SII-SWORD/CoKE huggingface dataset:
Munc13 homology 1 (Munc13_1)
Type: Domain

This entry represents the Munc13 homology domain 1.

Munc13 proteins constitute a family of three highly homologous molecules (Munc13-1, Munc13-2 and Munc13-3) with homology to Caenorhabditis elegans Unc-13. Munc13 proteins contain a phorbol ester-binding C1 domain and two C2 domains, which are Ca2+/phospholipid binding domains. Sequence analyses have uncovered two regions called Munc13 homology domains 1 (MHD1) and 2 (MHD2) that are arranged between two flanking C2 domains. MHD1 and MHD2 domains are present in a wide variety of proteins from Arabidopsis thaliana, C. elegans, Drosophila melanogaster (Fruit fly), Mus musculus (Mouse), Rattus norvegicus (Rat) and Homo sapiens (Human), some of which may function in a Munc13-like manner to regulate membrane trafficking .

The MHD1 and MHD2 domains are predicted to be α-helical . Some proteins known to contain MHD1 and MHD2 domains are listed below:

Mammalian Munc13-1. It is specifically targeted to presynaptic active zones and has a central priming function in synaptic vesicle exocytosis from glutaminergic synapses.

Mammalian Munc13-2. It plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.

Mammalian Munc13-3. It probably plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.

Mammalian Munc13-4. It is predominantly expressed in lung where it is localized to goblet cells of the bronchial epithelium and to alveolar type II cells, both of which are cell types with secretory function.

C. elegans Unc-13. It may form part of a signal transduction pathway, transducing the signal from diacylglycerol to effector functions.

Mammalian BAI1-associated protein 3 (BAP3), which exhibits the typical Munc13-like domain structure with two C2 domains flanking the MHD1 and MHD2 domains, but which lack the long N terminus with the C1 domain.

Animal calcium-dependent activator proteins for secretion (CAPSs), regulators of large dense-core vesicle secretion. They contain only a MHD1 domain and are otherwise unrelated to Munc13 proteins.

A. thaliana hypothetical proteins with MHD1 and MHD2 domains but without C1 and C2 domains.

Saccharomyces cerevisiae uncharacterised protein YOR296W, where MHD1 and MHD2 enclose a central C2 domain. YOR296W is presumably involved in bud formation.

Schizosaccharomyces pombe hypothetical protein C11E3.02c in chromosome I, where MHD1 and MHD2 enclose a central C2 domain.
Apoptosis, Bim N-terminal (Apoptosis_Bim_N)
Type: Domain

Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans . In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.

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 . At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.

Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 . Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily . Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.

This entry represents the N-terminal region of several mammal specific Bim proteins. The Bim protein is one of the BH3-only proteins, members of the Bcl-2 family that have only one of the Bcl-2 homology regions, BH3.
Mammalian uncoordinated homology 13, domain 2 (Munc13_dom-2)
Type: Domain

This entry represents the Munc13 homology domain 2.

Munc13 proteins constitute a family of three highly homologous molecules (Munc13-1, Munc13-2 and Munc13-3) with homology to Caenorhabditis elegans Unc-13. Munc13 proteins contain a phorbol ester-binding C1 domain and two C2 domains, which are Ca2+/phospholipid binding domains. Sequence analyses have uncovered two regions called Munc13 homology domains 1 (MHD1) and 2 (MHD2) that are arranged between two flanking C2 domains. MHD1 and MHD2 domains are present in a wide variety of proteins from Arabidopsis thaliana, C. elegans, Drosophila melanogaster (Fruit fly), Mus musculus (Mouse), Rattus norvegicus (Rat) and Homo sapiens (Human), some of which may function in a Munc13-like manner to regulate membrane trafficking .

The MHD1 and MHD2 domains are predicted to be α-helical . Some proteins known to contain MHD1 and MHD2 domains are listed below:

Mammalian Munc13-1. It is specifically targeted to presynaptic active zones and has a central priming function in synaptic vesicle exocytosis from glutaminergic synapses.

Mammalian Munc13-2. It plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.

Mammalian Munc13-3. It probably plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.

Mammalian Munc13-4. It is predominantly expressed in lung where it is localized to goblet cells of the bronchial epithelium and to alveolar type II cells, both of which are cell types with secretory function.

C. elegans Unc-13. It may form part of a signal transduction pathway, transducing the signal from diacylglycerol to effector functions.

Mammalian BAI1-associated protein 3 (BAP3), which exhibits the typical Munc13-like domain structure with two C2 domains flanking the MHD1 and MHD2 domains, but which lack the long N terminus with the C1 domain.

Animal calcium-dependent activator proteins for secretion (CAPSs), regulators of large dense-core vesicle secretion. They contain only a MHD1 domain and are otherwise unrelated to Munc13 proteins.

A. thaliana hypothetical proteins with MHD1 and MHD2 domains but without C1 and C2 domains.

Saccharomyces cerevisiae uncharacterised protein YOR296W, where MHD1 and MHD2 enclose a central C2 domain. YOR296W is presumably involved in bud formation.

Schizosaccharomyces pombe hypothetical protein C11E3.02c in chromosome I, where MHD1 and MHD2 enclose a central C2 domain.
Virulence factor YopE, GAP domain (YopE_GAP_dom)
Type: Domain

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior. There have been four secretion systems described in animal enteropathogens, such as Salmonella and Yersinia, with further sequence similarities in plant pathogens like Ralstonia and Erwinia .

The type III secretion system is of great interest, as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis. However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part of the flagellum itself , type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.

Exotoxins secreted by the type III system do not possess a secretion signal, and are considered unique for this reason . Yersinia secrete a Rho GTPase-activating protein, YopE , that disrupts the host cell actin cytoskeleton. YopE is regulated by another bacterial gene, SycE , that enables the exotoxin to remain soluble in the bacterial cytoplasm. A similar protein, exoenzyme S (ExoS) from Pseudomonas aeruginosa, has both ADP-ribosylation and GTPase activity .

This entry refers to the GTPase-activating protein (GAP) domain found in YopE, ExoS, and also SptP (Secreted effector protein) .
KaiC-like domain (KaiC-like_dom)
Type: Domain

This entry represents a domain found in KaiC, which is a core component of the KaiBC clock oscillator complex that constitutes the main circadian regulator in cyanobacteria . The Circadian clock oscillator protein KaiC, is encoded in the kaiABC operon that controls circadian rhythms and may be universal in Cyanobacteria. Each member contains two copies of this domain, which is also found in other proteins. KaiC performs autophosphorylation and acts as its own transcriptional repressor .

This entry also includes FlaH, a component of the archaella motility machinery . The FlaH adopts a P-loop NTPase fold (

,

) that binds ATP which is essential for its interaction with FlaI and for archaellum assembly. FlaH interacts with the C terminus of FlaX, which is essential for FlaX ring formation and to mediate interaction with FlaI.

This domain is also found in DNA repair protein RadA from Brucella abortus, a DNA-dependent ATPase involved in processing of recombination intermediates that play a role in repairing DNA breaks .

This group of proteins also include uncharacterised archaeal proteins that belong to the UPF0273 family.
L27 domain, C-terminal (L27_C)
Type: Domain

The L27 domain is found, among others, in receptor targeting proteins Lin-2 and Lin-7 .
Tetrapyrrole methylase, subdomain 2 (4pyrrole_Mease_sub2)
Type: Homologous_superfamily

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway . The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including cobalamin (vitamin B12), haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin .

This entry represents the C-terminal subdomain 2 from several tetrapyrrole methylases, which consist of two non-similar domains. These enzymes catalyse the methylation of their substrates using S-adenosyl-L-methionine as a methyl source. Enzymes in this family include:

Uroporphyrinogen III methyltransferase (

) (SUMT), which catalyses the conversion of uroporphyrinogen III to precorrin-2 at the first branch-point of the tetrapyrrole synthesis pathway, directing the pathway towards cobalamin or sirohaem synthesis .

Precorrin-2 C20-methyltransferase CobI/CbiL (

), which introduces a methyl group at C-20 on precorrin-2 to produce precorrin-3A during cobalamin biosynthesis. This reaction is key to the conversion of a porphyrin-type tetrapyrrole ring to a corrin ring . In some species, this enzyme is part of a bifunctional protein.

Precorrin-4 C11-methyltransferase CobM/CbiF (

), which introduces a methyl group at C-11 on precorrin-4 to produce precorrin-5 during cobalamin biosynthesis .

Sirohaem synthase CysG (

), domains 4 and 5, which synthesizes sirohaem from uroporphyrinogen III, at the first branch-point in the tetrapyrrole biosynthetic pathway, directing the pathway towards sirohaem synthesis .

Diphthine synthase (

), which carries out the methylation step during the modification of a specific histidine residue of elongation factor 2 (EF-2) during diphthine synthesis.
Tetrapyrrole methylase, subdomain 1 (4pyrrole_Mease_sub1)
Type: Homologous_superfamily

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway . The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including cobalamin (vitamin B12), haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin .

This entry represents the N-terminal subdomain 1 from several tetrapyrrole methylases, which consist of two non-similar domains. These enzymes catalyse the methylation of their substrates using S-adenosyl-L-methionine as a methyl source. Enzymes in this family include:

Uroporphyrinogen III methyltransferase (

) (SUMT), which catalyses the conversion of uroporphyrinogen III to precorrin-2 at the first branch-point of the tetrapyrrole synthesis pathway, directing the pathway towards cobalamin or sirohaem synthesis .

Precorrin-2 C20-methyltransferase CobI/CbiL (

), which introduces a methyl group at C-20 on precorrin-2 to produce precorrin-3A during cobalamin biosynthesis. This reaction is key to the conversion of a porphyrin-type tetrapyrrole ring to a corrin ring . In some species, this enzyme is part of a bifunctional protein.

Precorrin-4 C11-methyltransferase CobM/CbiF (

), which introduces a methyl group at C-11 on precorrin-4 to produce precorrin-5 during cobalamin biosynthesis .

Sirohaem synthase CysG (

), domains 4 and 5, which synthesizes sirohaem from uroporphyrinogen III, at the first branch-point in the tetrapyrrole biosynthetic pathway, directing the pathway towards sirohaem synthesis .

Diphthine synthase (

), which carries out the methylation step during the modification of a specific histidine residue of elongation factor 2 (EF-2) during diphthine synthesis.
tRNA pseudouridine synthase II, TruB (tRNA_psdUridine_synth_TruB)
Type: Family

This family represents TruB proteins found in the three domains of life which includes bacterial TruB, TruB1 from mammals and PUS4 from yeast. TruB is responsible for the pseudouridine residue present in the T loops of virtually all tRNAs. TruB recognises the preformed 3D structure of the T loop primarily through shape complementarity. It accesses its substrate uridyl residue by flipping out the nucleotide and disrupts the tertiary structure of tRNA .

Saccharomyces cerevisiae tRNA pseudouridine synthase 4 (PUS4, also known as YNL292w), is the pseudouridine 55 synthase of both cytosolic and mitochondrial compartments, active at no other position on tRNA and the only enzyme active at that position in the species . It also catalyses the pseudouridylation of mRNAs with the consensus sequence 5'-GGUUCRA-3' . A distinct yeast protein centromere/microtubule-binding protein CBF5 (also known as YLR175w), is an rRNA pseudouridine synthase, and the archaeal set is much more similar to CBF5 than to PUS4 (see

). It is unclear whether the archaeal proteins found by this model are tRNA pseudouridine 55 synthases like TruB, rRNA pseudouridine synthases like CBF5, or (as suggested by the absence of paralogs in the Archaea) both. CBF5 likely has additional, eukaryotic-specific functions.

Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are :

Pseudouridine synthase I, TruA.

Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.

Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.

Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.

Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.
Anthrax toxin, lethal/endema factor, N-/C-terminal (Anthrax_toxin_lethal/edema_N/C)
Type: Domain

Anthrax toxin is a plasmid-encoded toxin complex produced by the Gram-positive, spore-forming bacteria, Bacillus anthracis. The toxin consists of three non-toxic proteins: the protective antigen (PA), the lethal factor (LF) and the edema factor (EF) . These component proteins self-assemble at the surface of host cell receptors, yielding a series of toxic complexes that can produce shock-like symptoms and death. Anthrax toxin is one of a large group of Bacillus and Clostridium exotoxins referred to as binary toxins, forming independent enzymatic (A moiety) and binding (B moiety) components. The LF and EF proteins are the enzymes (A moiety) that act on cytosolic substrates, while PA is a multi-functional protein (B moiety) that binds to cell surface receptors, mediates the assembly and internalisation of the complexes, and delivers them to the host cell endosome . Once PA is attached to the host receptor , it must then be cleaved by a host cell surface (furin family) protease before it is able to bind EF and LF. The cleavage of the N terminus of PA enables the C-terminal fragment to self-associate into a ring-shaped heptameric complex (prepore) that can bind LF or EF competitively. The PA-LF/EF complex is then internalised by endocytosis, and delivered to the endosome, where PA forms a pore in the endosomal membrane in order to translocate LF and EF to the cytosol. LF is a Zn-dependent metalloprotease that cleaves and inactivates mitogen-activated protein (MAP) kinases, kills macrophages, and causes death of the host by inhibiting cell proliferation . EF is a calcium-and calmodulin-dependent adenylyl cyclase that can cause edema (fluid-filled swelling) when associated with PA. EF is not toxic by itself, and is required for the survival of germinated Bacillus spores within macrophages at the early stages of infection. EF dramatically elevates the level of host intracellular cAMP, a ubiquitous messenger that integrates many processes of the cell; increases in cAMP can interfere with host intracellular signalling .

This entry represents the N- and C-terminal domains found in both lethal factor and edema factor proteins of anthrax toxin.
Peptidase M1, membrane alanine aminopeptidase (Peptidase_M1_dom)
Type: Domain

This group of metallopeptidases belong to the MEROPS peptidase family M1 (clan MA(E)), the type example being aminopeptidase N from Homo sapiens (Human). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA.

Membrane alanine aminopeptidase (

) is part of the HEXXH
+
E group; it consists entirely of aminopeptidases, spread across a wide variety of species . Functional studies show that CD13/APN catalyses the removal of single amino acids from the amino terminus of small peptides and probably plays a role in their final digestion; one family member (leukotriene-A4 hydrolase) is known to hydrolyse the epoxide leukotriene-A4 to form an inflammatory mediator . This hydrolase has been shown to have aminopeptidase activity , and the zinc ligands of the M1 family were identified by site-directed mutagenesis on this enzyme CD13 participates in trimming peptides bound to MHC class II molecules and cleaves MIP-1 chemokine, which alters target cell specificity from basophils to eosinophils . CD13 acts as a receptor for specific strains of RNA viruses (coronaviruses) which cause a relatively large percentage of upper respiratory tract infections.

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .
Copper type II, ascorbate-dependent monooxygenase, histidine-cluster-2 conserved site (Cu2_ascorb_mOase_CS-2)
Type: Conserved_site

Copper type II, ascorbate-dependent monooxygenases are a class of enzymes that requires copper as a cofactor and which uses ascorbate as an electron donor. This family contains two related enzymes, dopamine-beta-monooxygenase (

) and peptidyl-glycine alpha-amidating monooxygenase (

). There are a few regions of sequence similarities between these two enzymes, two of these regions contain clusters of conserved histidine residues which are most probably involved in binding copper.

This entry represents a conserved site that covers the second cluster of conserved histidine residues.
Copper type II, ascorbate-dependent monooxygenase-like, C-terminal (Cu2_ascorb_mOase-like_C)
Type: Homologous_superfamily

Copper type II, ascorbate-dependent monooxygenases are a class of enzymes that requires copper as a cofactor and which uses ascorbate as an electron donor. This family contains two related enzymes, dopamine-beta-monooxygenase (

) and peptidyl-glycine alpha-amidating monooxygenase (

). There are a few regions of sequence similarities between these two enzymes, two of these regions contain clusters of conserved histidine residues which are most probably involved in binding copper.

This superfamily represents the C-terminal domain of the enzyme which has a PNGase F-like fold.
Anaphase-promoting complex subunit 2, C-terminal (ANAPC2_C)
Type: Domain

This entry represents a domain found in the C-terminal of APC subunit 2 (ANAPC2).

ANAPC2 is part of the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle .

The anaphase-promoting complex (APC) or cyclosome is a multi-subunit E3 protein ubiquitin ligase that regulates important events in mitosis, such as the initiation of anaphase and exit from telophase. The APC, in conjunction with other enzymes, assembles multi-ubiquitin chains on a variety of regulatory proteins, thereby targeting them for proteolysis by the 26S proteasome .
Phosphoserine phosphatase RsbU, N-terminal (PSer_Pase_RsbU_N)
Type: Domain

The phosphoserine phosphatase RsbU acts as a positive regulator of the general stress-response factor of Gram-positive organisms, sigma-B. RsbU dephosphorylates rsbV in response to environmental stress conveyed from the rsbXST module. The phosphatase activity of RsbU is stimulated during the stress response by associating with the RsbT kinase. This association leads to the induction of sigmaB activity. The N-terminal domain forms a helix-swapped dimer that is otherwise similar to the KaiA domain dimer. Deletions in the N-terminal domain are deleterious to the activity of RsbU. The C-terminal domain of RsbU is similar to the catalytic domains of PP2C-type phosphatases .