SII-SWORD/CoKE huggingface dataset:
Light-harvesting complex (Light-harvesting_complex)
Type: Homologous_superfamily

Bacterial light-harvesting complexes are also known as the antenna complexes. This entry represents the membrane all-α fold found in the alpha- and beta-chains of the antenna complexes.

The antenna complexes of photosynthetic bacteria function as light-harvesting systems that absorb light and transfer the excitation energy to the reaction centres. The antenna complexes usually comprise 2 polypeptides (alpha- and beta-chains), 2-3 bacteriochlorophyll molecules and some carotenoids .
The alpha- and beta-chains are small proteins of 40-70 residues. Each has an N-terminal hydrophilic cytoplasmic domain, a single transmembrane (TM) region, and a small C-terminal hydrophilic periplasmic domain. In both chains, the TM domain houses a conserved His residue, presumed to be involved in binding the magnesium atom of a bacteriochlorophyll group. The beta-chains are characterised by a further histidine at the C-terminal extremity of the cytoplasmic domain, which is also thought to be involved in bacteriochlorophyll binding.
Anti-sigma-28 factor FlgM superfamily (Anti-sigma-28_factor_FlgM_sf)
Type: Homologous_superfamily

FlgM binds and inhibits the activity of the transcription factor sigma 28. Inhibition of sigma 28 prevents the expression of genes from flagellar transcriptional class 3, which include genes for the filament and chemotaxis. Correctly assembled basal body-hook structures export FlgM, relieving inhibition of sigma 28 and allowing expression of class 3 genes. NMR studies show that free FlgM is mostly unfolded, which may facilitate its export. The C-terminal half of FlgM adopts a tertiary structure when it binds to sigma 28. All mutations in FlgM that prevent sigma 28 inhibition affect the C-terminal domain and is the region thought to constitute the binding domain. A minimal binding domain has been identified between Glu 64 and Arg 88 in Salmonella typhimurium (

).The N-terminal portion remains unstructured and may be necessary for recognition by the export machinery .
CheY-binding domain of CheA (CheY-binding_CheA)
Type: Homologous_superfamily

The CheY binding domain is found in the response regulator histidine kinase CheA. It adopts a secondary structure consisting of an open-face β/α sandwich, with four antiparallel β-strands and two α-helices. It binds to a corresponding domain on CheY, with subsequent phosphorylation of the CheY Asp57 residue, and activation of CheY, which then affects flagellar rotation .
C2 domain superfamily (C2_domain_sf)
Type: Homologous_superfamily

The C2 domain is a Ca
2+
-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain . Regions with significant homology to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding and in membrane targetting processes such as subcellular localisation.

The 3D structure of the C2 domain of synaptotagmin has been reported , the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key . Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca
2+
-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
HPr-like superfamily (HPr-like_sf)
Type: Homologous_superfamily

This entry represents a structural domain found in both the histidine-containing phosphocarrier protein HPr, as well as its structural homologues, which includes the catabolite repression protein Crh found in Bacillus subtilis . This domain has a α+β structure found in two layers with an overall architecture of an open faced β-sandwich in which a β-sheet is packed against three α-helices.
AN1-like Zinc finger (AN1-like_Znf)
Type: Homologous_superfamily

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

This entry represents the AN1-type zinc finger domain, which has a dimetal (zinc)-bound α/β fold. This domain was first identified as a zinc finger at the C terminus of AN1

, a ubiquitin-like protein in Xenopus laevis . The AN1-type zinc finger contains six conserved cysteines and two histidines that could potentially coordinate 2 zinc atoms.

Certain stress-associated proteins (SAP) contain AN1 domain, often in combination with A20 zinc finger domains (SAP8) or C2H2 domains (SAP16) . For example, the human protein Znf216 has an A20 zinc-finger at the N terminus and an AN1 zinc-finger at the C terminus, acting to negatively regulate the NFkappaB activation pathway and to interact with components of the immune response like RIP, IKKgamma and TRAF6. The interact of Znf216 with IKK-gamma and RIP is mediated by the A20 zinc-finger domain, while its interaction with TRAF6 is mediated by the AN1 zinc-finger domain; therefore, both zinc-finger domains are involved in regulating the immune response . The AN1 zinc finger domain is also found in proteins containing a ubiquitin-like domain, which are involved in the ubiquitination pathway . Proteins containing an AN1-type zinc finger include:

Ascidian posterior end mark 6 (pem-6) protein .

Human AWP1 protein (associated with PRK1), which is expressed during early embryogenesis .

Human immunoglobulin mu binding protein 2 (SMUBP-2), mutations in which cause muscular atrophy with respiratory distress type 1 .
Toll/interleukin-1 receptor homology (TIR) domain superfamily (Toll_tir_struct_dom_sf)
Type: Homologous_superfamily

Toll proteins or Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R) superfamily are both involved in innate antibacterial and antifungal immunity in insects as well as in mammals. These receptors share a conserved cytoplasmic domain of approximately 200 amino acids, known as the Toll/IL-1R homologous region (TIR). The similarity between TLRs and IL-1Rs is not restricted to sequence homology since these proteins also share a similar signalling pathway. They both induce the activation of a Rel type transcription factor via an adaptor protein and a protein kinase . Interestingly, MyD88, a cytoplasmic adaptor protein found in mammals, contains a TIR domain associated to a DEATH domain . Besides the mammalian and Drosophila proteins, a TIR domain is also found in a number of plant cytoplasmic proteins implicated in host defense .

Site directed mutagenesis and deletion analysis have shown that the TIR domain is essential for Toll and IL-1R activities. Sequence analysis have revealed the presence of three highly conserved regions among the different members of the family: box 1 (FDAFISY), box 2 (GYKLC-RD-PG), and box 3 (a conserved W surrounded by basic residues). It has been proposed that boxes 1 and 2 are involved in the binding of proteins involved in signalling, whereas box 3 is primarily involved in directing localization of receptor, perhaps through interactions with cytoskeletal element .

Resolution of the crystal structures of the TIR domains of human Toll-like receptors 1 and 2 has shown that they contain a central five-stranded parallel β-sheet that is surrounded by a total of five helices on both sides, with connecting loop structures . The loop regions appear to play an important role in mediating the specificity of protein-protein interactions .
TAZ domain superfamily (TAZ_dom_sf)
Type: Homologous_superfamily

TAZ (Transcription Adaptor putative Zinc finger) domains are zinc-containing domains found in the homologous transcriptional co-activators CREB-binding protein (CBP) and the P300. CBP and P300 are histone acetyltransferases (

) that catalyse the reversible acetylation of all four histones in nucleosomes, acting to regulate transcription via chromatin remodelling. These large nuclear proteins interact with numerous transcription factors and viral oncoproteins, including p53 tumour suppressor protein, E1A oncoprotein, MyoD, and GATA-1, and are involved in cell growth, differentiation and apoptosis . Both CBP and P300 have two copies of the TAZ domain, one in the N-terminal region, the other in the C-terminal region. The TAZ1 domain of CBP and P300 forms a complex with CITED2 (CBP/P300-interacting transactivator with ED-rich tail), inhibiting the activity of the hypoxia inducible factor (HIF-1alpha) and thereby attenuating the cellular response to low tissue oxygen concentration . Adaptation to hypoxia is mediated by transactivation of hypoxia-responsive genes by hypoxia-inducible factor-1 (HIF-1) in complex with the CBP and p300 transcriptional coactivators .

Proteins containing this domain also include a group of land-plant specific proteins, know as the BTB/POZ and TAZ domain-containing (BT) protein. The reports of their interaction with CUL3 are contradictory. They are multifunctional scaffold proteins essential for male and female gametophyte development .
Dbl homology (DH) domain superfamily (DBL_dom_sf)
Type: Homologous_superfamily

The DH domain is composed of 11 α helices that are folded into a flattened, elongated α-helix bundle in which two of the three conserved regions, conserved region 1 (CR1) and conserved region 3 (CR3), are exposed near the centre of one surface. CR1 and CR3, together with a part of alpha-6 and the DH/PH junction site, constitute the Rho GTPase interacting pocket .
Colicin E immunity protein superfamily (Colicin_E_sf)
Type: Homologous_superfamily

This family includes bacterial colicin and pyocin immunity proteins . These immunity proteins can bind specifically to the DNase-type colicins and pyocins and inhibit their bactericidal activity. The 1.8-angstrom crystal structure of the ImmE7 protein consists of four antiparallel α-helices . Sequence similarities between colicins E2, A and E1 are less striking. The colicin E2 (pyocin) immunity protein does not share similarity with either the colicin E3 or cloacin DF13 immunity proteins. Pyocin protects a cell that harbours the plasmid ColE2 encoding colicin E2 against colicin E2; it is thus essential both for autonomous replication and colicin E2 immunity .
GIY-YIG endonuclease superfamily (GIY-YIG_endonuc_sf)
Type: Homologous_superfamily

Nucleases of the GIY-YIG family are involved in many cellular processes, including DNA repair and recombination, transfer of mobile genetic elements, and restriction of incoming foreign DNA. The GIY-YIG superfamily groups together nucleases characterised by the presence of a domain of typically ~100 amino acids, with two short motifs "GIY" and "YIG" in the N-terminal part, followed by an Arg residue in the centre and a Glu residue in the C-terminal part .

The GIY-YIG domain forms a compact structural domain, which serves as a scaffold for the coordination of a divalent metal ion required for catalysis of the phosphodiester bond cleavage. The GIY-YIG domain has an α/β-sandwich architecture with a central three-stranded antiparallel β-sheet flanked by three-helices. The three-stranded antiparallel β-sheet contains the GIY-YIG sequence elements. The most conserved and putative catalytic residues are located on a shallow, concave surface and include a metal coordination site .

The GIY-YIG domain has been implicated in a variety of cellular processes involving DNA cleavage, from self-propagation with or without introns, to restriction of foreign DNA, to DNA repair and maintenance of genome stability .

Some proteins known to contain a GIY-YIG domain include:

Eukaryotic Slx-1 proteins, involved in the maintenance of the rDNA copy number. They have a C-terminal RING finger Zn-binding domain.

Mammalian ankyrin repeat and LEM domain- containing protein 1 (ANKLE1).

Bacterial and archaeal UvrC subunits of (A)BC excinucleases, which remove damaged nucleotides by incising the damaged strand on both sides of the lesion.

Phage T4 endonucleases SegA to E, probably involved in the movement of the endonuclease-encoding DNA.

Phage T4 intron-associated endonuclease 1 (I-TevI), specific to the thymidylate synthase (td) gene splice junction and involved in intron homing.

This entry represents GIY-YIG nuclease superfamily, and identifies the GIY-YIG domain in diverse and distantly related superfamily members, such as Slx1 .
Nucleoside phosphorylase/phosphoribosyltransferase catalytic domain superfamily (Nuc_phospho_transferase)
Type: Homologous_superfamily

The nucleoside phosphorylase and the phosphoribosyltransferase catalytic domain belongs to the glycosyl transferase family. The glycosyl transferase family includes anthranilate phosphoribosyltransferase (TrpD,

) and thymidine phosphorylase (

). All these proteins can transfer a phosphorylated ribose substrate. Thymidine phosphorylase (

) catalyses the reversible phosphorolysis of thymidine, deoxyuridine and their analogues to their respective bases and 2-deoxyribose 1-phosphate. This enzyme regulates the availability of thymidine and is therefore essential to nucleic acid metabolism.

The structure is composed of three layers (α/β/α) arranged in parallel β-sheets of five strands.
HesB-like domain superfamily (HesB-like_dom_sf)
Type: Homologous_superfamily

The HesB family is found in species as divergent as Homo sapiens (Human) and Haemophilus influenzae, suggesting that these proteins are involved in basic cellular functions .

A-type assembly protein (ATAP) is a conserved and essential member of the ISC, SUF, and NIF systems and plays an indispensable role in the FeS cluster assembly and the transfer process. The ATAP family consists of several subfamilies:

Prokaryotic ISC system: IscA

Eukaryotic ISC system: ISCA1, ISCA2

SUF system: SufA

NIF system: HesB (IscAnif)

Additional proteins: ErpA, cpIscA

ATAPs are characterised by a conserved motif, Cys-Xn-Cys-X-Cys, by which ATAPs can bind transiently to Fe-S clusters, presumably using the three Cys residues in this motif, and transfer the FeS cluster to apoproteins .

ErpA may interact with ISC and SUF. It binds to Fe-S clusters and transfers them to apo-IspG, which is involved in quinone biosynthesis among many other cell components . It is essential for bacterial growth under aerobic conditions. cpIscA is a SufA-like ATAP that was transferred from cyanobacteria to plants through endosymbiosis events and now is only harboured by plant plastids .
Chorismate synthase AroC superfamily (Chorismate_synth_AroC_sf)
Type: Homologous_superfamily

The chorismate synthase AroC consists of two DCoH-like β(2)-α-β(2)-α structural repeats.

Chorismate synthase (CS; 5-enolpyruvylshikimate-3-phosphate phospholyase; 1-carboxyvinyl-3-phosphoshikimate phosphate-lyase; E.C. 4.2.3.5) catalyzes the seventh and final step in the shikimate pathway which is used in prokaryotes, fungi and plants for the biosynthesis of aromatic amino acids. It catalyzes the 1,4-trans elimination of the phosphate group from 5-enolpyruvylshikimate-3-phosphate (EPSP) to form chorismate which can then be used in phenylalanine, tyrosine or tryptophan biosynthesis. Chorismate synthase requires the presence of a reduced flavin mononucleotide (FMNH2 or FADH2) for its activity. Chorismate synthase from various sources shows a high degree of sequence conservation . It is a protein of about 360 to 400 amino-acid residues.

Depending on the capacity of these enzymes to regenerate the reduced form of FMN, chorismate synthases are divided into two groups: enzymes, mostly from plants and eubacteria, that sequester CS from the cellular environment, are monofunctional, while those that can generate reduced FMN at the expense of NADPH, such as found in fungi and the ciliated protozoan Euglena gracilis, are bifunctional, having an additional NADPH:FMN oxidoreductase activity. Recently, bifunctionality of the Mycobacterium tuberculosis enzyme (MtCS) was determined by measurements of both chorismate synthase and NADH:FMN oxidoreductase activities. Since shikimate pathway enzymes are present in bacteria, fungi and apicomplexan parasites (such as Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum) but absent in mammals, they are potentially attractive targets for the development of new therapy against infectious diseases such as tuberculosis (TB) .
Barstar-like superfamily (Barstar-like_sf)
Type: Homologous_superfamily

Barstar is an intracellular inhibitor of barnase, an extracellular ribonuclease of Bacillus amyloliquefaciens. Barstar binds tightly to the barnase active site and sterically blocks it thus inhibiting its potentially lethal RNase activity inside the cell . Barstar also binds and inhibits a ribonuclease called RNase Sa (produced by Streptomyces aureofaciens) which belongs to the same enzyme family as does barnase .

The structure of the barstar consists of two layers of parallel β-sheet of three strands. Barstar inhibits barnase by statically blocking the active site with a helix and adjacent loop segment .
MetI-like superfamily (MetI-like_sf)
Type: Homologous_superfamily

The Escherichia coli MetI subunit of the L-methionine transmembrane transporter is organised around a core of five transmembrane helices that correspond to a subset of the helices observed in the larger membrane-spanning subunits of the molybdate (ModBC) and maltose (MalFGK) ABC transporters, which contain six helices .

This superfamily represents proteins that have MetI-like structure.
7,8-Dihydro-6-hydroxymethylpterin-pyrophosphokinase HPPK superfamily (Hppk_sf)
Type: Homologous_superfamily

7,8-Dihydro-6-hydroxymethylpterin-pyrophosphokinase (

) (HPPK) catalyses the attachment of pyrophosphate to 6-hydroxymethyl-7,8-dihydropterin to form 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate. This is the first step in a three-step pathway leading to 7,8 dihydrofolate. Bacterial HPPK (gene folK or sulD) is a protein of 160 to 270 amino acids. In the lower eukaryote Pneumocystis carinii, HPPK is the central domain of a multifunctional folate synthesis enzyme (gene fas) .

The structure of HPPK consists of an α/β sandwich with antiparallel β sheets.
ATP synthase, F0 complex, subunit A superfamily (F0_ATP_A_sf)
Type: Homologous_superfamily

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

This superfamily represents the up-and-down bundle of four transmembrane helices structure found in the F0 complex subunit A. This subunit is a key component of the proton channel, and may play a direct role in the translocation of protons across the membrane. Catalysis in the F1 complex depends upon the rotation of the central stalk and F0 c-ring, which in turn is driven by the flux of protons through the membrane via the interface between the F0 c-ring and subunit A. The peripheral stalk links subunit A to the external surface of the F1 domain, and is thought to act as a stator to counter the tendency of subunit A and the F1 α(3)β(3) catalytic portion to rotate with the central rotary element
.
Methylesterase CheB, C-terminal (CheB_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain of the methylesterase CheB involved in chemotaxis. CheB methylesterase is responsible for removing the methyl group from the gamma-glutamyl methyl ester residues in the methyl-accepting chemotaxis proteins (MCP). The enzyme catalyses the reaction: protein L-glutamate O-methyl ester and water is converted to protein L-glutamate and methanol. The CheB structure consists of three layers (α-β-α) arranged in seven strands with parallel β-sheets.
RyR/IP3 receptor binding core, RIH domain superfamily (RyR/IP3R_RIH_dom_sf)
Type: Homologous_superfamily

Ryanodine (RyR) and Inositol 1,4,5-trisphosphate (IP3) receptors are intracellular Ca
2+
-release channels. The RIH (RyR and IP3R Homology) domain is an extracellular domain from these two types of calcium channels. This domain may form a binding site for IP3 .

The structure of the IP3 receptor consists of two (curved) layers α/α and a right-handed superhelix.
MurE/MurF, N-terminal (MurE/MurF_N)
Type: Homologous_superfamily

The MurF protein contains three domains. The N-terminal domain consists of a small α/β fold and contacts the larger central domain across a broad hydrophobic interface. The central domain and the C-terminal domain adopt mononucleotide and dinucleotide (Rossmann) folds, respectively, and are connected by a short linker peptide that is poorly ordered in the crystal .

This superfamily represents the N-terminal domain of the MurE/F proteins. They are ligases involved in the formation of UDP-N-acetylmuramyl-pentapeptide and have been considered as antibacterial targets .
Enhancer of rudimentary superfamily (EHR_sf)
Type: Homologous_superfamily

The enhancer of rudimentary gene, e(r), of Drosophila melanogaster encodes an enhancer of rudimentary (ER) protein with functions implicated in pyrimidine biosynthesis and the cell cycle. The ER homologue (ERH) is highly conserved among vertebrates, invertebrates, and plants .

The monomeric structure of ERH comprises a single domain consisting of three α-helices and four β-strands. In the crystal structure, ERH assumes a dimeric structure, through interactions between the β-sheet regions. The long flexible loop is significantly conserved, suggesting that this loop region may be important for the functions of ERH. The putative phosphorylation sites are located at the start of the beta2-strand (Thr18) and at the start of the alpha1-helix (Ser24), implying that the phosphorylation might cause some structural changes .