SII-SWORD/CoKE huggingface dataset:
Atrial natriuretic peptide-converting enzyme corin (Corin)
Type: Family

Atrial natriuretic peptide (ANP) is a cardiac hormone essential for the regulation of blood pressure. In cardiac myocytes, ANP is synthesized as a precursor, pro-ANP, which is converted to biologically active ANP by the serine peptidase corin .

This entry represents the atrial natriuretic peptide-converting enzyme corin, which is a type II transmembrane serine protease that belongs to MEROPS peptidase family S1A (clan PA(S)), which is abundantly expressed in the heart. Other serine proteases such as thrombin and kallikrein had previously also been shown to cleave pro-ANP in vitro, but corin has now been shown to be the endogenous pro-ANP convertase in cardiomyocytes . For corin to cleave its substrate, pro-ANP, it should be catalytically active and located in close proximity . Corin is highly sequence specific. Corin-mediated pro-ANP activation may play a role in regulating blood pressure .

N-Glycosylation may influence the subcellular localization and biological activity of corin and tunicamycin treatment also significantly reduces corin activity .

Corin in involved in promoting trophoblast invasion and spiral artery remodelling in pregnancy. Mutations in the corin gene cause pre-eclampsia/eclampsia 5 (PEE5) .
Response regulator B-type, plant (Response_reg_B-typ_pln)
Type: Family

Members of this group are plant response regulators of the B type. B-type plant response regulators most closely resemble the classical microbial response regulators.

Classical two-component signal transduction systems--consisting of a histidine protein kinase (HK) to sense signal input and a response regulator (RR) to mediate output--are widespread in prokaryotes. Their counterparts are also found in eukaryotes, indicating that they represent an ancient and evolutionarily conserved signalling mechanism. In plants, two-component systems are involved in phytohormone, stress, and light signalling . Plant response regulators (called ARRs in Arabidopsis thaliana (Mouse-ear cress)) fall into three distinct families based on domain architecture: A-type RRs are stand-alone receiver domains; B-type RRs contain an N-terminal receiver domain fused to a Myb-like DNA-binding domain and a variable C-terminal domain; pseudo-response regulators contain an atypical receiver domain.

The classical microbial RRs consist of an N-terminal CheY-like receiver (phosphoacceptor) domain and a C-terminal output (usually DNA-binding) domain. In a typical microbial signal transduction system, in response to an environmental stimulus, a phosphoryl group is transferred from the His residue of sensor histidine kinase to an Asp residue in the CheY-like receiver domain of the cognate response regulator . Phosphorylation of the receiver domain induces conformational changes that activate an associated output domain, which in turn triggers the response. Phosphorylation-induced conformational changes in response regulator molecules have been demonstrated in direct structural studies .

The output domain of B-type plant RRs is a central Myb-like DNA-binding domain (with the B, or GARP, motif) which is not found in two-component prokaryotic systems. This domain is believed to be responsible for the promoter-binding and transcription factor activity of the B-type plant RRs . The B motif contains a helix-turn-helix structure and a potential nuclear localization signal, and is considered to be a multifunctional domain responsible for both nuclear localization and DNA binding .

A variable C-terminal domain may also play a role as part of the output module and provides the basis for defining several small subgroups. The functions of these unique C-terminal domains and biological significance of the subgroups are unclear.
Cobalamin reductase PduS (PduS)
Type: Family

Cobalamin reductase PduS from Citrobacter freundii is a bifunctional enzyme that converts cob(III)alamin to cob(II)alamin and then to cob(I)alamin in the BMC dedicated to 1,2-propanediol (1,2-PD) degradation .

Bacterial microcompartments (BCMs) function as organelles by sequestering particular metabolic processes within the cell. The shells of varied microcompartments are built primarily from small proteins belonging to the BMC domain family.
Signal transduction histidine kinase, DctB (C4-dicarboxylate transport system regulator) (Sig_transdc_His_kinase_DctB)
Type: Family

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms . Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation , and CheA, which plays a central role in the chemotaxis system . Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

This entry represents signal transduction histidine kinases such as DctB, which is also known as the C4-dicarboxylate transport system regulator. These proteins are found in proteobacteria and are involved in the regulation of transport systems for C4-dicarboxylates, such as malate, fumarate and succinate.
Phosphoesterase, HI0762, predicted (P-Estase_HI0762_prd)
Type: Family

This group represents a predicted phosphoesterase, HI0762 type.
Ent-kaurene synthase, fungal (Ent-kaurene_synthase_fun)
Type: Family

This entry includes a group of fungal lyases, including ent-kaurene synthase CPS/KS, phyllocladan-16-alpha-ol synthase, aphidicolan-16-beta-ol synthase and copalyl diphosphate synthase . In Gibberella fujikuroi, CPS/KS is part of the gene cluster that mediates the biosynthesis of gibberellins (GAs), diterpenoids that may provide a selective advantage during infection of the preferred host plant, rice .
Major membrane immunogen, tpp15, predicted (Major_M_immunogen_Tpp15_prd)
Type: Family

This group represents a predicted major membrane immunogen, tpp15 type.
[NiFe]-hydrogenase-3-type complex Eha, membrane protein EhaH, predicted (NiFe-hyd_3_EhaH_prd)
Type: Family

This group contains membrane proteins that are predicted to be transmembrane subunits (EhaH) of multisubunit membrane-bound [NiFe]-hydrogenase Eha complexes.

The energy-converting hydrogenase A (
eha
) operon encodes a putative multisubunit membrane-bound [NiFe]-hydrogenase Eha in Methanobacterium thermoautotrophicum (strain Marburg / DSM 2133). Sequence analysis of the
eha
operon indicates that it encodes at least 20 proteins, including the [NiFe]-hydrogenase large subunit, the [NiFe]-hydrogenase small subunit, and two broadly conserved integral membrane proteins (one this entry). These four proteins show high sequence similarity to subunits of the Ech hydrogenase from Methanosarcina barkeri, Escherichia coli hydrogenases 3 and 4 (Hyc and Hyf), and CO-induced hydrogenase from Rhodospirillum rubrum (Coo), all of which form a distinct group of multisubunit membrane-bound [NiFe]-hydrogenases (together called hydrogenase-3-type hydrogenases). In addition to these four subunits, the
eha
operon encodes a 6[4Fe-4S] polyferredoxin, a 10[4Fe-4S] polyferredoxin, ten other predicted integral membrane proteins (

,

,

,

,

,

,

,

,

,

), and four hydrophilic subunits (

,

,

) (the latter hydrophilic subunits is a member of well-characterised enzyme family but lack the essential amino acids assumed to form the active site ). All of these proteins are expressed and therefore thought to be functional subunits of the Eha hydrogenase complex . Note, however, that the ten additional predicted integral membrane proteins are absent from Ech, Coo, Hyc, and Hyf complexes (and therefore from corresponding organisms), indicating that those complexes have a simpler membrane component than Eha .

Members of this group are homologous to the N-terminal domain of EhbF, HyfF of E. coli hydrogenase 4, amongst others. Therefore, this type of membrane subunit of Eha complex is conserved across the various hydrogenase-3-type hydrogenases (that is, they are not limited to the Eha subgroup). A protein with sequence similarity to the C-terminal part of EhbF is not present in the Eha complex (not encoded by the
eha
operon).

Based on sequence similarity and genome context analysis, other organisms such as Methanopyrus kandleri,Methanocaldococcus jannaschii, and M. thermoautotrophicum also encode Eha-like [NiFe]-hydrogenase-3-type complexes and have very similar
eha
operon structure.
Acid sphingomyelinase-like phosphodiesterase, predicted (ASM-like_Pdiesterase_prd)
Type: Family

This group represents a predicted acid sphingomyelinase-like phosphodiesterase (ASMLPD).

The ASMLPD 3b precursor (also known as ASML3B) has a possible interaction with the anti-CD20 monoclonal antibodies called rituximab . This protein, which has in vitro phosphodiesterase activity, functions as a negative regulator of Toll-like receptors (TLRs) and plays a role in immune responses .

ASML3A (ASM-like phosphodiesterase 3a or Cyclic GMP-AMP phosphodiesterase SMPDL3A) acts as a negative regulator of innate immunity by mediating degradation of 2',3'-cGAMP, thereby inhibiting the cGAS-STING signalling . This protein has in vitro nucleotide phosphodiesterase activity but it does not show sphingomyelin phosphodiesterase activity .
Ribonuclease H1, eukaryote (RNase_H1_euk)
Type: Family

This entry represents ribonuclease H1 (RNase H1;

) from eukaryotes. RNase H1 specifically degrades the RNA of RNA-DNA hybrids through endonucleolytic cleavage to 5'-phosphomonoester in the presence of magnesium. Human RNase H1 has a DNA-binding channel that, together with the conserved phosphate-binding pocket, confers specificity for the B form and 2'-deoxy form of DNA; the RNA strand is recognised by four consecutive 2'-OH groups and cleaved by a two-metal ion mechanism .

In the yeasts
Saccharomyces cerevisiae
and
Schizosaccharomyces pombe
, this enzyme is named ribonuclease H (RNH1).
Protein disulphide-isomerase A4 (Protein_diS-isomerase_A4)
Type: Family

This entry represents protein disulphide-isomerase A4 (also known as endoplasmic reticulum protein 72kDa or ERp-72) (

), which acts as a molecular ER chaperone. ER chaperones are critical not only for quality control of proteins processed in the ER, but also for regulation of ER signalling in response to ER stress . ERp-72 catalyses the rearrangement of -S-S- bonds in proteins. It is part a large chaperone multiprotein complex comprising CABP1, DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PPIB, SDF2L1, UGT1A1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX. ERp-72 may functionally associate with NADPH oxidase 1 (NOX1) .
Maltodextrin glucosidase (MalZ)
Type: Family

This group represents a maltodextrin glucosidase (MalZ). MalZ has been identified as an enzyme hydrolyzing maltotriose and longer maltodextrins to glucose and maltose . It is controlled by MatT, the transcriptional activator of the maltose system. It cleaves glucose from the reducing end of maltotriose and longer maltodextrins with a chain length of up to 7 glucose units . Interestingly, in E. coli, a Trp to Cys exchange at position 292 gains MalZ the ability to transfer dextrinyl moieties to glucose, maltose, and other maltodextrins . When incubated with 5% maltotriose (G3), MalZ obtains the transglycosylation ability and helps to produce a nigerose-containing oligosaccharide in vitro .
Uncharacterised conserved protein UCP036920, phosphoglycerate mutase, plant X4/Y4 (UCP036920_PGAM-like_plant)
Type: Family

Silene latifolia (White campion) and Silene dioica (Red campion) are plants with separate sexes and with X and Y sex chromosomes. The presence or absence of the Y chromosome determines which sex organs will develop. Y4 is a Y-linked gene that has a homologue on the X chromosome, X4. Both Y4 and X4 are expressed and potentially encode enzymes related to phosphoglycerate mutase and fructose-2,6-bisphosphatase . This group also includes sequences from plants that do not have separate sexes, such as Arabidopsis and other species of Silene, thus providing examples for comparison of substitution rates in the X-and Y-linked genes of plants .
Transcription elongation factor Spt5, eukaryote (TF_Spt5_eukaryote)
Type: Family

This family consists of several eukaryotic transcription elongation Spt5 proteins. These proteins contain two copies of a domain (Supt5;

) that is characteristic of proteins involved in chromatin regulation. An NGN domain separates the Supt5 domains. In yeast Spt5 protein, this domain possesses a RNP-like fold and it is thought to confer affinity for Spt4 protein. Supt5 domains are followed by four to five copies of a KOW domain (

), present in many ribosomal proteins.

Three transcription-elongation factors Spt4, Spt5, and Spt6 are conserved among eukaryotes and are essential for transcription via modulation of chromatin structure. Spt4 and Spt5 are tightly associated in a complex, while the physical association Spt6 is considerably weaker. It has been demonstrated that Spt4, Spt5, and Spt6 play roles in transcription elongation in both yeast and humans, including a role in activation by Tat. It is known that Spt4, Spt5, and Spt6 are general transcription-elongation factors, controlling transcription both positively and negatively in important regulatory and developmental roles .

This information was partially derived from InterPro (

).
Transcription elongation factor Spt6 (TF_Spt6)
Type: Family

Spt6 is an essential histone chaperone that mediates nucleosome reassembly during gene transcription. The N-terminal ~300 residues are highly acidic, predicted to be disordered, and are necessary for binding both nucleosomes and the transcription factor Spn1/IWS1 . Spt6 associates with RNAPII via a tandem Src2 homology domain . Spt6-RNAPII association is required for efficient recruitment of the Ccr4-Not de-adenylation complex to transcribed genes for mRNA turnover . Spt6 has a key function in transcription elongation. In yeast, Spt6's interaction with phosphorylated tyrosine 1 at the C-terminal domain of RNAPII prevents pre-mature recruitment of termination factors to genes .
Hepatocyte growth factor-regulated tyrosine kinase substrate/VPS27 (HGS/VPS27)
Type: Family

Members of this group are characterised by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a FYVE domain and one or two ubiquitin-interacting motifs.

VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking and are often localised to membranes. FYVE domains are membrane localisation domains that specifically bind phosphatidylinositol 3-phosphate, regulating membrane trafficking and signalling pathways . The ubiquitin-interacting motif is found in many proteins involved in the endocytic pathway and is capable of binding ubiquitin.

The three dimensional structure of the VHS and FYVE tandem domain unit of Drosophila melanogaster (Fruit fly) Hrs reveals a pyramidal structure in which the much larger VHS domain forms a rectangular base and the FYVE domain occupies the apical end. The VHS domain is composed of an unusual superhelix of eight α helices, and the FYVE domain is mainly built of loops, two double-stranded antiparallel sheets, and a helix stabilised by two tetrahedrally coordinated zinc atoms. Dimerisation creates two identical pockets designed for binding ligands with multiple negative charges such as citrate or phosphatidylinositol 3-phosphate . The FYVE domain of the Hrs orthologue in yeast is consistent with this structure .

Members of this group regulate endosome maturation and trafficking between endosomes and the degradative organelles (lysosome/vacuole) . Monoubiquitination functions as a signal for sorting transmembrane proteins into intraluminal vesicles of multivesicular bodies (MVB) and subsequent delivery to the degradative organelles . The sorting of proteins into the inner vesicles of multivesicular bodies is required for many key cellular processes, ranging from the downregulation of activated signalling receptors to the proper stimulation of the immune response . A molecular machine that contains the ubiquitin-binding protein Hrs as well as three multi-subunit complexes, ESCRT (endosome-associated complex required for transport) -I, -II and -III, are essential for both sorting and MVB formation .

A conserved sequence motif, PT/(S)AP, found in structural proteins of several RNA viruses (e.g. HIV gag), promotes release of virus from the cell by recruiting the ESCRT machinery to the viral budding sites at the plasma membrane. The same motif is also found in Hrs and recruits the ESCRT I complex to endosomes through direct interaction with one of its components, TSG101. Fusion of Hrs with the gag gene of HIV-1 lacking this motif can complement a defect in virus budding. Further challenging data indicate a wider role for Hrs in the regulation of endosome dynamics .

Rat GalCer expression factor 1 (GEF-1), which shows high sequence similarity to Hrs, induces GalCer expression, morphological changes, and cell growth inhibition in COS-7 cells .
mRNA capping enzyme, bifunctional (mRNA_cap_enz_bifunc)
Type: Family

This entry represents bifunctional mRNA-capping enzymes that exhibit RNA 5'-triphosphatase activity (

) in the N-terminal region and mRNA guanylyltransferase activity (

) in the C-terminal region . These enzymes catalyse the first two steps of cap formation via the following steps:

Removing the gamma-phosphate from the 5'-triphosphate end of nascent mRNA to yield a diphosphate end.

Followed by the transfer of the gmp moiety of GTP to the 5'-diphosphate terminus.
mRNA capping enzyme, alpha subunit (mRNA_cap_enzyme_alpha)
Type: Family

This entry represents the alpha subunit of the mRNA capping enzyme (also known as mRNA guanylyltransferase;

), which catalyses the second step of mRNA capping . This enzyme catalyses the transfer of the GMP moiety of GTP to the 5'-end of RNA via an enzyme-GMP covalent reaction intermediate. The mRNA-capping enzyme is composed of two separate chains alpha and beta, respectively a mRNA guanylyltransferase and an RNA 5'-triphosphatase.
Kremen (Kremen)
Type: Family

This entry includes Kremen1 and Kremen2. They are receptors for Dickkopf protein that cooperate with Dickkopf to block Wnt/beta-catenin signalling .
Uncharacterised protein family Ycf55, algae (Uncharacterised_Ycf55_algae)
Type: Family

This entry represents proteins annotated as Ycf55, which are encoded in the chloroplast genomes of algae. Other members are found in plants and in the cyanobacteria. The function is unknown, though there are two completely conserved residues (L and D) that may be functionally important. As the family is exclusively found in phototrophic organisms it may play a role in photosynthesis.
Uncharacterised conserved protein UCP036978, histidinol phosphatase-related hydrolase, SCO0789 (UCP036978_PHPhdr)
Type: Family

This group represents a predicted histidinol phosphatase-related hydrolase, SCO0789 type.
Zeaxanthin epoxidase (Zeaxanthin_epoxidase)
Type: Family

This entry represents the enzyme zeaxanthin epoxidase (

), which is involved in the epoxidation of zeaxanthin as part of the biosynthesis of the plant hormone abscisic acid (ABA). ABA is a sesquiterpenoid (15-carbon) which is partially produced via the mevalonic pathway in chloroplasts and other plastids (therefore its biosynthesis primarily occurs in the leaves). The production of ABA is accentuated by stresses such as water loss and freezing temperatures.

The enzyme zeaxanthin epoxidase converts zeaxanthin into antheraxanthin and subsequently into violaxanthin. This enzyme also acts on beta-cryptoxanthin. Zeaxanthin epoxidase plays an important role in resistance to stresses, seed development and dormancy .
Uncharacterised conserved protein UCP036990, CBS, BON (UCP036990_CBS_BON)
Type: Family

This group represents an uncharacterised protein with CBS and BON domains.
Small ribosomal subunit protein mS35 (Ribosomal_mS35)
Type: Family

This entry represents a mitochondrial ribosomal protein mS35, previously known as Rsm24, from fungi. It is a mitochondrial ribosomal protein of the small subunit .
Small ribosomal subunit protein mS29, fungal (Ribosomal_mS29_fun)
Type: Family

This entry represents the small ribosomal subunit protein mS29, previously known as Rsm23, specific to fungi. It is required for maintenance of mitochondrial DNA .
RNA editing complex, nuclease subunit MP42 (RNA_edit_cplx_Nase-su_MP42)
Type: Family

This entry represents the nuclease subunit MP42 from the RNA editing complex found in Trypanosoma and Leishmania. The editing process is performed by the editosome, a multi-protein complex that catalyses the insertion and deletion of uridylates (U) that occurs during RNA editing. Uridylate insertion/deletion editing, which appears to be unique to these organisms, processes most mitochondrial pre-mRNAs to produce mature mRNAs. Editosomes consist of several components and in Trypanosoma these include: REL1/MP52 and REL2/Mp48 RNA ligases; MP18, MP42, MP63 and MP81 that contain zinc fingers .
RNA editing complex, subunit MP18 (RNA_edit_cplx_su_MP18)
Type: Family

This entry represents subunit MP18 from the RNA editing complex found in Trypanosoma and Leishmania. The editing process is performed by the editosome, a multi-protein complex that catalyses the insertion and deletion of uridylates (U) that occurs during RNA editing. Uridylate insertion/deletion editing, which appears to be unique to these organisms, processes most mitochondrial pre-mRNAs to produce mature mRNAs. Editosomes consist of several components and in Trypanosoma these include: REL1/MP52 and REL2/Mp48 RNA ligases; MP18, MP42, MP63 and MP81 that contain zinc fingers .
RNA editing complex, structural subunit MP81 (RNA_edit_cplx_Nase-su_MP81)
Type: Family

This entry represents structural subunit MP81 from the RNA editing complex found in Trypanosoma and Leishmania. The editing process is performed by the editosome, a multi-protein complex that catalyses the insertion and deletion of uridylates (U) that occurs during RNA editing. Uridylate insertion/deletion editing, which appears to be unique to these organisms, processes most mitochondrial pre-mRNAs to produce mature mRNAs. Editosomes consist of several components and in Trypanosoma these include: REL1/MP52 and REL2/Mp48 RNA ligases; MP18, MP42, MP63 and MP81 that contain zinc fingers .