SII-SWORD/CoKE huggingface dataset:
Protein Kinase B, pleckstrin homology domain (PH_PKB)
Type: Domain

PKB (also called Akt) is a phosphatidylinositol 3'-kinase (PI3K)-dependent Ser/Thr kinase which alters the activity of the targeted protein . Among its many roles, Akt appears to be common to signaling pathways that mediate the metabolic effects of insulin in several physiologically important target tissues. Human Akt has three isoforms derived for distinct genes: Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma. All Akts have an N-terminal PH domain with an activating Thr phosphorylation site, a kinase domain, and a short C-terminal regulatory tail with an activating Ser phosphorylation site . The PH domain recruits Akt to the plasma membrane by binding to phosphoinositides (PtdIns-3,4-P2) and is required for activation. The phosphorylation of Akt at its Thr and Ser phosphorylation sites leads to increased Akt activity toward forkhead transcription factors, the mammalian target of rapamycin (mTOR), and the Bcl-xL/Bcl-2-associated death promoter (BAD), all of which possess a consensus motif R-X-R-XX-ST-B (X = amino acid, B = bulky hydrophobic residue) for Akt phosphorylation .

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized .
PDK/BCKDK protein kinase (BCKD/PDK)
Type: Family

This entry includes [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase (BCKDK) and [Pyruvate dehydrogenase (acetyl-transferring)] kinase (PDK). BCKDK is a serine/threonine-protein kinase component of macronutrients metabolism. It forms a functional kinase and phosphatase pair with PPM1K, serving as a metabolic regulatory node that coordinates branched-chain amino acids (BCAAs) with glucose and lipid metabolism via two distinct phosphoprotein targets: mitochondrial BCKDHA subunit of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex and cytosolic ACLY, a lipogenic enzyme of Krebs cycle .
Mucolipin (Mucolipin)
Type: Family

Mucolipin (TRPML) family members, including Mucolipin 1/2/3 (TRPML1/2/3), are ion channel proteins that belong to the transient receptor potential (TRP) superfamily of cation channels. They are non-selective cation channels with six predicted transmembrane domains and intracellular N and C terminus regions. They have a channel pore located between TM5 and TM6 that is permeable to sodium (Na+) and calcium ions (Ca2+) . The TRPMLs exist as homomeric or heteromeric channels . They may play a role in endosome-lysosome fusion, scission of endo-lysosomal hybrid organelle, autophagy, vacuolar pH regulation, exocytosis, and metal homeostasis .
Rim-like (Rim-like)
Type: Family

RIM proteins are scaffolding proteins at the active zone which bind to several other presynaptic proteins. The long isoforms of RIM proteins, which contain N-terminal Rab3 and Munc13 interacting domains, as well as a central PDZ domain and two C-terminal C2 domains, are encoded by two genes, Rim1 and Rim2 . They have multiple isoforms (alpha, beta, gamma) diverging in their structural composition, which mediate overlapping and distinct functions . These isoforms are involved in determining Ca2+ channel density and vesicle docking at the presynaptic active zone .

This entry includes Rim and related proteins. In Caenorhabditis elegans Rim acts after vesicle docking likely via regulating priming .
Inositol 3,4-bisphosphate 4-phosphatase (INPP4)
Type: Family

This entry includes INPP4A and INPP4B. They are inositol lipid 4-phosphatases that hydrolyze PtdIns(3,4)P2, a phosphoinositide generated by PI3K signaling . They contain a C2 domain in their N termini and a phosphatase domain at their C termini. INPP4A is a suppressor of glutamate excitotoxicity in the central nervous system , while INPP4B acts as a tumour suppressor .
Granulin family (Granulin_fam)
Type: Family

Metazoan granulins are a family of cysteine-rich peptides of about 6 kDa which may have multiple biological activity. A precursor protein (known as acrogranin) potentially encodes seven different forms of granulin (grnA to grnG) which are probably released by post-translational proteolytic processing. Granulins are evolutionary related to PMP-D1, a peptide extracted from the pars intercerebralis of migratory locusts . In humans, Progranulin (PGRN) is of 7.5 granulin repeats encoded by the granulin (GRN) gene. It is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis . Progranulin can be processed in the lysosome through the actions of cathepsins . Haploinsufficiency of progranulin causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL) .
Aspartyl/asparaginyl beta-hydroxylase family (ASPH)
Type: Family

Aspartyl/asparaginyl beta-hydroxylase hydroxylates an Asp or Asn residue in certain epidermal growth factor-like domains of a number of proteins .
RAI1-like family (RAI1-like_fam)
Type: Family

Yeast RAI1 is homologous to Caenorhabditis elegans DOM-3 and human DOM3Z (DXO). They have both decapping and 5'-3' exoribonuclease activity and are a component of the mRNA 5'-end capping quality control mechanism . RAI1 is a single-copy gene in most organisms; however S. cerevisiae contains a second homologue, DXO1, which also possesses decapping and 5'-3' exoribonuclease activity, whereas RAI1 has decapping and pyrophosphohydrolase activities . This domain is also found in DXO1 homologue from Arabidopsis .

This entry also includes protein Cutoff (Cuff) from Drosophila. Differently from Rai1, Cuff does not display a Dom3Z domain, which is critical for Rai1 activity. Rai1 has been shown to regulate piRNA cluster expression and piRNA production in the Drosophila germline .
NAB family (NAB_fam)
Type: Family

Proteins in this family are transcriptional regulators, including Nab (NGFI-A-binding protein) from Drosophila and Nab1/2 from mammals. Nab1 and Nab2 are co-repressors that specifically interact with and repress transcription mediated by the three members of the NGFI-A (Egr-1, Krox24, zif/268) family of eukaryotic (metazoa) transcription factors . Drosophila Nab controls the activity of zinc-finger transcription factors, such as Squeeze and Rotund, in Drosophila development .
Nav/unc-53 family (Nav/unc-53)
Type: Family

This entry include Nav1/2/3 from mammals, unc-53 from C. elegans. They contain a calponin homology (CH) domain in the N terminus, several coiled-coil regions, polyproline rich SH3 binding motifs, and an ATPases associated with diverse cellular activities domain (AAA domain) . They are required for the migration of cells and neuronal processes. Nav2 has been shown to rescue the mechanosensory neuron outgrowth defects of unc-53 mutants . Unc-53 has been found to bind to ABI-1, a regulator of Arp2/3 mediated actin filament nucleation . The Drosophila Nav2 homologue Sickie, also included in this family, regulates F-actin-mediated axonal growth .
UDP-N-acetylglucosamine transferase subunit Alg13-like (Alg13-like)
Type: Family

Alg13 is the catalytic component of UDP-GlcNAc transferase essential for the second step of the dolichol-linked oligosaccharide pathway. The UDP-GlcNAc transferase complex consists of Alg13 and Alg14, Alg14 being a membrane-spanning subunit required to recruit Alg13 to the cytosolic face of the ER . Alg13 has homology to the C-terminal domain of the bacterial glycosyltransferase Murg .
Zinc finger protein-like 1 (ZFPL1)
Type: Family

ZFPL1 is a ring finger protein required for cis-Golgi integrity and efficient ER-to-Golgi transport . It may have a role in regulating autophagy .
tRNA:m(4)X modification enzyme Trm13 (Trm13)
Type: Family

Trm13 is a tRNA methylase that catalyzes 2'-O-methyladenosine (Am) nucleoside formation on tRNA(Gly)(GCC) . In rice Trm13 regulates salt stress tolerance .
Schwannomin interacting protein 1 (SCHIP_1)
Type: Family

SCHIP-1 is a coiled-coil protein that specifically associates with schwannomin in vitro and in vivo. The product of the neurofibromatosis type 2 (NF2) tumour suppressor gene, known as schwannomin or merlin, is involved in NF2-associated and sporadic schwannomas and meningiomas. It is closely related to the ezrin-radixin-moesin family members, which link membrane proteins to the cytoskeleton. Association with SCHIP-1 can be observed only with some naturally occurring mutants of schwannomin, or a schwannomin spliced isoform lacking exons 2 and 3, but not with the schwannomin isoform exhibiting growth-suppressive activity .

This entry also includes IQ motif containing J-Schwannomin-Interacting Protein 1 (IQCJ-SCHIP-1), an isoform of the SCHIP-1. IQCJ-SCHIP-1 is a multipartner ankyrin- and spectrin-binding protein involved in the organization of nodes of ranvier .
PDPK1 family (PDPK1)
Type: Family

This family includes 3-phosphoinositide-dependent protein kinase 1 (PDK1 or PDPK1) and related kinases from yeast: Pkh1 and Pkh2 from S. cerevisiae, which function similarly to PDK1 , and Ksg1 and Ppk21 from S. pombe .

PDK1 is the kinase responsible for the phosphorylation of PKB/Akt on the activation loop, at threonine 308, which is essential for Akt activation . Beyond Akt, PDK1 is responsible for the phosphorylation of many other AGC kinases including serum/glucocorticoid regulated kinase (SGK) and the members of protein kinase C (PKC) family . PDK1 is implicated in signaling pathways frequently altered in cancer, such as PI3K/Akt, Ras/MAPK and Myc . It is a key regulator of cell migration and tumor invasion . PDK1 binds to the insulin receptor, followed by tyrosine phosphorylation of PDK1 by the insulin receptor, which is necessary for insulin metabolic signaling .
Phosphorylated adapter RNA export protein (PHAX)
Type: Family

The phosphorylated adaptor for RNA export (PHAX) protein is required for nuclear export of snRNAs in metazoans and also involved in the intranuclear transport of snoRNAs to Cajal bodies .
Mitochondrial pseudouridylate synthase Trub2 (Trub2)
Type: Family

Pseudouridine, the most common RNA modification, has been suggested to play a role in RNA stability, RNA folding/secondary structure, and translation efficiency and fidelity. Trub2 has been identified as a pseudouridine synthase that contributes to the conversion of uridine to pseudouridine (PSI) at position 390 in mitochondrial COXI (MT-CO1) mRNA and at position 697-699 in mitochondrial COXIII (MT-CO3) mRNA . Trub2 also catalyses pseudouridylation of some tRNAs, including synthesis of pseudouridine(55) from uracil-55, in the psi GC loop of a subset of tRNAs .
Elongin B (ELOB)
Type: Family

Elongin B is a subunit of the transcription factor B (SIII) complex, which activates elongation by mammalian RNA polymerase II by suppressing transient pausing of the polymerase at many sites within transcription units. Elongin is a heterotrimer composed of A, B, and C subunits. Elongin A functions as the transcriptionally active component of Elongin (SIII), while Elongin B and C are regulatory subunits .

Elongin B has been shown to form complex with Elongin C and VHL (von Hippel-Lindau, a tumour suppressor). This complex, known as the VBC complex, shows structural similarities with the SCF complex . The VBC complex binds to hypoxia-inducible factor 1alpha (HIF-1alpha) via VHL and targets HIF-1alpha for ubiquitination .
GATA zinc finger domain-containing protein 1 (GATAD1)
Type: Family

The function of GATAD1 is not clear. It interacts with H3K4me3 and Jarid1a/EMSY/Sin3 and is thought to be involved in epigenetic repression .
SE-cephalotoxin-like (SE-CTX-like)
Type: Family

SE-cephalotoxin was reported in the salivary gland of the cuttlefish Sepia esculenta. Cephalopods contain toxins in their salivary glands, which may help to paralyze prey animals. This protein seems to be conserved in bonyfishes; it has been found in the swim bladder of the European Eel .

This entry also includes protein rapunzel, whose function is still not clear. Mutations of the rapunzel gene cause skeletal overgrowth in Zebrafish .
Antitoxin PemI-like (Antitox_PemI-like)
Type: Family

This family includes antitoxin components of a type II toxin-antitoxin (TA) system belongig to the PemI family. The PemI/PemK plasmid addiction system consists of PemK, an endoribonuclease toxin, and its cognate antitoxin, PemI. Toxin PemK inhibits cell growth by acting as an endoribonuclease, and antitoxin PemI prevents PemK activity by direct binding . PemI and PemK, found in E. coli plasmid R100, are responsible for its stable inheritance during cell division .

Other antitoxins in this family are MazE and ChpS . These are part of chromosomal addiction modules. The mechanism of antidote-toxin recognition is common to both chromosomal and plasmid-borne addiction modules.
Int12, PHD finger (Int12_PHD)
Type: Domain

Int12 is a component of integrator, a multi-protein mediator of small nuclear RNA processing. The integrator complex directly interacts with the C-terminal domain of RNA polymerase II (RNAPII) largest subunit and mediates the 3' end processing of small nuclear RNAs (snRNAs) U1 and U2 . Different from other components of integrator, Int12 contains a PHD finger, which is not required for snRNA 3' end cleavage. Instead, Int12 harbors a small microdomain at its N terminus which is necessary and sufficient for Int12 function; this microdomain facilitates Int12 binding to Int1 and promotes snRNA 3' end formation .

This entry represents the PHD finger of Int12.
MCU family (MCU_fam)
Type: Family

This entry represents the MCU family, whose members include MCU and MCUb from mammals and MCU1-6 from Arabidopsis. MCU is a mitochondrial inner membrane calcium uniporter that mediates calcium uptake into mitochondria . MCUb negatively regulates the activity of MCU .
CDC42 small effector protein (SPEC)
Type: Family

This entry represents a group of Cdc42-binding proteins known as SPECs (for small protein effector of Cdc42), including SPEC1 and SPEC2 from humans. SPECs modulate the activity of the Rho GTPase Cdc42, which plays important roles in actin polymerization and kinase signaling . SPEC1 and SPEC2 play a role in F-actin accumulation in activated T lymphocytes and may play a role in early contractile events in phagocytosis .
Sporulation-specific protein 22/ZIP4 (Spo22/ZIP4)
Type: Family

Spo22/Zip4 is a meiosis-specific protein that promotes chromosome synapsis and regulates crossover distribution in budding yeast . This family includes the homologue from plants .
Yippee family (Yippee_fam)
Type: Family

The Yippee-like (YPEL) family proteins share homology to drosophila Yippee, a zinc finger binding protein. YPEL proteins are found in essentiallly all the eukaryotes and hence they must play important roles in the maintenance of life. Subcellular localization of all YPEL proteins to the centrosomes and the mitotic apparatus suggest their role in the mitosis-associated function. YPEL proteins contain a Yippee domain, which is a putative zinc-finger-like, metal-binding domain .
Major vault protein (MVP)
Type: Family

The major vault protein is the major polypeptide component of a large cellular ribonuclear protein complex found in the cytoplasm of eukaryotic cells (known as vaults). Several roles for vaults have been proposed. Vault proteins have been associated with development of multi-drug resistance . They have also being implicated in the regulation of several cellular processes including transport mechanisms, signal transmission and immune responses .
Antitoxin HigA (Antitox_HigA)
Type: Family

HigA is the antitoxin component of a type II toxin-antitoxin (TA) system HigB/HigA. The toxin protein HigB is a ribosome-dependent mRNA interferase belonging to RelE family, which cleave mRNAs at the ribosomal A site. The antitoxin HigA possesses DNA binding activity within its helix-turn-helix fold (HTH) and modulates HigBA expression .
MDN2-binding protein (MTBP)
Type: Family

This entry represents the MDM2-binding protein (MTBP). MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination of p53, leading to its degradation by the proteasome . MTBP inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability, and this promotes MDM2-mediated ubiquitination of p53 and its subsequent degradation . Mouse MTBP also inhibits cancer cell migration by interacting with alpha-actinin-4 (ACTN4) .
Spermatogenesis-associated protein 1 (SPAT1)
Type: Family

The spermatogenesis associated 1 (SPATA1) protein is thought to be involved in spermatogenesis and is a potential marker for male fertility .
Riboflavin kinase, CTP-dependent (RibK_CTP-dep)
Type: Family

This entry represents the CTP-dependent riboflavin kinase, found primarily in archaea, that catalyses the phosphorylation of riboflavin to form flavin mononucleotide in riboflavin biosynthesis. It uses CTP as the donor nucleotide. Its structure resembles a RIFT barrel, structurally similar to but topologically distinct from bacterial and eukaryotic examples . The N-terminal is a winged helix-turn-helix DNA-binding domain, and the C-terminal half is most similar in sequence to a group of cradle-loop barrels.
Zinc finger protein 750-like, zinc finger (ZNF750_Znf)
Type: Domain

This entry represents a zinc finger found in ZNF750 and related proteins. ZNF750 is a transcription factor that controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes . Proteins containing this domain also include proline-rich protein 35. Its function is not clear.
AcoX-like (AcoX-like)
Type: Family

Members of this group are predicted to be kinases (possibly ATP-NAD kinases) from prokaryotes. Some of them are known as AcoX, as they are encoded by genes found in clusters responsible for acetoin catabolism in some bacteria and archaea .
Hepatocyte nuclear factor 1 (HNF-1)
Type: Family

Hepatocyte nuclear factor 1-alpha (HNF1A, TCF1) and hepatocyte nuclear factor 1-beta (HNF1B, TCF2) are homeodomain-containing transcription factors expressed in the pancreas, liver, kidney, and intestine, where they direct tissue-specific gene regulation . They play an essential role in the development and differentiation of pancreatic precursor cells . Mutations in HNF1beta and HNF1alpha cause autosomal dominant diabetes maturity-onset diabetes of the young (MODY), which is a monogenic form of non-insulin-dependent type 2 diabetes. Mutations in HNF1A are responsible for type 3 MODY (MODY3) , whereas the HNF1B gene is linked to a rare case of type 5 MODY (MODY5) .
Pyrroloquinoline-quinone synthase-like (PqqC-like)
Type: Family

This entry describes the coenzyme PQQ (pyrrolo-quinoline-quinone) biosynthesis protein PqqC and its related protein, CADD. Pyrroloquinoline quinone (PQQ) is the prosthetic group of several bacterial enzymes, including methanol dehydrogenase of methylotrophs and the glucose dehydrogenase of a number of bacteria . PQQC is an oxidase whose reaction involves a ring closure and eight-electron oxidation of its substrate (AHQQ) to produce PQQ .

Chlamidia specific toxin CADD, also known as PqqC-like protein, which induces apoptosis in mammalian cell lines . BesC from Streptomyces cattleya, shows homology to CADD, has been shown to catalyse formation of 4-Cl-allylglycine from 4-Cl-lysine and requires Fe(II) as a cofactor .
Carbohydrate esterase 7 family (CE7)
Type: Family

Carbohydrate esterase 7 (CE7) enzymes possess multifunctional deacetylase activity against a range of small substrates. The family includes cephalosporin-C deacetylases and acetylxylan esterases (AXEs) . These enzymes preferably deacetylate cephalosporin C, acetylated xylose, and short xylooligosaccharides.
ATP synthase protein I, Bacilli-type (ATP_synth_I_Bacilli)
Type: Family

The atp operon of most prokaryotes contains the structural genes for the F-ATPase (ATP synthase), which are preceded by an atpI gene that encodes a membrane protein of unknown function. AtpI is thought to support optimal ATP synthase assembly and stability . A role in magnesium uptake has also been suggested .

Proteins in this entry are found only in Gram-positive bacteria from the phylum Firmicutes.
GGGP/HepGP synthase group I (GGGP/HepGP_synthase_I)
Type: Family

Geranylgeranylglyceryl phosphate synthase (GGGPS) family enzymes catalyse the formation of an ether bond between glycerol-1-phosphate and polyprenyl diphosphates. They are essential for the biosynthesis of archaeal membrane lipids, and also occur in bacterial species. Two phylogenetic groups (I and II) of GGGPS family enzymes exist. Bacterial group I enzymes are heptaprenylglyceryl phosphate synthases .
Cell division protein DivIC (DivIC)
Type: Family

DivIC was identified as a gene required for vegetative and sporulation septum formation in Bacillus subtilis . DivIC forms a trimeric complex with another two proteins that are essential for cell division, DivIB and FtsL. The trimeric complex localizes at the septum and is regulated during the cell cycle through controlled formation of the DivIC/FtsL heterodimer . DivIC seems to stabilizes FtsL against RasP cleavage .
SNAP25, N-terminal SNARE motif, chordates (SNAP-25_N_SNARE_chord)
Type: Domain

This entry represents the N-terminal SNARE motif of SNAP25 and similar proteins from chordates.

SNARE proteins are involved in the fusion of vesicles with their target membranes. Synaptosomal-associated protein 25 (SNAP25) regulates Kv2.1 voltage-dependent K(+) channels in pancreatic beta cells . It may also play a role in neurotansmiiter release form the synapse. It is a component of the SNARE core complex, which also includes VAMP2 and STX1A . In some fish species (goldfish, zebrafish) there are two homologues known as SNAP-25A and SNAP-25B.
Gastric inhibitory polypeptide (GIP)
Type: Family

Gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide (GIP) is a hormone released from duodenal K cells in a glucose-dependent manner . It is considered an incretin hormone as it stimulates the secretion of insulin in the presence of elevated glucose; the other incretin being glucagon-like peptide-1 (GLP-1). It acts through the GIP receptor (GIPR) expressed in pancreatic beta-cells . GIP plays a role in glucose and lipid metabolism. It increases lipoprotein lipase (LPL) expression and activity, and promotes fatty acid incorporation and synthesis . It is associated with obesity and insulin resistance .
Thrombospondin-5, coiled coil domain (TSP-5_CC)
Type: Domain

This entry represents the N-terminal coiled coil region of TSP-5, also known as cartilage oligomeric matrix protein (COMP). It forms a pentameric left-handed coiled coil (COMPcc) with a channel that is a unique carrier for lipophilic compounds . It is known to bind hydrophilic signaling molecules such as vitamin D3 and vitamin A, making it a possible targeted drug delivery system . TSP-5/COMP is expressed in all types of cartilage as well as in the vitreous of the eye, tendons, vascular smooth muscle cells, and heart. The pentamer is stabilized by inter-subunit disulfide bonds formed between cysteine residues adjacent to the C-terminal end of the coiled coil region .
DDB1- and CUL4-associated factor 10 (DCA10)
Type: Family

DCA10 may function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex .
Deubiquitinating protein VCPIP1 (VCPIP1)
Type: Family

VCPIP1, also known as VCIP135, is a deubiquitinating enzyme that functions in p97/p47-mediated Golgi reassembly . It hydrolyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitin chains . It has also been found to dictate the duration of botulinum neurotoxin type A intoxication . VCPIP1 can also deubiquitinate SPRTN (a metalloprotease that cleaves DNA-protein crosslinks) and promotes its chromatin relocalization .
Immunoglobulin superfamily member 6 (IGSF6)
Type: Family

The function of IGSF6 (also known as DOwn-Regulated by Activation or DORA) is not clear. The human gene is encoded with an intron of the METTL9 gene; this locus is locus associated with inflammatory bowel disease and activation of dendritic cells by CD40L down-regulates the DORA gene .