SII-SWORD/CoKE huggingface dataset:
Axin interactor, dorsalization-associated protein, N-terminal domain superfamily (AIDA_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of the axin interactor, dorsalization-associated protein (AIDA) superfamily . AIDA acts as a ventralizing factor during embryogenesis. It inhibits axin-mediated JNK activation by binding axin and disrupting axin homodimerization. This in turn antagonizes a Wnt/beta-catenin-independent dorsalization pathway activated by axin/JNK-signaling .

The core structure of the AIDA N-terminal domain consists of four helices arranged in a close or partly open bundle fold with left-handed twist going up-and-down.
Subtilisin inhibitor-like superfamily (Subtilisin_inhibitor-like_sf)
Type: Homologous_superfamily

The Streptomyces family of bacteria produce a number of proteinase inhibitors, which belong to MEROPS inhibitor family I16, clan IY. They are characterised by their strong activity towards subtilisin (MEROPS peptidase family S8,

) and are collectively known as Streptomyces subtilisin inhibitors (SSI). Some SSI also inhibit trypsin, chymotrypsin (MEROPS peptidase family S1,

) and griselysin (MEROPS peptidase family M4,

) . Mutation of the active site residue can influence inhibition specificity .

SSI is a homodimer, each monomer containing 2 anti-parallel β-sheets and 2 short α-helices. Protease binding induces the widening of a channel-like structure, in which hydrophobic side-chains are sandwiched between 2 lobes . Loss of the C-terminal tetrapeptide VFAF drastically reduces the inhibitory effect of the proteins when there is less than one molecule of inhibitor present per molecule of enzyme. This implies that the tetrapeptide is neccessary to maintain the correct 3D fold . Structural similarities between the primary and secondary contact loops of SSI, and the ovomucoid and pancreatic secretory trypsin inhibitor family suggest evolution of the 2 families from a common ancestor .
Archease domain superfamily (Archease_dom_sf)
Type: Homologous_superfamily

The archease superfamily of proteins are represented in all three domains of life. Archease genes are generally located adjacent to genes encoding proteins involved in DNA or RNA processing and therefore have been predicted to be modulators or chaperones involved in DNA or RNA metabolism. Many of the roles of archeases remain to be established experimentally.

The function of one of the archeases from the hyperthermophile Pyrococcus abyssi has been determined. The gene encoding the archease (PAB1946) is located in a bicistronic operon immediately upstream from a second open reading frame (PAB1947), which encodes a tRNA m5C methyltransferase. The methyl transferase catalyses m5C formation at several cytosine's within tRNAs with preference for C49; the specificity of the methyltransferase reaction being increased by the archease. The archease protects the tRNA (cytosine-5-)-methyltransferase PAB1947 against aggregation and increases its specificity. The archease exists in monomeric and oligomeric states, with only the oligomeric forms able to bind the methyltransferase .

The function of this family of archeases as chaperones is supported by structural analysis of

from Methanobacterium thermoautotrophicum, which shows homology to heat shock protein 33, which is a chaperone protein that inhibits the aggregation of partially denatured proteins .

Structurally, the archeases are composed of a single three layer β-α-β sandwich domain similar to those found in other chaperones.
Peptide deformylase superfamily (Peptide_deformylase_sf)
Type: Homologous_superfamily

Peptide deformylase (PDF) is an essential metalloenzyme required for the removal of the formyl group at the N terminus of nascent polypeptide chains in eubacteria:

. The enzyme acts as a monomer and binds a single metal ion, catalysing the reaction:

N-formyl-L-methionine + H
2
O = formate + methionyl peptide

Catalytic efficiency strongly depends on the identity of the bound metal .

These enzymes utilize Fe(II) as the catalytic metal ion, which can be replaced with a nickel or cobalt ion with no loss of activity. There are two types of peptide deformylases, types I and II, which differ in structure only in the outer surface of the domain. Because these enzymes are essential only in prokaryotes (although eukaryotic gene sequences have been found), they are a target for a new class of antibacterial agents .

The structure of these enzymes is known . PDF, a zinc metalloenzyme from the mitochondrion, comprises an active core domain of 147 residues and a C-terminal tail of 21 residue. The 3D fold of the catalytic core has been determined by X-ray crystallography and NMR. Overall, the structure contains a series of anti-parallel β-strands that surround two perpendicular α-helices. The C-terminal helix contains the characteristic HEXXH motif of metalloenzymes, which is crucial for activity. The helical arrangement, and the way the histidine residues bind the zinc ion, is reminiscent of metalloproteases such as thermolysin or metzincins. However, the arrangement of secondary and tertiary structures of PDF, and the positioning of its third zinc ligand (a cysteine residue), are quite different. These discrepancies, together with notable biochemical differences, suggest that PDF constitutes a new class of zinc-metalloenzymes .
CutC-like domain superfamily (CutC-like_dom_sf)
Type: Homologous_superfamily

CutC was originally thought to be involved in copper tolerance in Escherichia coli, as mutation in the corresponding gene lead to an increased copper sensitivity . However, this phenotype has been later reported to depend on the levels of the mRNA-interfering complementary RNA regulator MicL, which is transcribed from a promoter located within the coding sequence of the cutC gene in the enterobacteria . In the plant pathogen Xylella fastidiosa, this protein has been reported as specific for copper efflux . The structure of this protein in the bacteria Shigella flexneri showed a monomer structure that adopts a common TIM β/α barrel with 8 β-strands surrounded by 8 α-helices .

The human homologue of this protein, which structure showed a potential copper-binding site, has an important role in intracellular copper homeostasis .
Small ribosomal subunit protein uS7 domain superfamily (Ribosomal_uS7_dom_sf)
Type: Homologous_superfamily

This entry represents the uS7 structural domain superfamily, which consists of a bundle of six helices and an extended β hairpin between helices 3 and 4, with two or more RNA-binding sites on its surface .

This entry includes the small ribosomal subunit protein uS7, formerly referred to as 30S ribosomal proteins S7 (bacterial, archaeal, plastid, mitochondrial), and eukaryotic 40S ribosomal proteins S5 (cytoplasmic) . 30S ribosomal protein S7 contacts ribosomal proteins S9 and S11. It is also one of the primary rRNA binding proteins - it binds directly to 16S rRNA - where it nucleates assembly of the head domain of the 30S subunit . S7 is located at the subunit interface close to the decoding centre, where it has been shown to contact mRNA. It has also been shown to contact tRNA in both the P and E sites; it probably blocks exit of the E site tRNA.

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 .
Nucleoplasmin core domain superfamily (Nucleoplasmin_core_dom_sf)
Type: Homologous_superfamily

This entry represents the core structural domain superfamily for the nucleoplasmin (Np) family of histone chaperone proteins. This core domain is formed by an 8-stranded β barrel .

The three branches of the Np family, including nucleophosmin (NO38/B23), nucleoplasmin (Np), and nucleoplasmin-like proteins (NLP), bind core histones and assemble nucleosomes
in vitro
assays. Even though they have different histone preferences, it has been suggested that Np family members may share a general mechanism for binding histones .
MTH865-like superfamily (MTH865-like_sf)
Type: Homologous_superfamily

This entry represents a domain superfamily of uncharacterised hypothetical proteins from archaea and bacteria, including the 8.4kDa protein MTH865 from Methanobacterium thermoautotrophicum. The NMR structure of MTH865 reveals an EF-Hand-like fold consisting of four helices in two hairpins .
Cytochrome f large domain superfamily (Cyt_f_lg_dom_sf)
Type: Homologous_superfamily

The cytochrome b6f integral membrane protein complex transfers electrons between the two reaction centre complexes of oxygenic photosynthetic membranes, and participates in formation of the transmembrane electrochemical proton gradient by also transferring protons from the stromal to the internal lumen compartment. The cytochrome b6f complex contains four polypeptides: cytochrome f (285 aa); cytochrome b6 (215 aa); Rieske iron-sulphur protein (179 aa); and subunit IV (160 aa) . In its structure and functions, the cytochrome b6f complex bears extensive analogy to the cytochrome bc1 complex of mitochondria and photosynthetic purple bacteria; cytochrome f (cyt f) plays a role analogous to that of cytochrome c1, in spite of their different structures .

The 3D structure of Brassica rapa (Turnip) cyt f has been determined . The lumen-side segment of cyt f includes two structural domains: a small one above a larger one that, in turn, is on top of the attachment to the membrane domain. The large domain consists of an anti-parallel β-sandwich and a short haem-binding peptide, which form a three-layer structure. The small domain is inserted between β-strands F and G of the large domain and is an all-beta domain. The haem nestles between two short helices at the N terminus of cyt f. Within the second helix is the sequence motif for the c-type cytochromes, CxxCH (residues 21-25), which is covalently attached to the haem through thioether bonds to Cys-21 and Cys-24. His-25 is the fifth haem iron ligand. The sixth haem iron ligand is the alpha-amino group of Tyr-1 in the first helix . Cyt f has an internal network of water molecules that may function as a proton wire . The water chain appears to be a conserved feature of cyt f.

This entry represents the large domain superfamily of cytochrome f.
She2 domain superfamily (She2_dom_sf)
Type: Homologous_superfamily

This entry represents the main structural domain of She2.

She2 is a RNA binding protein which binds to RNA via a helical hairpin. The protein is required for the actin dependent transport of ASH1 mRNA in yeast, a form of mRNP translocation . She2 contains a globular domain consisting of a bundle of five α-helices .
TTHA1528-like superfamily (TTHA1528-like_sf)
Type: Homologous_superfamily

This domain superfamily, whose function is unknown, is found in bacterial proteins. Its structure has a β-α-β(3)-α-β-α(2)-β fold arranged into three layers (α/β/α) with mixed β-sheet.
Hypothetical protein TM0875 (TM0875)
Type: Homologous_superfamily

The domain forms an unusual α/β fold where a six-stranded antiparallel β-sheet is wrapped around a central α-helix, flanked by an additional α-helix and a small sub-domain consisting of a single β-strand and a two-stranded antiparallel β-sheet . It shows weak structural similarities to phosphoribosylformylglycinamidine synthases and some thioesterase superfamily members, but its function is unknown.
Polyphosphate kinase middle domain superfamily (PP_kinase_middle_dom_sf)
Type: Homologous_superfamily

Polyphosphate kinase (Ppk) catalyses the formation of polyphosphate from ATP, with chain lengths of up to a thousand or more orthophosphate molecules . This entry represents the Ppk middle domain superfamily.
HNS-dependent expression A superfamily (HdeA_sf)
Type: Homologous_superfamily

HNS (histone-like nucleoid structuring)-dependent expression A (HdeA) protein is a stress response protein found in highly acid resistant bacteria such as Shigella flexneri and Escherichia coli, but which is lacking in mildly acid tolerant bacteria such as Salmonella . HdeA is one of the most abundant proteins found in the periplasmic space of E. coli, where it is one of a network of proteins that confer an acid resistance phenotype essential for the pathogenesis of enteric bacteria . HdeA is thought to act as a chaperone, functioning to prevent the aggregation of periplasmic proteins denatured under acidic conditions. The HNS protein, a chromatin-associated protein that influences the gene expression of several environmentally-induced target genes, represses the expression of HdeA. HdeB, which is encoded within the same operon, may form heterodimers with HdeA. HdeA is a single domain α-helical protein with an overall fold that is similar to the fold of the N-terminal subdomain of the GluRS anticodon-binding domain.

This entry represents the acid stress chaperone HdeA superfamily.
Polyphosphate kinase N-terminal domain superfamily (PPK_N_dom_sf)
Type: Homologous_superfamily

Polyphosphate kinase (PPK) catalyses the formation of polyphosphate from ATP, with polyphosphate chain lengths of up to a thousand or more orthophosphate molecules.

The N-terminal domain of PPK consists of three α helices arranged in a close bundle fold with left-handed twist going up-and-down.
Beta-galactosidase, domain 3 superfamily (BetaGal_dom3_sf)
Type: Homologous_superfamily

This is the third domain of the five-domain beta-galactosidase enzyme that altogether catalyses the hydrolysis of beta(1-3) and beta(1-4) galactosyl bonds in oligosaccharides, as well as the inverse reaction of enzymatic condensation and trans-glycosylation. This domain has an Ig-like fold .
Bcl-2-like superfamily (Bcl-2-like_sf)
Type: Homologous_superfamily

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 .
Replication modulator SeqA, C-terminal DNA-binding domain superfamily (SeqA_DNA-bd_C_sf)
Type: Homologous_superfamily

The binding of the negative modulator of initiation of replication (SeqA) protein to hemimethylated GATC sequences is important in the negative modulation of chromosomal initiation at oriC, and in the formation of SeqA foci necessary for Escherichia coli chromosome segregation . SeqA tetramers are able to aggregate or multimerize in a reversible, concentration-dependent manner . Apart from its function in the control of DNA replication, SeqA may also be a specific transcription factor .

The C-terminal domain binds DNA, binding to hemimethylated GATC sequences at oriC . The structure of the C-terminal domain consists of seven α-helices and three-stranded β-sheet.
Agouti domain superfamily (Agouti_dom_sf)
Type: Homologous_superfamily

The agouti signaling protein (ASIP or the agouti protein) and its neuropeptide homologue the agouti-related protein (AgRP) are paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. ASIP antagonizes the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (MC1R), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). The effect of ASIP on pigment type-switching is responsible for a variety of coat color patterns accross a broad range of mammalian species. AgRP is involved in energy balance and acts normally at the MC3R and MC4R to control body weight regulation and metabolism .

Sequence similarity between ASIP and AgRP is confined to their Cys-rich C-terminal domains, which are also responsible for melanocortin receptor binding activity in vitro. Approximately 40 residues in length, there are ten cysteine residues in the C-terminal domain that form a network of five disulfide bonds. The agouti C-terminal domain contains a three-stranded antiparallel β sheet, where the last two strands form a β hairpin. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The agouti C-terminal domain adopts the inhibitor cystine knot (ICK) or knottin fold identified in numerous invertebrate toxins .

The agouti domain covers the 10 cysteines involved in disulfide bonds.
Cation efflux protein, cytoplasmic domain superfamily (Cation_efflux_CTD_sf)
Type: Homologous_superfamily

The cation diffusion facilitator family (CDF) have members in both prokaryotes and eukaryotes, several of which have been shown to transport cobalt, cadmium and/or zinc. CDF transporters share a common two-modular architecture, consisting of a transmembrane domain (TMD) followed by a C-terminal domain (CTD) protruding into the cytoplasm .

This entry represents the CDF C-terminal cytoplasmic domain superfamily. The cytoplasmic domain of Zinc transporter YiiP adopts a metallochaperone-like fold. The use of this common structural module to regulate metal coordination chemistry may enable a tunable transport activity in response to cytoplasmic metal fluctuations . It is the dimerisation region of the whole molecule of zinc transporters since the full-length members form a homodimer during activity. The domain lies within the cytoplasm and exhibits an overall structural similarity with the copper metallochaperone Hah1 (

) exhibiting an open α-β domain with two α helices (H1 and H2) aligned on one side and a three-stranded mixed β-sheet (S1 to S3) on the other side .
Small ribosomal subunit protein uS10 domain superfamily (Ribosomal_uS10_dom_sf)
Type: Homologous_superfamily

Structurally, the small ribosomal subunit protein uS10 domain has a ferredoxin-like fold, which consists of an α+β sandwich with antiparallel β-sheet.

Evidence suggests that, in prokaryotes, the peptidyl transferase reaction is performed by the large subunit 23S rRNA, whereas proteins probably have a greater role in eukaryotic ribosomes. Most of the proteins lie close to, or on the surface of, the 30S subunit, arranged peripherally around the rRNA . The small subunit ribosomal proteins can be categorised as primary binding proteins, which bind directly and independently to 16S rRNA; secondary binding proteins, which display no specific affinity for 16S rRNA, but its assembly is contingent upon the presence of one or more primary binding proteins; and tertiary binding proteins, which require the presence of one or more secondary binding proteins and sometimes other tertiary binding proteins.

The small ribosomal subunit protein uS10 consists of about 100 amino acid residues. In Escherichia coli, uS10 is involved in binding tRNA to the ribosome, and also operates as a transcriptional elongation factor . Experimental evidence has revealed that uS10 has virtually no groups exposed on the ribosomal surface, and is one of the "split proteins": these are a discrete group that are selectively removed from 30S subunits under low salt conditions and are required for the formation of activated 30S reconstitution intermediate (RI*) particles. uS10 belongs to a family of proteins that includes: bacteria uS10; algal chloroplast uS10c; cyanelle uS10; archaebacterial uS10; Marchantia polymorpha and Prototheca wickerhamii mitochondrial S10; Arabidopsis thaliana mitochondrial uS10m (nuclear encoded); vertebrate uS10 (also known as S20); plant u S10 (also known as S20); and yeast uS10 (URP2).
7,8-dihydroneopterin aldolase (MptD) superfamily (MptD_sf)
Type: Homologous_superfamily

This superfamily of archaeal 7,8-dihydroneopterin aldolase (also known as dihydroneopterin aldolase) catalyses the conversion of 7,8-dihydroneopterin (H2Neo) to 6-hydroxymethyl-7,8-dihydropterin diphosphate (6-HMDP) . 6-HMDP is the precursor of the pterin containing moiety of the essential C1-carriers tetrahydrofolate and tetrahydromethanopterin.
YqbF domain superfamily (YqbF_dom_sf)
Type: Homologous_superfamily

The YqbF domain is found at the N-terminal of the uncharacterised protein YqbF from Bacillus subtilis. Its function is not known.
Vascular endothelial growth factor, heparin-binding domain superfamily (VEGF_C_sf)
Type: Homologous_superfamily

This short domain is found at the C terminus of vascular endothelial growth factor (VEGF). It has been shown to have heparin binding activity .

Proteins containing this domain include VEGF-A, which is a growth factor active in angiogenesis, vasculogenesis and endothelial cell growth . VEGF-A also promotes a wide range of neuronal functions, including neurogenesis, neuronal migration, neuronal survival and axon guidance .
AF2331-like superfamily (AF2331-like_sf)
Type: Homologous_superfamily

AF2331-like protein is a 11kDa orphan protein from Archaeoglobus fulgidus. The structure consists of an α + β fold formed by an unusual homodimer, where the two core β-sheets are interdigitated, containing strands alternating from both subunits. AF2331 contains multiple negatively charged surface clusters and is located on the same operon as the basic protein AF2330. It is suggested that AF2331 and AF2330 may form a charge-stabilised complex in vivo, though the role of the negatively charged surface clusters is not clear .