SII-SWORD/CoKE huggingface dataset:
ASH1-like, Bromodomain (Bromo_ASH1L)
Type: Domain

This entry includes ASH1 from flies and ASH1L from mammals. ASH1/ASH1L are the members of the Trithorax family.

In Drosophila melanogaster, ASH1 (absent, small, or homeotic 1) is an epigenetic transcriptional regulator of HOX genes. Drosophila ASH1 has been shown to methylate specific lysines in histones H3 and H4. Mammalian ASH1 has been shown to methylate histone H3 .

ASH1L methylates Lys36 of histone H3 independently of transcriptional elongation to promote the establishment of Hox gene expression by counteracting Polycomb silencing . It can suppress interleukin-6 (IL-6), and tumour necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20 . ASH1L contains an associated with SET domain (AWS), a SET domain, a post-SET domain, a bromodomain, a bromo-adjacent homology domain (BAH), and a plant homeodomain (PHD) finger .

This entry represents the Bromodomain domain of ASH1 and ASH1L.
BACH, basic leucine zipper (bZIP) domain (bZIP_BACH)
Type: Domain

BACH proteins are Cap'n'Collar (CNC) Basic leucine zipper (bZIP) transcription factors that are defined by a conserved 43-amino acid region (called the CNC domain) located N-terminal to the bZIP DNA-binding domain. In addition, they contain a BTB domain (Broad complex-Tramtrack-Bric-a-brac domain, also known as the POZ [poxvirus and zinc finger] domain) that is absent in other CNC proteins.

Veterbrates contain two members, BACH1 and BACH2. BACH1 forms heterodimers with small Mafs such as MafK to function as a repressor of heme oxygenase-1 (HO-1) gene (Hmox-1) enhancers . It has also been implicated as the master regulator of breast cancer bone metastasis . The BACH1 bZIP transcription factor should not be confused with the protein originally named as BRCA1-Associated C-terminal Helicase1 (BACH1), which has been renamed BRIP1 (BRCA1 Interacting Protein C-terminal Helicase1) and also called FANCJ. BACH2 is a B-cell specific transcription factor that plays a critical role in oxidative stress-mediated apoptosis . It plays an important role in class switching and somatic hypermutation of immunoglobulin genes .
C-terminal binding protein (CtBP)
Type: Family

The transcriptional corepressor CtBP is a dehydrogenase with sequence and structural similarity to the d2-hydroxyacid dehydrogenase family. CtBP was initially identified as a protein that bound the PXDLS sequence at the adenovirus E1A C-terminal, causing the loss of CR-1-mediated transactivation. CtBP binds NAD(H) within a deep cleft, undergoes a conformational change upon NAD binding, and has NAD-dependent dehydrogenase activity .
Peptidyl-prolyl cis-trans isomerase PIN4 (PIN4)
Type: Family

PIN4, also known as Par14, is a member of the parvulin family of peptidyl-prolyl cis-trans isomerases. It is involved in rRNA processing, microtubule formation and the glucose metabolism . It also binds DNA and associates with chromatin .
PKHG1/2/3, pleckstrin homology domain (PH_PLEKHG1_G2_G3)
Type: Domain

PLEKHG1 (also called ARHGEF41), PLEKHG2 (also called ARHGEF42 or CLG/common-site lymphoma/leukaemia guanine nucleotide exchange factor2), and PLEKHG3 (also called ARHGEF43) have RhoGEF DH/double-homology domains in tandem with a PH domain which is involved in phospholipid binding. They function as a guanine nucleotide exchange factor (GEF) and are involved in the regulation of Rho protein signal transduction . Mutations in PLEKHG1 have been associated panic disorder (PD), an anxiety disorder characterised by panic attacks and anticipatory anxiety .

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 polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.
Alpha-Amylase Inhibitors (AAI), Lipid Transfer (LT) and Seed Storage (SS) Protein (LTSS)
Type: Family

This entry represents a protein family unique to higher plants that includes cereal-type alpha-amylase inhibitors , lipid transfer proteins , seed storage proteins, and similar proteins . Proteins in this family are known to play important roles, in defending plants from insects and pathogens, lipid transport between intracellular membranes, and nutrient storage . Many proteins of this family have been identified as allergens in humans . These proteins contain a common pattern of eight cysteines that form four disulfide bridges.
Ras GTPase GNL1-like (GNL1-like)
Type: Family

GNL1, also known as HSR1, is localized to the human MHC class I region and is highly homologous to a putative GTP-binding protein, MMR1 from mouse. These proteins represent a new subfamily of GTP-binding proteins that has only eukaryote members .

This entry also includes Lsg1 from budding yeasts, LSG1-2 from Arabidopsis and Ns3 from fruit flies. Yeast Lsg1 is involved in 60S ribosomal subunit biogenesis . LSG1-2 is required for 40S maturation . Ns3 regulates insulin signaling and control body size
.
C2H2-type zinc-finger protein GLI-like (GLI-like)
Type: Family

This entry includes a group of zinc finger transcription regulators, including GLI1-3, GLIS1-3 and ZIC1-5 from humans.

GLI1-3 are central effectors of the Hedgehog (Hh) pathway in vertebrates . GLI1 is an obligatory activator, whereas GLI2 and GLI3 carry activator and repressor functions . The full-length GLI3 form, after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while its C-terminally truncated form acts as a repressor (GLI3R). GLI3 participates in the patterning and growth of many organs, including the central nervous system (CNS) and limbs .

ZIC1-5 are transcriptional activators that control several developmental processess . ZIC3 is required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. It binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3' . ZIC4/5 show DNA-binding activity to the Gli-binding sequence (GLIS), similar to ZIC1-3 proteins

]. ZIC5 is essential for neural crest development, converting cells from an epidermal fate to a neural crest cell fate .

GLIS1-3 play key roles in the regulation of a number of physiological processes and have been implicated in several pathologies. Glis1-3 share a highly homologous zinc finger domain (ZFD) containing five Cys2-His2-type zinc finger (ZF) motifs with members of the Gli and Zic family .
PP2B (PP2B)
Type: Family

PP2B (calcineurin) is a unique serine/threonine protein phosphatase in its regulation by a second messenger (calcium acting via calmodulin) . PP2B is involved in many biological processes including immune responses, the second messenger cAMP pathway, sodium/potassium ion transport in the nephron, cell cycle progression in lower eukaryotes, cardiac hypertrophy and memory formation. PP2B is highly conserved from yeast to humans, but is absent from plants. PP2B is a heterodimer consisting of a catalytic subunit (CnA) and a regulatory subunit (CnB); CnB contains four Ca2 binding motifs referred to as EF hands .
DnaJ homolog subfamily C member 16, TRX domain (DNAJC16_TRX)
Type: Domain

This entry represents the TRX domain found in DNAJC16.

DNAJC16 contains an N-terminal DnaJ domain followed by one redox active TRX domain. DnaJ is a member of the 40kDa heat-shock protein (Hsp40) family of molecular chaperones, which regulate the activity of Hsp70s. TRX is involved in the redox regulation of many protein substrates through the reduction of disulfide bonds. TRX has been implicated to catalyse the reduction of Hsp33, a chaperone holdase that binds to unfolded protein intermediates. The presence of DnaJ and TRX domains in members of this family suggests that they could be involved in a redox-regulated chaperone network .
NACHT domain- and WD repeat-containing protein 1 (NWD1)
Type: Family

NWD1 is involved in androgen receptor (AR) signaling .
HECTD4 (HECTD4)
Type: Family

The function of HECTD4 is not clear.
Phospholipase A1 PLIP1/2/3, chloroplastic (PLIP1/2/3)
Type: Family

This entry includes a group of plant glycerolipid A1 lipases, including PLIP1/2/3 from Arabidopsis. PLIP1 is a plastid phospholipase A1 that releases polyunsaturated fatty acids from chloroplast phosphatidylglycerol, leading to the export of the fatty acids to the ER for seed oil biosynthesis . PLIP2/3 are also present in the chloroplasts. They respond to ABA and are involved in jasmonic acid biosynthesis .
Peptidyl-prolyl cis-trans isomerase FKBP3 (FKBP3)
Type: Family

FKBP3, also known as FKBP25, contains the N-terminal basic tilted helix bundle (BTHB) domain and the C-terminal PPIase domain. It is a nuclear prolyl isomerase that interacts directly with nucleic acids . It interacts with the histone deacetylases HDAC1 and HDAC2 as well as with their transcriptional regulator Yin Yang 1 (YY1) . It is also a microtubule-associated protein that shuttles between nucleus and cytoplasm and stabilizes the microtubule network by direct binding of the C-terminal PPIase domain . It plays a role in the proliferation of non-small cell type lung cancer cells (NSCLC) by modulating Sp1/HDAC2/p27 .
Melanoma-derived growth regulatory protein (MIA)
Type: Family

Melanoma-derived growth regulatory protein or Melanoma inhibitory activity (MIA) is a 12kDa protein that is secreted from both chondrocytes and malignant melanoma cells. It has effects on cell growth and adhesion and it may play a role in melanoma metastasis and cartilage development. MIA elicits growth inhibition on melanoma cells in vitro. It is possible that secretion of MIA in vivo leads to decreased adhesiveness of melanocytic cells and thereby promotes melanoma progression and invasion .
Ionotropic glutamate receptor, delta subfamily (IGluR_D)
Type: Family

Glutamate delta-1 (GluD1) and delta-2 (GluD2) constitute the delta subfamily of ionotropic glutamate receptors. They have a crucial role in synapse formation by interacting with presynaptic proteins such as Neurexin-1. GluD1 is expressed diffusively throughout the forebrain and cerebellum during early development and adulthood, with high levels in the hippocampus , whereas GluD2 is predominantly expressed in the Purkinje cells of the cerebellum .

It has been shown that delta receptors (GluD1, GluD2) might play a role in the underlying pathophysiology of autism and schizophrenia .

This entry represents the ionotropic glutamate receptors delta 1 and delta 2.
GPCR-associated sorting protein 1-3 (GASP1-3)
Type: Family

This entry includes a group of GPCR-associated sorting proteins, including GASP1, GASP2 and GASP3 (also known as BHLHb9/p60TRP).

GASP3/BHLHb9 modulates the phosphorylation and proteolytic processing of amyloid precursor protein (App), N-catherin (Cdh), presenilin (Psen) and tau protein, which might be a new therapeutic target for the treatment of Alzheimer's disease. It also regulates Ngf-dependent neuronal survival and differentiation, promoting neurosynaptogenesis . GASP3 is expressed in central nervous system, heart and skeletal muscle, conferring a possible involvement in cardiovascular functions .

GASP-1 regulates the degradation of several GPCRs that traffic to lysosomes after agonist-induced endocytosis. It also interacts with Beclin 2, which is essential for GPCR degradation .

GASP-2 is thought to play a role in the regulation of a variety of GPCRs.
Fibrous sheath CABYR-binding protein (FSCB)
Type: Family

Fibrous sheath CABYR (Calcium Binding Tyrosine-(Y)-Phosphorylation Regulated) binding protein (FSCB) is a testis- and sperm-specific protein that is expressed post-meiotically and localised in mouse sperm flagella. FSCB homologues are present in other mammals, including rat and human. Conserved motifs in FSCB include PXXP, proline-rich and extensin-like regions .

FSCB is regulated by protein kinase A (PKA)-mediated tryrosine phosphorylation. Its capacity of being phosphorylated and binding to calcium enhances the spermatozoa flagellar movement, spermatozoa capacitation and activation. FSCB phosphorylation activates spermatozoa motility and inhibits SUMOylation of two crucial proteins ROPN1/ROPN1L that are associated with PKA/A kinase activity and spermatozoa motility .
Protein NPG1-like (NPG1-like)
Type: Family

This entry includes a group of plant proteins, including NPG1 and related proteins (NPGR1 and NPGR2). In Arabidopsis, NPG1 (No Pollen Germination1) is expressed only in pollen, whereas the NPG-related proteins (NPGR1 and NPGR2) are expressed in pollen and other tissues. NPG1 is a calmodulin-binding protein that is essential for pollen germination .
Glutathione S-transferase T1/2/3 (GSTT1/2/3)
Type: Family

This entry represents a group of glutathione S-transferases from plants, including GSTT1/2/3 from Arabidopsis .
Paired mesoderm homeobox protein 1/2 (PRRX1/2)
Type: Family

This entry includes the paired-class homeobox proteins Prx1 and Prx2. They play essential roles in limb, heart and craniofacial development . They are required for correct mouse skeletogenesis in many structures . They may be involved in the early stage of rat pituitary differentiation and play a role in morphogenesis of the chick mandibular processes .
Ankyrin and armadillo repeat-containing protein (ANKAR)
Type: Family

The function of ANKAR is not clear.
Germ cell-less protein-like (Gcl-like)
Type: Family

This entry includes protein germ cell-less (Gcl) from Drosophila melanogaster and related proteins, such as GMCL1 and GMCL2 from mammals. Gcl is required for germline formation . It promotes PGC (Primordial Germ Cells) fate by mediating degradation of Torso, a receptor tyrosine kinase (RTK) and major determinant of somatic cell fate .
Solute carrier family 15 member 2 (SLC15A2)
Type: Domain

Solute carrier family 15 member 2 (SLC15A2), also called peptide transporter 2 (PepT2), is a member of the proton-coupled oligopeptide transporter (POT) family of integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs. The POT family belongs to the Major Facilitator Superfamily (MFS) of membrane transport proteins. SLC15A2, as well as SLC15A1, mediate the proton-coupled active transport of a broad range of dipeptides and tripeptides, including zwitterionic, anionic and cationic peptides, as well as a variety of peptide-like drugs such as cefadroxil, enalapril, and valacyclovir . SLC15A2 is a high-affinity transporter and is abundantly expressed in the apical membrane of kidney proximal tubules and choroid plexus epithelial cells. It is the major transporter involved in the reclamation of peptide-bound amino acids and peptide-like drugs in the kidney, and is also called the renal isoform. In choroid plexus and the brain, it acts as an efflux transporter and plays a role in regulating peptide/neuropeptide homeostasis . SLC15A2, as a member of MFS, is thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.
Reprimo family (Reprimo_fam)
Type: Family

This entry includes Reprimo and Reprimo-like proteins.

Reprimo (RPRM) has been identified as a downstream effector of p53-induced cell cycle arrest at G2/M . Overexpression of RPRM induces G2 arrest by inhibiting both Cdc2 activity and nuclear translocation of the Cdc2-cyclin B1 complex. RPRM promoter methylation has been reported in several tumours .

The function of reprimo-like protein is not known. It is a paralogue of Reprimo, a downstream effector of p53-induced cell cycle arrest at G2/M .
Reticulophagy receptor 1/3 (RETREG1/3)
Type: Family

This entry include reticulophagy receptor 1 and reticulophagy receptor 3.

Reticulophagy receptor 1, previously known as FAM134B, is essential for endoplasmic reticulum (ER) homeostasis. It is a ER resident receptor that binds to autophagy modifiers LC3 and GABARAP, and facilitates ER degradation by autophagy. It may promote membrane remodelling and ER scission via the membrane-bending capacity of its reticulon domain, whereas its LIR motif may be necessary to target the ER fragments to autophagosomes for lysosomal degradation .

Reticulophagy regulator 3 (RETREG3), also known as FAM134C, mediates NRF1-enhanced neurite outgrowth. NRF1 (nuclear respiratory factor-1) is a major transcription factor that can positively regulate FAM134C . Members of the FAM134 protein family, including FAM134C, are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy .
Granule associated Rac and RHOG effector protein 1 (GARRE1)
Type: Family

This entry represents the granule associated Rac and RHOG effector protein 1 (GARRE1), also known as KIAA0355, associates with proteins found in RNA processing bodies . GARRE1 is found in vertebrates and has been shown to be an effector specific to the Rac subfamily of proteins .
Insulin-like INSL3/INSL4 (INSL3/INSL4)
Type: Family

This entry includes insulin-like 3 from mammals and insulin-like peptide 4 (Ilp4 or dILP4) from fruit flies .

Insulin-like 3 (INSL3) is a secreted protein produced by testicular Leydig cells and in lower amounts by ovarian follicular theca interna cells and the corpus luteum . It acts as a theca cell-derived growth factor for preantral follicle and its action is mediated by growth differentiation factor 9 . Signaling through INSL3 and its cognate G protein-coupled receptor RXFP2 is important for testicular descent. It seems to be dispensable for spermatogenesis and fertility in adult males .

The function of Ilp4 is not clear.
RNF141, RING finger, HC subclass (RING-HC_RNF141)
Type: Domain

RNF141, also known as zinc finger protein 230 (ZNF230), is a RING finger protein present primarily in the nuclei of spermatogonia, the acrosome, and the tail of spermatozoa . It may have a broad function during early development of vertebrates. It plays an important role in spermatogenesis, including spermatogenic cell proliferation and sperm maturation, as well as motility and fertilization . It also exhibits DNA binding activity . RNF141 corresponding ZNF230 gene mutation may be associated with azoospermia . RNF141 contains a C3HC4-type RING finger domain that may function as an activator module in transcription .
Glial cell line-derived neurotrophic factor family (GDNF_fam)
Type: Family

The GDNF family members (consists of GDNF, neurturin, artemin and persephin) are structurally similar to transforming growth factor-beta. Unlike other members of the TGF-beta superfamily, which signal through the receptor serine-threonine kinases, GDNF family ligands activate intracellular signalling cascades via the receptor tyrosine kinase Ret. GDNF family ligands binds to GDNF family receptor alpha (GFRalpha) and then the GDNF family ligand-GFRalpha complex binds to and stimulates autophosphorylation of Ret. For instance, GDNF binds to GFRalpha1, Neurturin binds to GFRalpha2, artemin to GFRalpha3 and persephin activates Ret by binding to GFRalpha4. The GDNF family members support the survival of dopamine neurons and motoneurons, and some of them also regulate the development of enteric, sympathetic and parasympathetic neurons .
Homeobox expressed in ES cells 1 (Hesx1)
Type: Family

Hesx1 is a class of homeodomain proteins that bind to DNA . It has been shown that Hesx1 functions as a transcriptional repressor required for normal forebrain development, eyes and other structures such as the olfactory placodes and pituitary gland . It has been described that alterations in Hesx1 produce impairment of its DNA binding properties leading to Septo-Optic Dysplasia (SOD) in humans, which exhibits optic nerve and pituitary gland hypoplasia as well as midline brain abnormalities like absence of the corpus callosum and septum pellucidum .

This entry represents Hesx1A, Hesx1B and ANF-1.
Protein Gurken/Spitz (Gurken/Spitz)
Type: Family

This entry represents a group of invertebrate proteins, including Gurken/Spitz from Drosophila melanogaster. They are TGFalpha-like protein that interacts with EGF (epidermal growth factor) receptor. Gurken plays an important role in defining the egg anterior-posterior and dorsal-ventral axes . Spitz is required for photoreceptor determination in the Drosophila eye . This entry also includes a myrmicitoxin from Manica rubida (European giant red ant) .
ATAXIN1-like (ATAXIN1-like)
Type: Family

This entry includes Ataxin1 and Ataxin1-like proteins. They are components of the Notch signalling pathway involved in transcriptional repression .

Ataxin-1 (ATXN1) is involved in the formation and regulation of multimeric protein complexes within the nucleus . It is the causative factor for spinocerebellar ataxia type 1 (SCA1), which manifests in poor co-ordination of hand and feet movement . ATXN1 is a transcription repressor in the Notch signalling pathway and colocalizes with the deubiquitinating enzyme USP7 in the nucleus .
Chondromodulin/Tenomodulin (Chondromodulin/Tenomodulin)
Type: Family

This entry includes chondromodulin (CNMD, also known as Leukocyte cell-derived chemotaxin 1) and chondromodulin-like protein (TNMD, Tenomodulin). CNMD is a transmembrane glycoprotein with two cleaved portions: the N-terminal contains a surfactant protein referred to as a chondrosurfactant protein, and the C-terminal of the precursor protein known as Chm-1. Mature Chm-1 is cleaved from pre-Chm-1 in a furin-like processing site. Mature Chm-1 then can be secreted into the extracellular matrix. Chm-1 is involved in the regulation of tissue angiogenesis, cartilage development and homeostasis. It has also been linked to the onset and progression of diseases, such as osteoarthritis, infective endocarditis, and cancer .

Chondromodulin-like protein, also known as Tenomodulin or CNMD, share protein sequence similarity with pre-Chm-1. However, CNMD is located on the cell surface. It is expressed in dense hypovascular connective tissue. It is involved in cell adhesion, determination of cell morphology, cell aging and bone mineral density .
Transmembrane glycoprotein EPCAM/Trop-2 (EPCAM/Trop-2)
Type: Family

This entry includes transmembrane glycoprotein EpCAM (epithelial cell adhesion molecule, also known as Trop-1) and Trop-2 (also known as tumor-associated calcium signal transducer 2, TACSTD2). They belong to the tumour-associated calcium signal transducer (TACSTD) family. They have been reported to directly interact with claudin-1 and claudin-7 .

EpCAM mediates homotypic cell contacts in epithelia tissues and regulates cell proliferation and cancer stemness. It has been used as a diagnostic marker for circulating tumour cells (CTCs) in the blood . EpCAM has been shown to contribute to formation of intestinal barrier by recruiting claudins to cell-cell junctions . Mutations in the EpCAM gene lead to congenital tufting enteropathy, severe intestinal epithelium homeostasis disorders, and Lynch syndrome .

Trop-2 is highly expressed in a variety of epithelial cancer cells. It has been identified as an oncogene leading to invasiveness and tumorigenesis . It has been shown to regulate integrin-dependent signalling for cell-substrate adhesion and cell migration. It also modulates Rac1 GTPase activity and induces activation of PAK4 .