SII-SWORD/CoKE huggingface dataset:
RNA polymerase sigma factor, RpoD/SigA, cyanobacteria (RNA_pol_sigma_RpoD/SigA_cyanob)
Type: Family

This family includes a number of closely related sigma-70 (

) factors in the cyanobacteria. All appear most closely related to the essential sigma-70 factor RpoD, and some are related to the RpoD C-terminal domain model (

).

The bacterial core RNA polymerase complex, which consists of five subunits, is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . RNA polymerase recruits alternative sigma factors as a means of switching on specific regulons. Most bacteria express a multiplicity of sigma factors. Two of these factors, sigma-70 (gene rpoD), generally known as the major or primary sigma factor, and sigma-54 (gene rpoN or ntrA) direct the transcription of a wide variety of genes. The other sigma factors, known as alternative sigma factors, are required for the transcription of specific subsets of genes.

With regard to sequence similarity, sigma factors can be grouped into two classes, the sigma-54 and sigma-70 families. Sequence alignments of the sigma70 family members reveal four conserved regions that can be further divided into subregions eg. sub-region 2.2, which may be involved in the binding of the sigma factor to the core RNA polymerase; and sub-region 4.2, which seems to harbor a DNA-binding 'helix-turn-helix' motif involved in binding the conserved -35 region of promoters recognised by the major sigma factors .

The plastids of higher plants originating from an ancestral cyanobacterial endosymbiont also contain sigma factors that are encoded by a small family of nuclear genes. All plastid sigma factors belong to the superfamily of sigmaA/sigma70 and have sequences homologous to the conserved regions 1.2, 2, 3, and 4 of bacterial sigma factors .
Alkaline-phosphatase-like, core domain superfamily (Alkaline_phosphatase_core_sf)
Type: Homologous_superfamily

This superfamily represents a structural domain with a core 3-layer α/β/α structure, which can sometimes contain additional subdomains (also covered by this entry). These domains form the core domain of alkaline phosphatases. This structural domain is found in:

Alkaline phosphatase (

); most use zinc and magnesium as cofactors .

Arylsulphatase (has an additional C-terminal α+β subdomain) (

) .

Phosphoglycerate mutase (catalytic domain) (

) .

Phosphonoacetate hydrolase (contains an α+β subdomain inserted near C terminus) (

); uses zinc as a cofactor.

Phosphoenolmutase (

).
Photosystem II extrinsic protein V, cytochrome c-550 precursor (PsbV_cyt_c550)
Type: Family

Cytochromes c (cytC) can be defined as electron-transfer proteins having one or several haem c groups, bound to the protein by one or, more generally, two thioether bonds involving sulphydryl groups of cysteine residues. The fifth haem iron ligand is always provided by a histidine residue. CytC possess a wide range of properties and function in a large number of different redox processes.

Ambler recognised four classes of cytC. Class 1 cytochromes have the haem-attachment site towards the N terminus, and can be further subdivided into five groups (1A to 1E) based on sequence similarity. Cytochrome C550 (CytC550) is a class 1A cytochrome. CytC550 (also known as Photosystem II extrinsic protein V, PsbV) is an extrinsic membrane protein that forms part of the oxygen-evolving complex in photosystem II, this complex being responsible for the splitting of water into O(2) and 4H+, the latter being used to reduce CO2 to glucose. CytC550 is only found in cyanobacteria and red algae , this protein having been lost during the evolution of green plants . Other Class 1A cytochrome C proteins include mitochondrial cytochrome C, which acts as an electron carrier between cytochrome reductase and the cytochrome oxidase complex, the final electron carrier in the mitochondrial electron transport chain; and cytochrome C6, which acts as an electron carrier between cytochrome b6f and photosystem I in cyanobacteria .
GPI ethanolamine phosphate transferase 1, C-terminal (GPI_EtnP_transferase_1_C)
Type: Domain

This entry represents the C-terminal region of GPI ethanolamine phosphate transferase 1 enzymes, including the yeast enzyme MCD4 and the mammalian homolgoue PIG-N (also known as phosphatidylinositolglycan class N) . These enzymes are multi-pass endoplasmic reticulum membrane proteins involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. These enzymes transfer ethanolamine phosphate to the first alpha-1,4-linked mannose of the GPI precursor of the GPI-anchor. Ethanolamine phosphate on the alpha-1,4-linked mannose is essential for further mannosylation by GPI10 and is necessary for an efficient recognition of GPI lipids and GPI proteins by the GPI transamidase, for the efficient transport of GPI anchored proteins from endoplasmic reticulum to Golgi and for the physiological incorporation of ceramides into GPI anchors by lipid remodeling. MCD4 is also involved in non-mitochondrial ATP movements across the membrane and participates in Golgi and endoplasmic reticulum function, and is required for the incorporation of BGL2 into the cell wall.
Glycoside hydrolase superfamily (GH)
Type: Homologous_superfamily

This entry represents the catalytic TIM β/α barrel common to many different families of glycosyl hydrolases found in all groups of organisms including viruses and Gene Transfer Agents (GTA) . In the GTA of Rhodobacter capsulatus (Rhodopseudomonas capsulata) a glycosyl hydrolase domain is associated with ORFg15 (RCAP_rcc01698) [

, see Fig.1, in

].

Structures have been determined for several proteins containing this glycosyl hydrolase domain, including family 13 glycosyl hydrolases

(such as alpha-amylase) , beta-glycanases , family 1 glycosyl hydrolases

(such as beta-glucosidase) , type II chitinases

, 1,4-beta-N-acetylmuraminidases

, and beta-N-acetylhexosaminidases

.

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.
Metallothionein domain superfamily (Metalthion_dom_sf)
Type: Homologous_superfamily

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds . An empirical classification into three classes has been proposed by Fowler and coworkers and Kojima . Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins,
fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units .

This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which basically proposes an MT family for each main taxonomic group of organisms .

This superfamily represents the structural domain of metallothioneins from both eukaryotes and prokayotes . These proteins have a metal (iron)-bound fold that is duplicated, consisting of clear structural/sequence repeats.
SMAD-like domain superfamily (SMAD-like_dom_sf)
Type: Homologous_superfamily

This superfamily represents SMAD (Mothers against decapentaplegic (MAD) homolog) (also called MH2 for MAD homology 2) domains as well as their structural homologues, such as the transactivation domain of interferon regulatory protein 3 (IRF3), both of which have a β-sandwich structural fold.

SMAD domains are found at the carboxy terminus of MAD related proteins such as Smads. SMAD domain proteins are found in a range of species from nematodes to humans. These highly conserved proteins contain an N-terminal MH1 domain that contacts DNA, and is separated by a short linker region from the C-terminal MH2 domain, the later showing a striking similarity to FHA domains. SMAD proteins mediate signalling by the TGF-beta/activin/BMP-2/4 cytokines from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins fall into three functional classes: the receptor-regulated SMADs (R-SMADs), including SMAD1, -2, -3, -5, and -8, each of which is involved in a ligand-specific signalling pathway ; the co-mediator SMADs (co-SMADs), including SMAD4, which interact with R-SMADs to participate in signalling ; and the inhibitory SMADs (I-SMADs), including SMAD6 and -7, which block the activation of R-SMADs and Co-SMADs, thereby negatively regulating signalling pathways .
Integrase-like, N-terminal (Integrase-like_N)
Type: Homologous_superfamily

This entry represents a structural domain with an α-helical, orthogonal bundle fold. Domains with this structure are found at the N-terminal (zinc-binding domain) of HIV integrase, and in the following hypothetical proteins: YebC from Escherichia coli, HP0162 from Helicobacter pylori (Campylobacter pylori) and aq1575 from Aquifex aeolicus .

Retroviral integrase mediates integration of a DNA copy of the viral genome into the host chromosome. Integrase is composed of three domains: an N-terminal zinc binding domain, a central catalytic core and a C-terminal DNA-binding domain . It is often found as part of the POL polyprotein.
Coagulation factor-like, Gla domain superfamily (Coagulation_fac-like_Gla_dom)
Type: Homologous_superfamily

This superfamily represents the Gla domain found in a subset of coagulation factors (VII, IX and X), related blood regulators (such as vitamin K), and gla-containing proteins. Venom prothrombin activator D found in snakes, also represented in this entry, is functionally similar to blood coagulation factor Xa . This entry also includes the hormone insulin-like peptide protein 05. In the mice's gut, it could play a role in promoting hepatic glucose production during periods of energy deprivation .

The GLA (gamma-carboxyglutamic acid-rich) domain contains glutamate residues that have been post-translationally modified by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla) . All glutamic acid (Glu) residues present in the GLA domain are potential carboxylation sites; in coagulation proteins, all Gu residues are modified to Gla, while in osteocalcin and matrix Gla proteins only some Glu residues are modified to Gla.

The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif is found in the middle of the domain, which seems to be important for substrate recognition by the carboxylase.

The 3D structure of the GLA domain has been solved . Calcium ions induce conformational changes in the GLA domain that are necessary for the proper folding of the GLA domain. A common structural feature of functional GLA domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane .
Treacle protein (Treacle)
Type: Family

Treacher Collins Syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate ; it is the most common of the human mandibulo-facial dysostosis disorders . The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified (TCOF1) . To date, 35 mutations have been reported in TCOF1, all but one of which result in the introduction of a premature-termination codon into the predicted protein, Treacle. The observed mutational spectrum supports the hypothesis that TCS results from haploinsufficiency.

Treacle is a low complexity protein of 1,411 amino acids whose predicted protein structure contains a set of highly polar repeated motifs . These motifs are common to nucleolar trafficking proteins in other species and are predicted to be phosphorylated by casein kinase. In concert with this observation, the full-length TCOF1 protein sequence also contains putative nuclear and nucleolar localisation signals . Throughout the open reading frame are found mutations in TCS families and several polymorphisms. It has thus been suggested that TCS results from defects in a nucleolar trafficking protein that is critically required during human craniofacial development.

This entry contains Treacle and other related proteins.
Peptidase M22, conserved site (Peptidase_M22_CS)
Type: Conserved_site

Glycoprotease (Gcp) (

) , or o-syaloglycoprotein endopeptidase, is a metalloprotease secreted by Pasteurella haemolytica which specifically cleaves O-sialoglycoproteins such as glycophorin A. It belongs to the peptidase family M22. The sequence of Gcp is highly similar to uncharacterised orthologues in most complete genomes of bacteria and archaebacteria as well as in yeast (QRI7 and YKR038c).

This entry represents a conserved site found in proteins classified as M22 peptidases, though there is a lack of experimental evidence to support peptidase activity as a general property of this family. This site contains two conserved histidines. It is possible that this region is involved in coordinating a metal ion such as zinc.
Kae1/TsaD family (KAE1/TsaD)
Type: Family

The first characterised member of the Kae1/TsaD family was annotated as Gcp for O-sialoglycoprotein endopeptidase , but this activity could not be confirmed . Later, its homologue, Kae1 from Pyrococcus abyssi, has been shown to have DNA-binding properties and apurinic-endonuclease activity . Members of this family have since been studied in yeast, archaea and bacteria resulting in sometimes conflicting data, several proposed functions and annotations but no definitive characterisation. For instance, some members have been linked to DNA maintenance in bacteria and mitochondria and transcription regulation and telomere homeostasis in eukaryotes , but their function remained unclear. Recent research indicates that this family is involved in the biosynthesis of N6-threonylcarbamoyl adenosine, a universal modification found at position 37 of tRNAs that read codons beginning with adenine .
SKI-interacting protein, SKIP (SKI-int_prot_SKIP)
Type: Family

SKIP (SKI-interacting protein) is an essential spliceosomal component and transcriptional coregulator, which may provide regulatory coupling of transcription initiation and splicing . SKIP was identified in a yeast 2-hybrid screen, where it was shown to interact with both the cellular and viral forms of SKI through the highly conserved region on SKIP known as the SNW domain . SKIP is now known to interact with a number of other proteins as well. SKIP potentiates the activity of important transcription factors, such as vitamin D receptor, CBF1 (RBP-Jkappa), Smad2/3, and MyoD. It works with Ski in overcoming pRb-mediated cell cycle arrest, and it is targeted by the viral transactivators EBNA2 and E7 .
Arrestin, conserved site (Arrestin_CS)
Type: Conserved_site

G protein-coupled receptors are a large family of signalling molecules that respond to a wide variety of extracellular stimuli. The receptors relay the information encoded by the ligand through the activation of heterotrimeric G proteins and intracellular effector molecules. To ensure the appropriate regulation of the signalling cascade, it is vital to properly inactivate the receptor. This inactivation is achieved, in part, by the binding of a soluble protein, arrestin, which uncouples the receptor from the downstream G protein after the receptors are phosphorylated by G protein-coupled receptor kinases. In addition to the inactivation of G protein-coupled receptors, arrestins have also been implicated in the endocytosis of receptors and cross talk with other signalling pathways. Arrestin (retinal S-antigen) is a major protein of the retinal rod outer segments. It interacts with photo-activated phosphorylated rhodopsin, inhibiting or 'arresting' its ability to interact with transducin . The protein binds calcium, and shows similarity in its C terminus to alpha-transducin and other purine nucleotide-binding proteins. In mammals, arrestin is associated with autoimmune uveitis.

Arrestins comprise a family of closely-related proteins that includes beta-arrestin-1 and -2, which regulate the function of beta-adrenergic receptors by binding to their phosphorylated forms, impairing their capacity to activate G(S) proteins; Cone photoreceptors C-arrestin (arrestin-X) , which could bind to phosphorylated red/green opsins; and Drosophila phosrestins I and II, which undergo light-induced phosphorylation, and probably play a role in photoreceptor transduction .

The crystal structure of bovine retinal arrestin comprises two domains of antiparallel β-sheets connected through a hinge region and one short α-helix on the back of the amino-terminal fold . The binding region for phosphorylated light-activated rhodopsin is located at the N-terminal domain, as indicated by the docking of the photoreceptor to the three-dimensional structure of arrestin.
F-actin capping protein, alpha subunit, conserved site (F-actin_cap_asu_CS)
Type: Conserved_site

The actin filament system, a prominent part of the cytoskeleton in eukaryotic cells, is both a static structure and a dynamic network that can undergo rearrangements: it is thought to be involved in processes such as cell movement and phagocytosis , as well as muscle contraction.

The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike gelsolin and severin this protein does not sever actin filaments. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha and beta (see

). Neither of the subunits shows sequence similarity to other filament-capping proteins .

The alpha subunit is a protein of about 268 to 286 amino acid residues whose sequence is well conserved in eukaryotic species .
Succinyl-CoA synthetase, beta subunit, conserved site (Succ-CoA_synthase_bsu_CS)
Type: Conserved_site

There are four different enzymes that share a similar catalytic mechanism which involves the phosphorylation by ATP (or GTP) of a specific histidine residue in the active site. These enzymes are: ATP citrate-lyase (

) , the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues, catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with the concomitant hydrolysis of ATP to ADP and phosphate. ATP-citrate lyase is a tetramer of identical subunits; Succinyl-CoA ligase (GDP-forming) (

) is a mitochondrial enzyme that catalyzes the substrate level phosphorylation step of the tricarboxylic acid cycle: the formation of succinyl-CoA from succinate with a concomitant hydrolysis of GTP to GDP and phosphate. This enzyme is a dimer composed of an alpha and a beta subunits; Succinyl-CoA ligase (ADP-forming) (

) is a bacterial enzyme that during aerobic metabolism functions in the citric acid cycle, coupling the hydrolysis of succinyl-CoA to the synthesis of ATP. It can also function in the other direction for anabolic purposes. This enzyme is a tetramer composed of two alpha and two beta subunits; and Malate-CoA ligase (

) (malyl-CoA synthetase) , is a bacterial enzyme that forms malyl-CoA from malate and CoA with the concomitant hydrolysis of ATP to ADP and phosphate. Malate-CoA ligase is composed of two different subunits.

This entry corresponds to a conserved region located in the first half of ATP citrate lyase and in the beta subunits of succinyl-CoA ligases and malate-CoA ligase.
Protein-tyrosine phosphatase, low molecular weight (Tyr_phospatase_low_mol_wt)
Type: Family

This entry represents the low molecular weight (LMW) protein-tyrosine phosphatases (or acid phosphatase), which act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates . The structure of a LMW PTPase has been solved by X-ray crystallography and is found to form a single structural domain. It belongs to the α/β class, with 6 α-helices and 4 β-strands forming a 3-layer α-β-α sandwich architecture.

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.
Filamin/ABP280 repeat-like (Filamin/ABP280_repeat-like)
Type: Repeat

The many different actin cross-linking proteins share a common architecture, consisting of a globular actin-binding domain and an extended rod. Whereas their actin-binding domains consist of two calponin homology domains (see

), their rods fall into three families.

The rod domain of the family including the Dictyostelium discoideum (Slime mould) gelation factor (ABP120) and human filamin (ABP280). It is constructed from tandem repeats of a 100-residue motif that is glycine and proline rich . The gelation factor's rod contains 6 copies of the repeat, whereas filamin has a rod constructed from 24 repeats. The resolution of the 3D structure of rod repeats from the gelation factor has shown that they consist of a β-sandwich, formed by two β-sheets arranged in an immunoglobulin-like fold . The repeat structure is common to the members of the gelation factor/filamin family.

This entry represents the entire filamin/ABP280 repeat.