SII-SWORD/CoKE huggingface dataset:
GTPase effector domain (GED_dom)
Type: Domain

Dynamin superfamily members are large GTPases, conserved through evolution, mainly described as mechanochemical enzymes involved in membrane scission events. The dynamin superfamily has been subdivided into several subgroups based on domain organisation: classical dynamin, dynamin-like proteins (Dlps), Mc proteins, optic atrophy 1 protein (OPA1), Mitofusins, guanylate-binding proteins (GBP) and alastatins. All members display a common architecture: a large GTPase (see

) domain followed by a 'middle domain' of ill-defined function and a downstream coiled-coil GTPase effector domain (GED) that functions in higher order assembly and as a GTPase activating protein (GAP) for dynamin's GTPase activity. Most members contain additional domains that characterise the different subgroups. For example, classical dynamins contain a lipid binding Pleckstrin-homology (PH) (see

) domain between the middle domain and the GED domain as well as a C-terminal proline-arginine rich domain (PRD) that interacts with numerous SH3 domain-containing binding partners while Dlps lack the PRD but have a PH domain, which may, however, be highly divergent. These various domains confer a variety of biochemical properties and cellular localisations to dynamin, that may explain the diversity of their biological implications in endocytosis, intracellular traffic, organelle fission and fusion, cytokinesis and pathogen resistance .

The GED is seen to be largely helical in nature, and its oligomerisation occurs via intermolecular packing of the helices .
Ribonucleotide reductase, class Ib, NrdI, bacterial (RNR_Ib_NrdI_bac)
Type: Family

Ribonucleotide reductases (RNRs) are enzymes that catalyse the conversion of ribonucleotides to the corresponding deoxyribonucleotides to provide the precursors of DNA synthesis. There are three classes (I-III) of RNRs and four known subclasses within class I RNRs (Ia-Id) , which differ by their metal cofactor, their stable organic radical and sequence . Class I consists of two homodimeric subunits: alpha2, which catalyses the reversible one-electron oxidation of a conserved cysteine residue to a thiyl radical, which is initiated by a dinuclear metallocofactor and tyrosyl radical positioned in the beta2 subunit. Class Ib RNR is encoded in four different genes: nrdH, nrdI, nrdE (alpha subunit) and nrdF (beta subunit) and has Mn2 in the dimetal cluster to oxidize a nearby tyrosine residue to a stable radical.

This family represents NrdI, a flavoprotein activase which provides superoxide that binds to the beta subunit and forms a hydrophilic channel connecting their active sites .

Note, this entry also includes Bacillus phage proteins.
Ureohydrolase, manganese-binding site (Ureohydrolase_Mn_BS)
Type: Binding_site

This entry represents a conserved region that contain charged residues which are involved in the binding of the two manganese ions in the active site. It is located in a loop segment of the central β-sheet .

The ureohydrolase superfamily includes arginase (

), agmatinase (

), formiminoglutamase (

) and proclavaminate amidinohydrolase (

) . These enzymes share a 3-layer α-β-α structure , and play important roles in arginine/agmatine metabolism, the urea cycle, histidine degradation, and other pathways.

Arginase, which catalyses the conversion of arginine to urea and ornithine, is one of the five members of the urea cycle enzymes that convert ammonia to urea as the principal product of nitrogen excretion . There are several arginase isozymes that differ in catalytic, molecular and immunological properties. Deficiency in the liver isozyme leads to argininemia, which is usually associated with hyperammonemia.

Agmatinase hydrolyses agmatine to putrescine, the precursor for the biosynthesis of higher polyamines, spermidine and spermine. In addition, agmatine may play an important regulatory role in mammals.
Circadian clock oscillator protein KaiA, C-terminal (Circadian_clock_protein_KaiA_C)
Type: Domain

This entry represents the C-terminal domain of Circadian clock protein KaiA.

Cyanobacteria are the most primitive organisms known to exhibit circadian rhythms. KaiA, kaiB and kaiC constitute the circadian clock
machinery in cyanobacteria, and kaiA activates kaiBC expression whereas kaiC represses it . Apparent homologues of kaiB and kaiC are found among non cyanobacteria eubacteria and the archaea. However kaiA appears confined within the cyanobacteria, which are the only prokaryotes with demonstrated circadian rhythms .

There are at least two types of kaiA proteins: long and short . The long versions consist of ~300 aminoacyl residues. There is limited sequence conservation in the N-terminal 200 residues of these proteins but a high degree of conservation in the C-terminal 100 residues. They thus appear to contain two independently folded domains, the amino and carboxyl regions, connected by a canonical linker. The short versions are essentially independent C-terminal domains.

The kaiA N-terminal domain consists of a central five-stranded (β1 to β5) parallel β-sheet flanked by two groups of α-helices (α1,
α4 and α2, α3) packed on either side of the β-sheet and an additional α-helix (α5) lying near the amino terminus of the central
β-strand . The structure of the N-terminal domain of kaiA is that of a pseudo-receiver domain, similar to those found in bacterial response regulators. Although the fold is that of a canonical receiver domain, the primary sequence is dissimilar, and it lacks the conserved aspartate residue necessary for phosphorylation. KaiA activation most likely involves direct protein-protein interactions of the N-terminal domain that result in functional modulation of the C-terminal effector domain.
The C-terminal kaiA domain is responsible for dimer formation, binding to kaiC, enhancing kaiC phosphorylation and generating the circadian oscillations . It adopts a novel all α-helical homodimeric structure . The kaiA C-terminal domain contains two parallel helix-hairpin-
helix motifs that form a four helix bundle, which represents a new protein folding motif.
Serum albumin, conserved site (Serum_albumin_CS)
Type: Conserved_site

A number of serum transport proteins are known to be evolutionarily related, including albumin, alpha-fetoprotein, vitamin D-binding protein and afamin . Albumin is the main protein of plasma; it binds water, cations (such as Ca
2+
, Na
+
and K
+
), fatty acids, hormones, bilirubin and drugs - its main function is to regulate the colloidal osmotic pressure of blood. Alphafeto- protein (alpha-fetoglobulin) is a foetal plasma protein that binds various cations, fatty acids and bilirubin. Vitamin D-binding protein binds to vitamin D and its metabolites, as well as to fatty acids. The biological role of afamin (alpha-albumin) has not yet been characterised. The 3D structure of human serum albumin has been determined by X-ray crystallography to a resolution of 2.8A . It comprises three homologous domains that assemble to form a heart-shaped molecule . Each domain is a product of two subdomains that possess common structural motifs . The principal regions of ligand binding to human serum albumin are located in hydrophobic cavities in subdomains IIA and IIIA, which exhibit similar chemistry. Structurally, the serum albumins are similar, each domain containing five or six internal disulphide bonds, as shown schematically below:

+---+ +----+ +-----+
| | | | | |
xxCxxxxxxxxxxxxxxxxCCxxCxxxxCxxxxxCCxxxCxxxxxxxxxCxxxxxxxxxxxxxxCCxxxxCxxxx
| | | | | |
+-----------------+ +-----+ +---------------+

This entry represents a conserved site that covers the three conserved cysteines at the end of the Serum albumin domain. It is built in such a way that it can detect all 3 repeats in albumin and human afamin, the first two in AFP and the first one in VDB and rat afamin.
Serum albumin-like (Serum_albumin-like)
Type: Homologous_superfamily

A number of serum transport proteins are known to be evolutionarily related, including albumin, alpha-fetoprotein, vitamin D-binding protein and afamin . Albumin is the main protein of plasma; it binds water, cations (such as Ca
2+
, Na
+
and K
+
), fatty acids, hormones, bilirubin and drugs - its main function is to regulate the colloidal osmotic pressure of blood. Alphafeto- protein (alpha-fetoglobulin) is a foetal plasma protein that binds various cations, fatty acids and bilirubin. Vitamin D-binding protein binds to vitamin D and its metabolites, as well as to fatty acids. The biological role of afamin (alpha-albumin) has not yet been characterised. The 3D structure of human serum albumin has been determined by X-ray crystallography to a resolution of 2.8A . It comprises three homologous domains that assemble to form a heart-shaped molecule . Each domain is a product of two subdomains that possess common structural motifs . The principal regions of ligand binding to human serum albumin are located in hydrophobic cavities in subdomains IIA and IIIA, which exhibit similar chemistry. Structurally, the serum albumins are similar, each domain containing five or six internal disulphide bonds, as shown schematically below:

+---+ +----+ +-----+
| | | | | |
xxCxxxxxxxxxxxxxxxxCCxxCxxxxCxxxxxCCxxxCxxxxxxxxxCxxxxxxxxxxxxxxCCxxxxCxxxx
| | | | | |
+-----------------+ +-----+ +---------------+
Roc domain (ROC)
Type: Domain

This entry represents the Roc domain found in small GTPase.

Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain . Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity .

Crystallographic analysis of various small G proteins revealed the presence of a 20kDa catalytic domain that is unique for the whole superfamily . The domain is built of five α helices (A1-A5), six β-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound form, allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg(2+) and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg(2+) binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base .

The small GTPase superfamily can be divided in 8 different families:

Arf small GTPases. GTP-binding proteins involved in protein trafficking by modulating vesicle budding and un-coating within the Golgi apparatus.

Ran small GTPases. GTP-binding proteins involved in nucleocytoplasmic transport. Required for the import of proteins into the nucleus and also for RNA export.

Rab small GTPases. GTP-binding proteins involved in vesicular traffic.

Rho small GTPases. GTP-binding proteins that control cytoskeleton reorganisation.

Ras small GTPases. GTP-binding proteins involved in signaling pathways.

Sar1 small GTPases. Small GTPase component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).

Mitochondrial Rho (Miro). Small GTPase domain found in mitochondrial proteins involved in mitochondrial trafficking.

Roc small GTPases domain. Small GTPase domain always found associated with the COR domain.
MIRO domain (MIRO_dom)
Type: Domain

Mitochondrial Rho (Miro) proteins are aberrant members of the small GTPase superfamily found in most eukaryotes. Miro contains a transmembrane region located at the C terminus anchors the protein to the outer membrane of mitochondria, the GTPase domains and EF-hands located in the cytoplasm. Miro and its cytoplasmic binding partner Milton/TRAK link mitochondria to kinesin and dynein molecular motors in various cell types . Mammals have two Miro orthologs , Miro1 and Miro2. They mediate mitochondrial trafficking in neurons by linking mitochondria to kinesin and dynein motor proteins for their transport in axons and dendrites . Yeasts have one Miro homologue, known as Gem1, which is part of the ERMES complex that links the ER to mitochondria . Interestingly, ERMES is absent in metazoa .

This entry represents the tandemly repeated GTPase domain from these proteins.
Triosephosphate isomerase, active site (Triosephosphate_isomerase_AS)
Type: Active_site

Triosephosphate isomerase (

) (TIM) is the glycolytic enzyme that catalyses the reversible interconversion of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. TIM plays an important role in several metabolic pathways and is essential for efficient energy production, highly conserved in prokaryotes and eukaryotes. In pathogenic organisms, this enzyme plays a crucial role obtaining energy for infection and survival. TIM is a dimer of identical subunits, each of which is made up of about 250 amino-acid residues. A glutamic acid residue is involved in the catalytic mechanism .

The tertiary structure of TIM has eight β/α motifs folded into a barrel structure. The TIM barrel fold occurs ubiquitously and is found in numerous other enzymes that can be involved in energy metabolism, macromolecule metabolism, or small molecule metabolism .

The sequence around the active site residue is perfectly conserved in all known TIM's. Deficiencies in TIM are associated with haemolytic anaemia coupled with a progressive, severe neurological disorder .

This entry represents a triosephosphate isomerase conserved site.
Membrane attack complex component/perforin domain, conserved site (MACPF_CS)
Type: Conserved_site

The membrane attack complex/perforin (MACPF) domain is conserved in bacteria, fungi, mammals and plants. It was originally identified and named as being common to five complement components (C6, C7, C8-alpha, C8-beta, and C9) and perforin. These molecules perform critical functions in innate and adaptive immunity. The MAC family proteins and perforin are known to participate in lytic pore formation. In response to pathogen infection, a sequential and highly specific interaction between the constituent elements occurs to form transmembrane channels which are known as the membrane-attack complex (MAC).Only a few other MACPF proteins have been characterised and several are thought to form pores for invasion or protection . Examples are proteins from malarial parasites , the cytolytic toxins from sea anemones , and proteins that provide plant immunity . Functionally uncharacterised MACPF proteins are also evident in pathogenic bacteria such as Chlamydia spp and Photorhabdus luminescens (Xenorhabdus luminescens) .

The MACPF domain is commonly found to be associated with other N- and C-terminal domains, such as TSP1 (see

), LDLRA (see

), EGF-like (see

),Sushi/CCP/SCR (see

), FIMAC or C2 (see

). They probably control or target MACPF function . The MACPF domain oligomerizes, undergoes conformational change, and is required for lytic activity.

The MACPF domain consists of a central kinked four-stranded antiparallel β sheet surrounded by α helices and β strands, forming two structural segments. Overall, the MACPF domain has a thin L-shaped appearance. MACPF domains exhibit limited sequence similarity but contain a signature [YW]-G-[TS]-H-[FY]-x(6)-G-G motif .

Some proteins known to contain a MACPF domain are listed below:

Vertebrate complement proteins C6 to C9. Complement factors C6 to C9 assemble to form a scaffold, the membrane attack complex (MAC), that permits C9 polymerisation into pores that lyse Gram-negative pathogens .

Vertebrate perforin. It is delivered by natural killer cells and cytotoxic T lymphocytes and forms oligomeric pores (12 to 18 monomers) in the plasma membrane of either virus-infected or transformed cells.

Arabidopsis thaliana (Mouse-ear cress) constitutively activated cell death 1 (CAD1) protein. It is likely to act as a mediator that recognises plant signals for pathogen infection .

Arabidopsis thaliana (Mouse-ear cress) necrotic spotted lesions 1 (NSL1) protein .

Venomous sea anemone Phyllodiscus semoni (Night anemone) toxins PsTX-60A and PsTX-60B .

Venomous sea anemone Actineria villosa (Okinawan sea anemone) toxin AvTX-60A .

Plasmodium sporozoite microneme protein essential for cell traversal 2 (SPECT2). It is essential for the membrane-wounding activity of the sporozoite and is involved in its traversal of the sinusoidal cell layer prior to hepatocyte-infection .

P. luminescens Plu-MACPF. Although nonlytic, it was shown to bind to cell membranes .

Chlamydial putative uncharacterised protein CT153 .
Membrane attack complex component/perforin (MACPF) domain (MACPF)
Type: Domain

The membrane attack complex/perforin (MACPF) domain is conserved in bacteria, fungi, mammals and plants. It was originally identified and named as being common to five complement components (C6, C7, C8-alpha, C8-beta, and C9) and perforin. These molecules perform critical functions in innate and adaptive immunity. The MAC family proteins and perforin are known to participate in lytic pore formation. In response to pathogen infection, a sequential and highly specific interaction between the constituent elements occurs to form transmembrane channels which are known as the membrane-attack complex (MAC).Only a few other MACPF proteins have been characterised and several are thought to form pores for invasion or protection . Examples are proteins from malarial parasites , the cytolytic toxins from sea anemones , and proteins that provide plant immunity . Functionally uncharacterised MACPF proteins are also evident in pathogenic bacteria such as Chlamydia spp and Photorhabdus luminescens (Xenorhabdus luminescens) .

The MACPF domain is commonly found to be associated with other N- and C-terminal domains, such as TSP1 (see

), LDLRA (see

), EGF-like (see

),Sushi/CCP/SCR (see

), FIMAC or C2 (see

). They probably control or target MACPF function . The MACPF domain oligomerizes, undergoes conformational change, and is required for lytic activity.

The MACPF domain consists of a central kinked four-stranded antiparallel β sheet surrounded by α helices and β strands, forming two structural segments. Overall, the MACPF domain has a thin L-shaped appearance. MACPF domains exhibit limited sequence similarity but contain a signature [YW]-G-[TS]-H-[FY]-x(6)-G-G motif .

Some proteins known to contain a MACPF domain are listed below:

Vertebrate complement proteins C6 to C9. Complement factors C6 to C9 assemble to form a scaffold, the membrane attack complex (MAC), that permits C9 polymerisation into pores that lyse Gram-negative pathogens .

Vertebrate perforin. It is delivered by natural killer cells and cytotoxic T lymphocytes and forms oligomeric pores (12 to 18 monomers) in the plasma membrane of either virus-infected or transformed cells.

Arabidopsis thaliana (Mouse-ear cress) constitutively activated cell death 1 (CAD1) protein. It is likely to act as a mediator that recognises plant signals for pathogen infection .

Arabidopsis thaliana (Mouse-ear cress) necrotic spotted lesions 1 (NSL1) protein .

Venomous sea anemone Phyllodiscus semoni (Night anemone) toxins PsTX-60A and PsTX-60B .

Venomous sea anemone Actineria villosa (Okinawan sea anemone) toxin AvTX-60A .

Plasmodium sporozoite microneme protein essential for cell traversal 2 (SPECT2). It is essential for the membrane-wounding activity of the sporozoite and is involved in its traversal of the sinusoidal cell layer prior to hepatocyte-infection .

P. luminescens Plu-MACPF. Although nonlytic, it was shown to bind to cell membranes .

Chlamydial putative uncharacterised protein CT153 .
Tetrahydrofolate dehydrogenase/cyclohydrolase, conserved site (THF_DH/CycHdrlase_CS)
Type: Conserved_site

Enzymes that participate in the transfer of one-carbon units require the coenzyme tetrahydrofolate (THF). Various reactions generate one-carbon derivatives of THF, which can be interconverted between different oxidation states by methylene-THF dehydrogenase (

), methenyl-THF cyclohydrolase (

) and formyl-THF synthetase (

) . The dehydrogenase and cyclohydrolase activities are expressed by a variety of multifunctional enzymes, including the tri-functional eukaryotic C1-tetrahydrofolate synthase ; a bifunctional eukaryotic mitochondrial protein; and the bifunctional Escherichia coli folD protein . Methylene-tetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclo-hydrolase share an overlapping active site , and as such are usually located together in proteins, acting in tandem on the carbon-nitrogen bonds of substrates other than peptide bonds.

The sequence of the dehydrogenase/cyclohydrolase domain is highly conserved in all forms of the enzyme. This entry contains two conserved signature patterns; the first one is located in the N-terminal part of these enzymes and contains three acidic residues. The second pattern is a highly conserved sequence of 9 amino acids, which is located in the C-terminal section.
Bifunctional enzyme Fae/Hps (Fae/Hps)
Type: Family

This bifunctional enzyme catalyses the condensation of formaldehyde with tetrahydromethanopterin (H4MPT) to 5,10-methylenetetrahydromethanopterin and the formation of ribulose-5-phosphate and formaldehyde from 3-hexulose-6-phosphate. Formaldehyde activating enzyme (Fae) was first discovered in methylotrophic bacteria, where it is involved in the oxidation of methanol to CO2 and in formaldehyde detoxification. The genome of Methanosarcina barkeri contains both the faeA gene as well as a second gene, faeB-hpsB, which is shown to code for a 42kDa protein with both Fae activity and hexulose-6-phosphate synthase (Hps) activity .
Exosome complex component Rrp42, archaea (Rrp42_archaea)
Type: Family

The archaeal exosome is a protein complex involved in the degradation and the posttranscriptional tailing of RNA . It degrades single-stranded RNA (ssRNA) in the 3'-5' direction, but also can catalyze the reverse reaction of adding nucleoside diphosphates to the 3'-end of RNA which has been shown to lead to the formation of poly-A-rich tails on RNA .

Rrp42 is a major subunit of the exosome, forming part of the catalytic core and contributing to substrate selectivity . Rrp42 is a member of the RNase_PH family, named after the bacterial Ribonuclease PH, a 3'-5' exoribonuclease. Structurally all members of this family form hexameric rings (trimers of dimers). In archaea, the ring is formed by three Rrp41:Rrp42 dimers. The central chamber within the ring contains three phosphorolytic active sites located in an Rrp41 pocket at the interface between Rrp42 and Rrp41. The ring is capped by three copies of Rrp4 and/or Csl4 which contain putative RNA interaction domains .
Uncharacterised protein family UPF0387, membrane (UPF0387_membrane)
Type: Family

This family of membrane proteins is found in Enterobacteria. Their function is unknown.