SII-SWORD/CoKE huggingface dataset:
Aurora kinase-like (Aur-like)
Type: Family

Aurora kinase was discovered by Glover and colleagues in a screen for genes required to maintain the centrosome cycle in Drosophila . Its yeast homologue Ipl1 (also known as spindle assembly checkpoint kinase) was found to regulate chromosome segregation . Subsequently, three mammal Aurora kinases, Aurora A, B and C, have been identified.

They are highly conserved serine/threonine kinases that regulate chromosomal alignment and segregation during mitosis and meiosis . They all contain a protein kinase domain and a destruction box (D-box) recognised by the multi-subunit E3-ubiquitin ligase anaphase promoting complex/cyclosome (APC/C), which mediates their proteasomal degradation. However, their N-terminal domains share little sequence identity and confer unique protein-protein interaction abilities among the Aurora kinases .
Protein bassoon, FYVE domain (Bsn_FYVE_dom)
Type: Domain

The active zone is the presynaptic region in the nerve terminals that mediates neurotransmitter release and is composed a dense collection of proteins called the cytomatrix at the active zone (CAZ). The CAZ proteins are thought to mediate synapse formation and regulate neurotransmitter release .

Bassoon is a CAZ protein that is involved in the formation of the retinal photoreceptor ribbon synapses, which is specialised for tonic release of neurotransmitter in the dark . It plays a part in the early formation and delivery of precursor spheres to nascent ribbon synaptic sites and in ribbon anchoring during later stages of photoreceptor ribbon synaptogenesis .

This entry represents the first FYVE domain of Protein bassoon, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains.
Synemin (SYNM)
Type: Family

Synemin, also known as desmuslin, is a type-VI intermediate filament (IF) protein which plays an important cytoskeletal role within the muscle cell cytoskeleton . It associates with the major IF proteins, desmin and/or vimentin, within muscle cells and forms heteropolymeric IFs .
Nephrocystin-1, SH3 domain (NPHP1_SH3)
Type: Domain

Nephronophthisis (NPHP) is a hereditary cystic kidney disorder that causes renal failure in children and young adults and can be associated with various extrarenal disorders, including retinitis pigmentosa. Six NPHP genes have been identified, one of which, Nephrocystin-1 (NPHP1), is localised to the ciliary transition zone of epithelial cells or its analogous structure, connecting cilia of retinal photoreceptors . It also plays an essential role in photoreceptor intraflagellar transport and in later steps of sperm morphogenesis in mice .

Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization . SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs.
Sugar 1,4-lactone oxidase (Sugar_lactone_oxidase)
Type: Family

This entry identifies a family of at least two different sugar 1,4 lactone oxidases, mainly from eukaryotes, both involved in synthesising ascorbic acid or a derivative. These include L-gulonolactone oxidase (

) from rat and D-arabinono-1,4-lactone oxidase (

) from Saccharomyces cerevisiae (Baker's yeast). Members are proposed to have the cofactor FAD covalently bound at a site specified by

.
NifH/chlL conserved site (NifH/chlL_CS)
Type: Conserved_site

Nitrogenase (

) is the enzyme system responsible for biological nitrogen fixation. Nitrogenase is an oligomeric complex which consists of two components: component 1 which contains the active site for the reduction of nitrogen to ammonia and component 2 (also called the iron protein).

Component 2 is a homodimer of a protein (gene nifH) which binds a single 4Fe-4S iron sulfur cluster . In the nitrogen fixation process nifH is first reduced by a protein such as ferredoxin; the reduced protein then transfers electrons to component 1 with the concomitant consumption of ATP.

A number of proteins are known to be evolutionary related to nifH. These proteins are:

Chloroplast encoded chlL (or frxC) protein . ChlL is encoded on the chloroplast genome of some plant species, its exact function is not known, but it could act as an electron carrier in the conversion of protochlorophyllide to chlorophyllide.

Photosynthetic bacteria proteins bchL and bchX . These proteins are also likely to play a role in chlorophyll synthesis.

There are a number of conserved regions in the sequence of these proteins: in the N-terminal section there is an ATP-binding site motif 'A' (P-loop) and in the central section there are two conserved cysteines which have been shown, in nifH, to be the ligands of the 4Fe-4S cluster. This entry represents two conserved sites which correspond to the regions around these cysteines.
Delta-aminolevulinic acid dehydratase, active site (ALAD_AS)
Type: Active_site

Delta-aminolevulinic acid dehydratase (

) (ALAD) or porphobilinogen synthase catalyses the second step in the biosynthesis of heme, the condensation of two molecules of 5-aminolevulinate to form porphobilinogen. The enzyme is an oligomer composed of eight identical subunits. Each of the subunits binds an atom of zinc or of magnesium (in plants). A lysine has been implicated in the catalytic mechanism . The sequence of the region in the vicinity of the active site residue is conserved in ALAD from various prokaryotic and eukaryotic species.
Telomeric repeat-binding factor 2 (TERF2)
Type: Family

This entry represents telomeric repeat-binding factor 2 (TERF2, also known as TRF2).

Telomeres function to shield chromosome ends from degradation and end-to-end fusions, as well as preventing the activation of DNA damage checkpoints. Telomeric repeat binding factor (TRF) proteins TRF1 and TRF2 are major components of vertebrate telomeres required for regulation of telomere stability. TRF1 and TRF2 bind to telomeric DNA as homodimers. Dimerisation involves the TRF homology (TRFH) subdomain contained within the dimerisation domain. The TRFH subdomain is important not only for dimerisation, but for DNA binding, telomere localisation, and interactions with other telomeric proteins. The dimerisation domains of TRF1 and TRF2 show the same multi-helical structure, arranged in a solenoid conformation similar to TPR repeats, which can be divided into an α-α superhelix and a long α hairpin .

The two related human TRF proteins hTRF1 and hTRF2 form homodimers and bind directly to telomeric TTAGGG repeats via the myb DNA binding domain

at the carboxy terminus . TRF1 is implicated in telomere length regulation and TRF2 in telomere protection . Other telomere complex associated proteins are recruited through their interaction with either TRF1 or TRF2. The fission yeast protein Taz1p (telomere-associated in Schizosaccharomyces pombe (Fission yeast) has similarity to both hTRF1 and hTRF2 and may perform the dual functions of TRF1 and TRF2 at fission yeast telomeres .
Macrophage colony-stimulating factor 1 receptor (CSF-1_receptor)
Type: Family

This entry represents a macrophage colony-stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR) or CD115 (Cluster of Differentiation 115). CSF1R is a tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes . CSF-1 and CSF-1R play an important role in the development of the mammary gland and may be involved in the process of mammary gland carcinogenesis . Mutations in the CSF1R gene cause hereditary diffuse leukoencephalopathy with spheroids, which is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes .

This entry also includes the tyrosine-protein kinase transforming protein v-fms from Feline sarcoma virus. CSF1R (the c-fms product) is its cellular counterpart. It differs in some amino acid substitutions and the replacement of 50 C-terminal amino acids by 11 unrelated residues in v-fms . v-fms can bind CSF-1 and has constitutive tyrosine-specific protein kinase activity, providing growth stimulatory signals in the absence of ligand .
SecY conserved site (SecY_CS)
Type: Conserved_site

The eubacterial secY protein plays an important role in protein export. It interacts with the signal sequences of secretory proteins as well as with two other components of the protein translocation system: secA and secE. SecY is an integral plasma membrane protein of 419 to 492 amino acid residues that apparently contains ten transmembrane segments. Such a structure probably confers to secY a 'translocator' function, providing a channel for periplasmic and outer-membrane precursor proteins.

Homologues of secY are found in archaebacteria . SecY is also encoded in the chloroplast genome of some algae where it could be involved in a prokaryotic-like protein export system across the two membranes of the chloroplast endoplasmic reticulum (CER) which is present in chromophyte and cryptophyte algae.

In eukaryotes, the evolutionary related protein sec61-alpha plays a role in protein translocation through the endoplasmic reticulum; it is part of a trimeric complex that also consist of sec61-beta and gamma .

This entry represents two conserved sites for secY. The first corresponds to the second transmembrane region, which is the most conserved section of these proteins. The second spans the C-terminal part of the fourth transmembrane region, a short intracellular loop, and the N-terminal part of the fifth transmembrane region.
High-affinity branched-chain amino acid transport ATP-binding protein (ABC_branched_ATPase_LivF/BraG)
Type: Family

This entry represents a group of ABC-type high-affinity branched-chain amino acid transport ATP-binding proteins, including LivF from E. coli and BraG from Pseudomonas aeruginosa .
SUMO-activating enzyme subunit Uba2 (Uba2)
Type: Family

The SUMO activating enzyme E1 enzyme facilitates conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins . This entry represents a subunit of the E1 enzyme, including Uba2 from yeasts and its homologue, SAE2 from animals . E1 enzymes mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2 .
Diphthine--ammonia ligase/Uncharacterised protein MJ0570 (DPH6/MJ0570)
Type: Family

This entry includes diphthine--ammonia ligases from eukaryotes and the uncharacterised protein MJ0570 from archaea. Diphthine--ammonia ligases are amidases that catalyse the last step of diphthamide biosynthesis using ammonium and ATP .
FAD-dependent oxidoreductase SdhA/FrdA/AprA (SdhA/FrdA/AprA)
Type: Family

Two distinct, membrane-bound, FAD-containing enzymes are responsible for the catalysis of fumarate and succinate interconversion; the fumarate reductase is used in anaerobic growth, and the succinate dehydrogenase is used in aerobic growth . Succinate dehydrogenase (Sdh), a primary respiratory dehydrogenase, catalyses electron transfer from succinate to membrane-bound quinone. Fumarate reductase (Frd) catalyses the opposite reaction.

The enzyme complex consists at least of four subunits. The hydrophilic catalytic domain consists of a flavoprotein that contains covalently bound FAD and an active site of the enzyme .

Adenylylsulphate (APS) reductase catalyses reversibly the two-electron reduction of APS to sulphite and AMP during dissimilatory sulphate reduction or sulphur oxidation. Found in several bacterial lineages and in Archaeoglobales, APS reductase is a heterodimer composed of an alpha subunit containing a noncovalently bound FAD, and a beta subunit containing two [4Fe-4S] clusters. The alpha subunit of APS reductase shares a common evolutionary origin with fumarate reductase/succinate dehydrogenase flavoproteins .
Circadian clock protein kinase KaiC (KaiC)
Type: Family

This entry represents circadian clock protein kinase KaiC from bacteria and some uncharacterised KaiC-like proteins from archaea.

The circadian clock protein KaiC, is encoded in the kaiABC operon that forms the KaiABC oscillator complex which controls circadian rhythms and may be universal in Cyanobacteria . Each member contains two copies of the KaiC domain, which is also found in other proteins. KaiC performs autophosphorylation and acts as its own transcriptional repressor. The complex composition changes during the circadian cycle to control KaiC phosphorylation. KaiA stimulates KaiC autophosphorylation, while KaiB sequesters KaiA, leading to KaiC autodephosphorylation . Clock output pathways impact the RpaA transcriptional regulator. KaiC enhances the autophosphorylation activity of SasA, which then transfers its phosphate group to RpaA to activate it. KaiB and KaiC together enhance the phospho-RpaA dephosphatase activity of CikA.Kai proteins (KaiA and KaiC) appear to positively and negatively regulate kaiBC transcription which is consistent with a transcription/translation oscillatory (TTO) feedback model, believed to be at the core of all self-sustained circadian timers. However, the cyanobacterial circadian clock is able to function without de novo synthesis of clock gene mRNAs and the clock proteins, and the period is accurately determined without TTO feedback and the system is also temperature-compensated. It has been demonstrated that these three purified proteins form a temperature-compensated molecular oscillator in vitro that exhibits rhythmic phosphorylation and dephosphorylation of KaiC .

A negative-stain electron microscopy study of Synechococcus elongatus (Thermosynechococcus elongatus) and Thermosynechococcus elongatus BP-1 KaiA-KaiC complexes in combination with site-directed mutagenesis reveals that KaiA binds exclusively to the CII half of the KaiC hexamer. The EM-based model of the KaiA-KaiC complex reveals protein-protein interactions at two sites: the known interaction of the flexible C-terminal KaiC peptide with KaiA, and a second postulated interaction between the apical region of KaiA and the ATP binding cleft on KaiC. This model brings KaiA mutation sites that alter clock period or abolish rhythmicity into contact with KaiC and suggests how KaiA might regulate KaiC phosphorylation .

This entry also includes KaiC3 which represents a nonstandard KaiC homologue that seems to be linked to dark adaption of Synechocystis cells, but is not as essential as the core oscillator KaiAB1C1 for the circadian cycle .
tRNA isopentenyltransferase, eukaryotes (IPP_transferase_euk)
Type: Family

The N(6)-(isopentenyl)adenosine (i(6)A) modification of some tRNAs at position A37 is found in all kingdoms and facilitates codon-specific mRNA decoding, but occurs in different subsets of tRNAs in different species . This entry represents tRNA isopentenyltransferase from eukaryotes. It catalyses the transfer of a dimethylallyl group onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs, leading to the formation of N6-(dimethylallyl)adenosine (i6A) .
NEDD8-activating enzyme E1 regulatory subunit APP-BP1 (APP-BP1)
Type: Family

APP-BP1 (beta-Amyloid precursor protein binding protein 1), also known as Ula1 in yeasts, is a regulatory subunit of the E1 enzyme. Human APP-BP1 is necessary for cell cycle progression through the S-M checkpoint . Drosophila APP-BP1 interacts antagonistically with APPL (APP-like protein) during Drosophila development .

Ubiquitin-like proteins (ublps) are conjugated to their targets by the sequential action of E1, E2 and often E3 enzymes. Each Ublp has a dedicated E1, or activating enzyme, that initiates its conjugation cascade. In humans the NEDD8 activating E1 enzyme is a heterodimer composed of APP-BP1 and UBA3 subunits. The ubiquitin-like protein (Ublp) NEDD8 regulates cell division, signalling and embryogenesis .
Spermidine/spermine synthase, eukaryotes (Spermi_synthase_euk)
Type: Family

The ubiquitous polyamines spermidine and spermine are involved in numerous cellular functions and they are essential for cell growth and proliferation. Spermidine synthase (

) (putrescine aminopropyltransferase) catalyses the last step in the biosynthesis of spermidine from arginine and methionine; the conversion of putrescine to spermidine using decarboxylated S-adenosylmethionine as the cofactor . Spermine synthase (

) (spermidine aminopropyltransferase) converts spermidine into spermine using decarboxylated S-adenosylmethionine as the cofactor .

This entry consists of spermidine and spermine synthases from eukaryotes.
Molybdenum storage protein subunit alpha/beta (MoSto_subunit_alpha/beta)
Type: Family

Molybdenum storage protein subunits alpha and beta (MosA/MosB) are involved in intracellular storage of molybdenum. Each protein molecule can store at least 90 Mo atoms. The Mo storage protein from the nitrogen-fixing bacterium, Azotobacter vinelandii, is characterised as an alpha4-beta4 octamer containing a polynuclear molybdenum-oxide cluster which is ATP-dependent to bind Mo and pH-dependent to release Mo . MosA and MosB are related to uridine monophosphate kinase (UMPK) enzymes.
Large ribosomal subunit protein uL10, eukaryotes (uL10_eukaryotes)
Type: Family

This entry represents the eukaryotic large ribosomal subunit protein uL10 (previously known as ribosomal protein P0). It is involved in interaction between translational elongation factors and the ribosome .
Protein transport Sec61-beta/Sbh (Sec61-beta/Sbh)
Type: Family

A conserved heterotrimeric integral membrane protein complex--the Sec61 complex (eukaryotes) or SecY complex (prokaryotes)--forms a protein-conducting channel that allows polypeptides to be transferred across (or integrated into) the endoplasmic reticulum (eukaryotes) or across the cytoplasmic membrane (prokaryotes) . This complex is itself a part of a larger translocase complex.

The alpha subunits (

), called Sec61alpha in mammals, Sec61p in Saccharomyces cerevisiae (Baker's yeast), and SecY in prokaryotes, and the gamma subunits, called Sec61gamma in mammals, Sss1p in S. cerevisiae, and SecE in prokaryotes, show significant sequence conservation. Both subunits are required for cell viability in S. cerevisiae and Escherichia coli. The beta subunits, called Sec61beta in mammals, Sbh in S. cerevisiae, and SecG in archaea, are not essential for cell viability. They are similar in eukaryotes and archaea, but show no obvious homology to the corresponding SecG subunits in bacteria.
Adenylate cyclase (Adcy)
Type: Family

This entry represents a group of adenylate cyclases (ACs) from animals, including adenylate cyclase type 1-8 from humans.

Cyclic AMP (cAMP) is a ubiquitous signalling molecule which mediates many cellular processes by activating cAMP-dependent kinases and also inducing protein-protein interactions. This molecule is produced by the adenylate cyclase (AC) enzyme, using ATP as its substrate. Mammalian adenylate cyclase has nine closely related membrane-bound isoforms (AC1-9) showing significant sequence homology and sharing the same overall structure: two hydrophobic transmembrane domains, and two cytoplasmic domains that are responsible for the catalytic activity. These isoforms differ in both their tissue specificity and their regulation. Regulatory factors known to influence one or more of these isoforms include G proteins, protein kinases, calcium and calmodulin .
Pyrophosphatase, GppA/Ppx-type (PyroPPase_GppA_Ppx)
Type: Family

This entry includes guanosine-5'-triphosphate,3'-diphosphate pyrophosphatases (also known as pppGpp-5'-phosphohydrolases) and exopolyphosphatases.

Guanosine pentaphosphate (pppGpp) is a cytoplasmic signalling molecule which together with ppGpp controls the "stringent response", an adaptive process that allows bacteria to respond to amino acid starvation, resulting in the coordinated regulation of numerous cellular activities. Guanosine-5'-triphosphate,3'-diphosphate pyrophosphatase (GppA), also known as guanosine pentaphosphate phosphohydrolase, catalyses the conversion of pppGpp to ppGpp.

Exopolyphosphatases (Ppx) is involved in the degradation of inorganic polyphosphates and belongs to the same family as the guanosine pentaphosphate phosphatase .
Nudix hydrolase, AtNUDT22-type (Nudix_hydrolase_AtNUDT22)
Type: Family

This entry represents nudix hydrolases, AtNUDT22 and AtNUDT15, from Arabidopsis.

The Nudix superfamily is widespread among eucaryotes, bacteria, archaea and viruses and consists mainly of pyrophosphohydrolases that act upon substrates of general structure NUcleoside DIphosphate linked to another moiety, X (NDP-X) to yield NMP plus P-X. Such substrates include (d)NTPs (both canonical and oxidised derivatives), nucleotide sugars and alcohols, dinucleoside polyphosphates (NpnN), dinucleotide coenzymes and capped RNAs. However, phosphohydrolase activity, including activity towards NDPs themselves, and non-nucleotide substrates such as diphosphoinositol polyphosphates (DIPs), 5-phosphoribosyl 1-pyrophosphate (PRPP), thiamine pyrophosphate (TPP) and dihydroneopterin triphosphate (DHNTP) have also been described. Some superfamily members, such as Escherichia coli mutT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In procaryotes and simple eucaryotes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Nudix hydrolases are typically small proteins, larger ones having additional domains with interactive or other catalytic functions .
Lipid binding protein BPI/LBP (BPI/LBP)
Type: Family

This entry represents the bactericidal permeability-increasing protein (BPI) and the lipopolysaccharide-binding protein (LBP). The crystal structures of BPI and LBP are similar , and they may represent a common gene family of lipid-binding proteins .

In mammals, LBP and BPI mediate the biological effects of LPS (lipopolysaccharide), a glycolipid present in the outer membrane of Gram-negative bacteria. LBP is a plasma protein that enhances the inflammatory response to LPS, whereas BPI is found in lysosomal granules of polymorphonuclear neutrophils, is bactericidal, and neutralises the toxic effects of LPS .
Citrate carrier CitT-related (CitT-rel)
Type: Family

CitT catalyses a homologous exchange of citrate or a heterologous exchange against succinate, fumarate, or tartrate. Since succinate is the end product of citrate fermentation in E. coli, it is likely that CitT functions in vivo as a citrate/succinate antiporter. CitT is related to other transporters that could constitute a novel family of eubacterial transporters involved in the transport of di- and tricarboxylic acids . Included in this group would be the L-tartrate/succinate antiporter TtdT (YgjE) from E. coli .
Bifunctional NAD(P)H-hydrate repair enzyme Nnr (Nnr)
Type: Family

Nnr, also known as yjeF in E. coli, is a bifunctional enzyme that catalyses the epimerisation of the S- and R-forms of NAD(P)HX and the dehydration of the S-form of NAD(P)HX at the expense of ADP, which is converted to AMP. This allows the repair of both epimers of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration .