3 (called domain 3b) found in VPS33.
Catalase, mono-functional, haem-containing, clade 2, helical domain (Catalase_clade2_helical)
Type: Homologous_superfamily

Catalases (

) are antioxidant enzymes that catalyse the conversion of hydrogen peroxide to water and molecular oxygen, serving to protect cells from its toxic effects . Hydrogen peroxide is produced as a consequence of oxidative cellular metabolism and can be converted to the highly reactive hydroxyl radical via transition metals, this radical being able to damage a wide variety of molecules within a cell, leading to oxidative stress and cell death. Catalases act to neutralise hydrogen peroxide toxicity, and are produced by all aerobic organisms ranging from bacteria to man. Most catalases are mono-functional, haem-containing enzymes, although there are also bifunctional haem-containing peroxidase/catalases (

) that are closely related to plant peroxidases, and non-haem, manganese-containing catalases (

) that are found in bacteria . Based on a phylogenetic analysis, catalases can be classified into clade 1, 2 and 3. Clade 1 contains small subunit catalases from plants and a subset of bacteria; clade 2 contains large subunit catalases from fungi and a second subset of bacteria; and clade 3 contains small subunit catalases from bacteria, fungi, protists, animals, and plants .

Structurally, catalases are composed of a long amino-terminal arm, an antiparallel eight-stranded β-barrel, an extended wrapping loop, a four-helical domain and, in large catalases, a carboxy-terminal domain with flavodoxin-like topology joined by a long loop . This entry represents the helical domain found in clade 2 of the mono-functional, haem-containing catalases.
Dynein heavy chain, AAA1 domain, small subdomain (Dynein_AAA1S)
Type: Homologous_superfamily

Dyneins are multiprotein complexes that move cargo along microtubules in the minus end direction. The largest component of the dynein complex is the heavy chain. Its C terminus forms the motor unit .

The 380kDa motor unit of dynein belongs to the AAA class of chaperone-like ATPases. The core of the 380kDa motor unit contains a concatenated chain of six AAA modules, of which four correspond to the ATP binding sites with P-loop signatures described previously, and two are modules in which the P loop has been lost in evolution. This domain is the D1 unit of the motor and contains the hydrolytic ATP binding site .

Each AAA domain can be subdivided into a "large" (AAAL) and a five helix bundle or "small" subdomain (AAAS). AAA1L, AAA1S and AAA2L enclose ADP.vanadate (ADP.Vi, ATP-hydrolysis transition state analogue). The AAA1L sensor-I loop, which varies in position depending on dynein's nucleotide state, swings in to contact AAA2L forming the important AAA1 nucleotide-binding site . This entry represents the small subdomain of the AAA1 domain .
Wnt, C-terminal domain (Wnt_C)
Type: Homologous_superfamily

Wnt proteins constitute a large family of secreted molecules that are involved in intercellular signalling during development. The name derives from the first 2 members of the family to be discovered: int-1 (mouse) and wingless (Drosophila) . It is now recognised that Wnt signalling controls many cell fate decisions in a variety of different organisms, including mammals . Wnt signalling has been implicated in tumourigenesis, early mesodermal patterning of the embryo, morphogenesis of the brain and kidneys, regulation of mammary gland proliferation and Alzheimer's disease .

Wnt-mediated signalling is believed to proceed initially through binding to cell surface receptors of the frizzled family; the signal is subsequently transduced through several cytoplasmic components to B-catenin, which enters the nucleus and activates the transcription of several genes important in development . Several non-canonical Wnt signalling pathways have also been elucidated that act independently of B-catenin. Canonical and noncanonical Wnt signaling branches are highly interconnected, and cross-regulate each other .

Members of the Wnt gene family are defined by their sequence similarity to mouse Wnt-1 and Wingless in Drosophila. They encode proteins of ~350-400 residues in length, with orthologues identified in several, mostly vertebrate, species. Very little is known about the structure of Wnts as they are notoriously insoluble, but they share the following features characteristics of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines that are probably involved in disulphide bonds. The Wnt proteins seem to adhere to the plasma membrane of the secreting cells and are therefore likely to signal over only few cell diameters. Fifteen major Wnt gene families have been identified in vertebrates, with multiple subtypes within some classes.

Wnt has a two-domain structure, resembling a "hand" with "thumb" and "index" fingers. This entry represents the C-terminal Wnt domain .
D-galactoside/L-rhamnose binding SUEL lectin domain superfamily (Lectin_gal-bd_sf)
Type: Homologous_superfamily

The D-galactoside binding lectin purified from sea urchin (Anthocidaris crassispina) eggs exists as a disulphide-linked homodimer of two subunits; the dimeric form is essential for hemagglutination activity . The sea urchin egg lectin (SUEL) forms a new class of lectins. Although SUEL was first isolated as a D-galactoside binding lectin, it was latter shown that it binds to L-rhamnose preferentially . L-rhamnose and D-galactose share the same hydroxyl group orientation at C2 and C4 of the pyranose ring structure.

A cysteine-rich domain homologous to the SUEL protein has been identified in the following proteins :

Plant beta-galactosidases (

) (lactases).

Mammalian latrophilin, the calcium independent receptor of alpha-latrotoxin (CIRL). The galactose-binding lectin domain is not required for alpha-latratoxin binding .

Human lectomedin-1.

Rhamnose-binding lectin (SAL) from catfish (Silurus asotus, Namazu) eggs. This protein is composed of three tandem repeat domains homologous to the SUEL lectin domain. All cysteine positions of each domain are completely conserved .

The hypothetical B0457.1, F32A7.3A and F32A7.3B proteins from Caenorhabditis elegans.

The human KIAA0821 protein.

Structurally, the rhamnose-binding lectin domain (also known as the N-terminal lectin domain, Lec) is composed of five β-strands , a single, long α-helix, and two small helical elements. The overall fold is that of a β-sandwich with two antiparallel sheets .
Dynein heavy chain, C-terminal domain, barrel region (Dynein_C_barrel)
Type: Homologous_superfamily

Dyneins are microtubule-based AAA motor complexes that power ciliary beating, cell division, cell migration and intracellular transport. The motor domain comprises the AAA ring and three additional structural units: the linker, stalk/strut (both of which are major functional units of the heavy chain) and C-terminal domain. The C-terminal domain is a complex structure comprising six α-helices and an incomplete six-stranded antiparallel β-barrel. The shape of this domain is distinctively flat, spreading over the AAA1, AAA5 and AAA6 domains .

This entry represents the barrel region of the C-terminal domain of dynein heavy chain.
Dedicator of cytokinesis, C-terminal, lobe A (DOCK_C_lobe_A)
Type: Homologous_superfamily

DOCK (dedicator of cytokinesis) proteins are potential guanine nucleotide exchange factors that activate some small GTPases, such as Rac, by exchanging bound GDP for free GTP . DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis . Nucleotide exchange is catalysed by a conserved catalytic DHR2 domain situated within the C-terminal region which consists of three lobes.

This entry represents lobe A of DHR2 which adopts a tetratricopeptide repeat-like fold of six antiparallel α-helices .
Dedicator of cytokinesis, C-terminal, lobe C (DOCK_C_lobe_C)
Type: Homologous_superfamily

DOCK (dedicator of cytokinesis) proteins are potential guanine nucleotide exchange factors that activate some small GTPases, such as Rac, by exchanging bound GDP for free GTP . DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis . Nucleotide exchange is catalysed by a conserved catalytic DHR2 domain situated within the C-terminal region which consists of three lobes.

This entry represents lobe C of DHR2 which folds to form an antiparallel α-helical bundle .
DsrC-like protein, N-terminal domain (DsrC-like_N)
Type: Homologous_superfamily

This superfamily includes TusE, a partner to TusBCD in a sulphur relay system for 2-thiouridine biosynthesis, a tRNA base modification process . Other members are DsrC , a functionally similar protein in species where the sulphur relay system exists primarily for sulphur metabolism , rather than tRNA base modification. Some members of this superfamily are known explicitly as the gamma subunit of sulphite reductases.

This superfamily represents the N-terminal domain found in DsrC and TusE proteins.
Large ribosomal subunit protein uL10-like, insertion domain superfamily (Ribosomal_uL10-like_insert_sf)
Type: Homologous_superfamily

This superfamily comprises the insertion domain found in archaeal and eukaryotic large ribosomal subunit protein uL10 (previously known as P0 homologue (L10E) and in ribosome assembly factor MRT4, a nuclear paralogue of these proteins . The RNA-binding domain and the adjacent domain are thought to exist in archaeal L10 and eukaryotic P0 proteins only. This domain contains three-stranded and two-stranded antiparallel β-sheets, located at approximately right angles to each other, and two α-helices between them. It is located on the outer side of the ribosome body between the C-terminal domain of L6, the N-terminal domain of L11, and the H42-H44 region of 23S rRNA .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Pseudouridine synthase, TruD, insertion domain superfamily (TruD_insert_sf)
Type: Homologous_superfamily

Pseudouridine synthase TruD modifies uracil-13 in tRNA . TruD belongs to a large family of pseudouridine synthases present in all kingdoms of life . It folds into a V-shaped molecule with an RNA-binding cleft formed between its two domains: a catalytic domain and an insertion domain. The catalytic domain differs in sequence but is structurally very similar to the catalytic domain of other pseudouridine synthases. The insertion (or TRUD) domain displays an α/β structure that forms a compact fold titled away from the catalytic domain to create a deep cleft in TruD which is lined with basic residues from each domain. The insertion domain is characterised by two conserved sequence motifs that form a part of the hydrophobic core, as well as by large insertions at several specific sites that are seen in many archaeal and eukaryotic homologues. The insertion domain is likely to be involved in substrate recognition and may represent a RNA binding module .

This superfamily represents the tRNA pseudouridine synthase D (TruD) insertion domain mostly found in bacteria.
LarA-like, C-terminal domain (LarA-like_C)
Type: Homologous_superfamily

LarA is a nickel-dependent lactate racemase from the larA-E operon of Lactobacillus plantarum, whereas LarB, LarC and LarE are accessory proteins required for the incorporation of Ni in the lactate racemase apoprotein .

LarA contains 18 β-strands and 16 α-helices arranged in a novel fold composed of two domains of similar size.

This entry represents the C-terminal domain of LarA and related proteins.
LpxI, C-terminal domain superfamily (LpxI_C_sf)
Type: Homologous_superfamily

Enzymes in lipid metabolism acquire and deliver hydrophobic substrates and products from within lipid bilayers. LpxI is an isozyme of a constitutive enzyme in lipid A biosynthesis. It is made up of 2 domains. This entry represents the C-terminal catalytic domain which comprises a five stranded β-sheet bracketed by one α-helix on one side and three on the other. This domain has structural homology, although no sequence homology, to a superfamily that includes cytosine deaminase and various other proteins that do not share conservation of active sites or mechanisms .
DegV, C-terminal domain (DegV_C)
Type: Homologous_superfamily

The DegV family of proteins includes paralogous sets in several species (B. subtilis, Deinococcus radiodurans, Mycoplasma pneumoniae) that are closer in percentage identity to each other than to most homologues from other species. This entry represents the C-terminal domain, it contains six β-strands and five α-helices in a two-layered α/β-arrangement .
Phosphomannomutase, cap domain (PMM_cap)
Type: Homologous_superfamily

Phosphomannomutase (PMM) catalyses the conversion of mannose-6-phosphate to mannose-1-phosphate, an essential step in mannose activation and the biosynthesis of glycoconjugates in all eukaryotes . Bacterial alpha-phosphoglucomutases share an overall fold similar to that of eukaryotic phosphomannomutases . PMM can be divided into two domains: the cap and core. This entry represents the cap domain. The heart of the cap domain is a four-stranded antiparallel β-sheet elaborated on one face with three α-helices .