SII-SWORD/CoKE huggingface dataset:
Peptidase S8 propeptide/proteinase inhibitor I9 superfamily (S8pro/Inhibitor_I9_sf)
Type: Homologous_superfamily

This entry represents the propeptide domains superfamily found at the N terminus of peptidases belonging to MEROPS family S8A, subtilisins. The subtilisin propeptides are known to function as molecular chaperones, assisting in the folding of the mature peptidase . The propeptide is removed by proteolytic cleavage; removal activating the enzyme. This domain is also found in members of MEROPS proteinase inhibitor family I9.

Proteinase propeptide inhibitors (sometimes refered to as activation peptides) are responsible for the modulation of folding and activity of the pro-enzyme or zymogen. The pro-segment docks into the enzyme moiety shielding the substrate binding site, thereby promoting inhibition of the enzyme. Several such propeptides share a similar topology , despite often low sequence identities . The propeptide region has an open-sandwich antiparallel-α/antiparallel-β fold, with two α-helices and four β-strands with a (β/α/β)x2 topology.
DNA-3-methyladenine glycosylase AlkA, N-terminal domain superfamily (AlkA_N_sf)
Type: Homologous_superfamily

AlkA (DNA-3-methyladenine glycosylase II) is a base excision repair glycosylase from Escherichia coli. It removes a variety of alkylated bases from DNA, primarily by removing alkylation damage from duplex and single stranded DNA. AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III. This suggests that the two may use similar mechanisms for base excision . The structural analysis of the AlkA and AlkA-hypoxanthine structures indicate that free hypoxanthine binding in the active site may inhibit glycosylase activity .

The AlkA protein consists of three domains: an N-terminal mixed α-β structure, a central seven-helix bundle, and a C-terminal domain of four a helices . This entry represents the N-terminal domain superfamily.
PITH domain superfamily (PITH_dom_sf)
Type: Homologous_superfamily

This entry represents the PITH domain superfamily (derived from Proteasome-Interacting THioredoxin). The protein Txnl1, which is a probable component of the 32kDa 26S proteasome, uses its C-terminal PITH domain to associate specifically with the 26S proteasome .

The PITH domain is dominated by a jelly roll β-sandwich structure. The β-sandwich is formed by face-to-face packing of two anti-parallel β-sheets. Another two-stranded β-sheet seals off one end of the β-barrel .
KorB, C-terminal domain superfamily (KorB_C_sf)
Type: Homologous_superfamily

This domain superfamily is found in several KorB transcriptional repressor proteins. The korB gene is a major regulatory element in the replication and maintenance of broad host-range plasmid RK2. It negatively controls the replication gene trfA, the host-lethal determinants kilA and kilB, and the korA-korB operon . This family is found in conjunction with

.
Domain of unknown function DUF1214, C-terminal domain superfamily (DUF1214_C_sf)
Type: Homologous_superfamily

This entry represents the domain of unknown function that is found in the C-terminal region of a number of uncharacterised bacterial proteins, as well as in other proteins.
Domain of unknown function DUF1254 superfamily (DUF1254_sf)
Type: Homologous_superfamily

This entry represents an immunoglobulin-like β-sandwich domain superfamily found in a group of hypothetical proteins of unknown function.
Four-carbon acid sugar kinase, N-terminal domain superfamily (4-carb_acid_sugar_kinase_N_sf)
Type: Homologous_superfamily

This conserved region is found in four-carbon acid sugar kinases from a range of Proteobacteria as well as the Gram-positive Oceanobacillus iheyensis. These four-carbon acid sugar kinases are composed of two domains: an N-terminal domain and a C-terminal domain connected by a variable linker sequence. The N-terminal domain exhibits an α/β-fold composed of an eight-stranded parallel β-sheet. The C-terminal domain also exhibits an α/β-fold composed of a seven-stranded mixed β-sheet. The acid sugar is bound by the N-terminal domain, while nucleotide by the C-terminal domain .

Proteins containing this domain include D-threonate kinase from Salmonella typhimurium (DtnK), 3-oxo-tetronate kinase from Methylobacterium radiotolerans, 3-oxo-isoapionate kinase from Paraburkholderia graminis and D-erythronate kinase from Heliobacterium modesticaldum. DtnK catalyzes the ATP-dependent phosphorylation of D-threonate to D-threonate 4-phosphate and is also able to phosphorylate 4-hydroxy-L-threonine, which may serve to deal with the toxicity of this compound .
Chemotaxis protein CheA, P2 response regulator-binding domain superfamily (CheA-like_P2_sf)
Type: Homologous_superfamily

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms . Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation , and CheA, which plays a central role in the chemotaxis system . Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

The response regulators for CheA bind to the P2 domain, which is found between

and

as either one or two copies. Highly flexible linkers connect P2 to the rest of CheA and impart remarkable mobility to the P2 domain. This feature is thought to enhance the inter CheA dimer phosphotransfer reactions within the signalling complex, thereby amplifying the phosphorylation signal .
Phage tail collar domain superfamily (Phage_tail_collar_dom_sf)
Type: Homologous_superfamily

This entry represents a domain superfamily found in Bacteriophage T4, Gp12. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.

This region is occasionally found in conjunction with

. Most of the proteins appear to be phage tail proteins; however some appear to be involved in other processes. For instance the RhiB protein (

) from Rhizobium leguminosarum may be involved in plant-microbe interactions . A related protein, microcystin related protein (MrpB,

) is involved in the pathogenicity of Microcystis aeruginosa. The finding of this family in a structural component of the phage tail fibre baseplate (

) suggests that its function is structural rather than enzymatic. Structural studies show this region consists of a helix and a loop and three β-strands. This alignment does not catch the third strand as it is separated from the rest of the structure by around 100 residues. This strand is conserved in homologues but the intervening sequence is not. Much of the function of

appears to reside in this intervening region. In the tertiary structure of the phage baseplate this domain forms part of the collar and may bind SO
4
. The long unconserved region maybe due to domain swapping in and out of a loop or due to rapid evolution.
Alpha-glucuronidase, C-terminal domain superfamily (A-glucoronidase_C_sf)
Type: Homologous_superfamily

Alpha-glucuronidases, components of an ensemble of enzymes central to the recycling of photosynthetic biomass, remove the alpha-1,2 linked 4-O-methyl glucuronic acid from xylans. This entry represents the C-terminal domain superfamily of alpha-glucuronidase, which is mainly α-helical. It wraps around the catalytic domain (

), making additional interactions both with the N-terminal domain (

) of its parent monomer and also forming the majority of the dimer-surface with the equivalent C-terminal domain of the other monomer of the dimer .
MHC class I-like antigen recognition-like superfamily (MHC_I-like_Ag-recog_sf)
Type: Homologous_superfamily

Class I MHC glycoproteins are expressed on the surface of all somatic nucleated cells, with the exception of neurons. MHC class I receptors present peptide antigens that are synthesised in the cytoplasm, which includes self-peptides (presented for self-tolerance) as well as foreign peptides (such as viral proteins). These antigens are generated from degraded protein fragments that are transported to the endoplasmic reticulum by TAP proteins (transporter of antigenic peptides), where they can bind MHC I molecules, before being transported to the cell surface via the Golgi apparatus . MHC class I receptors display antigens for recognition by cytotoxic T cells, which have the ability to destroy viral-infected or malignant (surfeit of self-peptides) cells.

MHC class I molecules are comprised of two chains: a MHC alpha chain (heavy chain), and a beta2-microglobulin chain (light chain), where only the alpha chain spans the membrane. The alpha chain has three extracellular domains (alpha 1-3, with alpha1 being at the N terminus), a transmembrane region and a C-terminal cytoplasmic tail. The soluble extracellular beta-2 microglobulin chain associates primarily with the alpha-3 domain and is necessary for MHC stability. The alpha1 and alpha2 domains of the alpha chain are referred to as the recognition region, because the peptide antigen binds in a deep groove between these two domains.

This entry represents MHC antigen-recognition-like domains from:

MHC class I, alpha-1 and alpha-2 domains

MHC class I homologue gammadelta T-cell ligand

MHC class I related Ulbp3

MHC class I related Fc (IgG) receptor, alpha-1 and alpha-2 domains

MHC class I related CD1, alpha-1 and alpha-2 domains

MHC class I related zinc-alpha-2-glycoprotein ZAG (fat depleting factor)

Immunomodulatory protein m144, alpha-1 and alpha-2 domains

Haemochromatosis protein Hfe, alpha-1 and alpha-2 domains

Endothelial protein C receptor (phospholipid-binding protein)

NK cell ligand RAE-1 . RAE-1 proteins (alpha, beta, delta, and gamma) are distant major histocompatibility complex (MHC) class I homologues, comprising isolated alpha-1 alpha-2 domains, and lack alpha3 domains .
Ribonuclease H1, N-terminal domain superfamily (RNase_H1_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain superfamily of RNase HI, which has a 3-layer α/β/α structure . This domain is lacking in retroviral and prokaryotic enzymes, but shows a striking structural similarity to the ribosomal protein L9 N-terminal domain, and may function as a regulatory RNA-binding module. However, the topology of this domain differs from structures of known RNA binding domains such as the double-stranded RNA binding domain (dsRBD), the hnRNP K homology (KH) domain and the RNP motif. Eukaryotic RNases HI possess either one or two copies of this small N-terminal domain, in addition to the well-conserved catalytic RNase H domain. RNase HI belongs to the family of ribonuclease H enzymes that recognise RNA:DNA hybrids and degrade the RNA component.
Flagellar hook protein FlgE superfamily (Falgellar_hook_FlgE_sf)
Type: Homologous_superfamily

This domain superfamily is found in several bacterial FlgE flagellar hook proteins . The flagellar hook is a short, curved, extracellular structure located between the basal body and the filament .
Rel homology domain (RHD), DNA-binding domain superfamily (RHD_DNA_bind_dom_sf)
Type: Homologous_superfamily

The Rel homology domain (RHD) is found in a family of eukaryotic transcription factors, which includes NF-kappaB, Dorsal, Relish, NFAT, among others. The RHD is composed of two structural domains: the N-terminal DNA binding domain that is similar to that found in P53, the C-terminal domain has an immunoglobulin-like fold (See

) that functions as a dimerisation domain. This entry represents the N-terminal DNA binding domain superfamily .
Lytic transglycosylase, superhelical linker domain superfamily (Lytic_TGlycoase_superhlx_L_sf)
Type: Homologous_superfamily

Bacterial lytic transglycosylases degrade murein via cleavage of the beta-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, with the concomitant formation of a 1,6-anhydrobond in the muramic acid residue. There are both soluble (Slt enzymes) and membrane-bound (Mlt enzymes) lytic transglycosylases that differ in size, sequence, activity, specificity and location. The multi-domain structure of the 70 Kd soluble lytic transglycosylase Slt70 is known . Slt70 has 3 distinct domains, each rich in α helices: an N-terminal superhelical U-shaped domain, a superhelical linker domain (L-domain,

), and a C-terminal catalytic domain (

). Both the U-and L-domain share a similar superhelical structure. These two domains are connected, and together form a closed ring with a large central hole; the catalytic domain is packed on top of, and interacts with, this ring. The catalytic domain has a lysosome-like fold.

This entry represents the superhelical linker domain (also called the L domain) superfamily, which contains two small and four large α helices, the latter forming a four-α-helical bundle with a double-layer, superhelical topology that is similar to that found in the U-shaped domain.
Malic enzyme, N-terminal domain superfamily (Malic_N_dom_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of malic enzymes.

Malic enzymes (malate oxidoreductases) catalyse the oxidative decarboxylation of malate to form pyruvate, a reaction important in a number of metabolic pathways - e.g. carbon dioxide released from the reaction may be used in sugar production during the Calvin cycle of photosynthesis . There are 3 forms of the enzyme : an NAD-dependent form that decarboxylates oxaloacetate; an NAD-dependent form that does not decarboxylate oxalo-acetate; and an NADPH-dependent form . Other proteins known to be similar to malic enzymes are the Escherichia coli scfA protein; an enzyme from Zea mays (Maize), formerly thought to be cinnamyl-alcohol dehydrogenase ; and the hypothetical Saccharomyces cerevisiae protein YKL029c.

Studies on the duck liver malic enzyme reveals that it can be alkylated by bromopyruvate, resulting in the loss of oxidative decarboxylation and the subsequent enhancement of pyruvate reductase activity . The alkylated form is able to bind NADPH but not L-malate, indicating impaired substrate or divalent metal ion-binding in the active site . Sequence analysis has highlighted a cysteine residue as the point of alkylation, suggesting that it may play an important role in the activity of the enzyme , although it is absent in the sequences from some species.

Malic enzyme is a tetramer comprised of subunits with four domains each .
Bacterial Pleckstrin homology domain superfamily (PHb_sf)
Type: Homologous_superfamily

This domain superfamily can be found in many bacterial hypothetical proteins. The structures of

, PDB:3hsa, and

, PDB:3dcx, show similarities to the PH or pleckstrin homology domain. First evidence of PH-like domains in bacteria suggests role in cell envelope stress response .
Formiminotransferase, N-terminal subdomain superfamily (Formiminotransferase_N_sf)
Type: Homologous_superfamily

The formiminotransferase (FT) domain of formiminotransferase-cyclodeaminase (FTCD) forms a homodimer, with each protomer being comprised of two subdomains. The formiminotransferase domain has an N-terminal subdomain that is made up of a six-stranded mixed β-pleated sheet and five α helices, which are arranged on the external surface of the β sheet. This, in turn, faces the β-sheet of the C-terminal subdomain to form a double β-sheet layer. The two subdomains are separated by a short linker sequence, which is not thought to be any more flexible than the remainder of the molecule. The substrate is predicted to form a number of contacts with residues found in both the N-terminal and C-terminal subdomains .

This entry represents the N-terminal subdomain superfamily of the formiminotransferase.
TonB-dependent receptor, plug domain superfamily (Plug_dom_sf)
Type: Homologous_superfamily

In Escherichia coli the TonB protein interacts with outer membrane receptor proteins that carry out high-affinity binding and energy-dependent uptake of specific substrates into the periplasmic space . These substrates are either poorly permeable through the porin channels or are encountered at very low concentrations. In the absence of TonB, these receptors bind their substrates but do not carry out active transport. TonB-dependent regulatory systems consist of six components: a specialised outer membrane-localized TonB-dependent receptor (TonB-dependent transducer) that interacts with its energizing TonB-ExbBD protein complex, a cytoplasmic membrane-localized anti-sigma factor and an extracytoplasmic function (ECF)-subfamily sigma factor . The TonB complex senses signals from outside the bacterial cell and transmits them via two membranes into the cytoplasm, leading to transcriptional activation of target genes. The proteins that are currently known or presumed to interact with TonB include BtuB , CirA, FatA, FcuT, FecA , FhuA , FhuE, FepA , FptA, HemR, IrgA, IutA, PfeA, PupA and Tbp1. The TonB protein also interacts with some colicins. Most of these proteins contain a short conserved region at their N terminus .

This entry represents the plug domain superfamily, which has been shown to be an independently folding subunit of the TonB-dependent receptors . It acts as the channel gate, blocking the pore until the channel is bound by a ligand. At this point it undergoes conformational changes and opens the channel.
Coatomer, gamma subunit, appendage domain superfamily (Coatomer_gsu_app_sf)
Type: Homologous_superfamily

Proteins synthesised on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. This traffic is bidirectional, to ensure that proteins required to form vesicles are recycled. Vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transfer . While clathrin mediates endocytic protein transport, and transport from ER to Golgi, coatomers primarily mediate intra-Golgi transport, as well as the reverse Golgi to ER transport of dilysine-tagged proteins . For example, the coatomer COP1 (coat protein complex 1) is responsible for reverse transport of recycled proteins from Golgi and pre-Golgi compartments back to the ER, while COPII buds vesicles from the ER to the Golgi . Coatomers reversibly associate with Golgi (non-clathrin-coated) vesicles to mediate protein transport and for budding from Golgi membranes . COPI coated vesicle assembly is initiated by recruitment of the small GTPase Arf1 which recruits the coatomer protein complex from the cytoplasm and anchors it at the membrane. Then, Arf1 is activated by a guanine exchange factor and hydrolyses GTP to mediate uncoating of the vesicle which subsequently fuses with its target membrane . As coat proteins polymerise, vesicles are formed and budded from membrane-bound organelles. Coatomer complexes also influence Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. In mammals, coatomer complexes can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins. Coatomer complexes are hetero-oligomers composed of at least an alpha, beta, beta', gamma, delta, epsilon and zeta subunits, and can be subdivided into an outer-coat and an adaptor subcomplex .

This entry represents a β-sandwich structural motif found in the appendage domain superfamily of the gamma subunit of coatomer complexes. This subdomain has an immunoglobulin-like β-sandwich fold containing 7 strands in 2 β-sheets in a Greek key topology . The appendage domain of the gamma coatomer subunit has a similar overall fold to the appendage domain of clathrin adaptors, and can also share the same motif-based cargo recognition and accessory factor recruitment mechanisms.
DNA primase, catalytic core, N-terminal domain superfamily (DNA_primase_core_N_sf)
Type: Homologous_superfamily

DNA primase (

) is a nucleotidyltransferase which synthesizes the oligoribonucleotide primers required for DNA replication on the lagging strand of the replication fork. It can also prime the leading strand and has been implicated in cell division . Primases comprise three domains: a zinc-binding domain (N-terminal) that is responsible for template recognition, a polymerase domain (catalytic core), and a domain that interacts with the replicative helicase, DnaB (C-terminal).

This superfamily represents the N-terminal part of the catalytic core domain of DNA primases.
Acyl-CoA dehydrogenase/oxidase, N-terminal domain superfamily (AcylCoA_DH/ox_N_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 N-terminal α-helical domain superfamily 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 .