SII-SWORD/CoKE huggingface dataset:
Zinc phosphodiesterase ELAC protein 2-like (RNZ2-like)
Type: Family

This family represents a group of zinc phosphodiesterases including zinc phosphodiesterase ELAC protein 2 (RNZ2/ELAC2, also known as ElaC homologue protein 2 and tRNase Z 2) from human and its homologues. RNZ2 has mitochondrial tRNA 3'-processing endonuclease activity. It is involved in tRNA maturation, by removing a 3'-trailer from precursor tRNA, playing an essential role in the production of mature tRNAs . The homologue from Drosophila has some tRNA 3'-processing endonuclease activity of nuclear and mitochondrial pre-tRNA. It may participate in tRNA processing in the developing embryo . Mutations in this protein have been associated with severe form of infantile cardiomyopathy and and prostate cancer . The homologue from C. elegans HOE-1 has been shown to compromise fertility .
Caudal homeobox (Caudal_homeobox)
Type: Family

This entry represents the caudal homeobox family, which includes homeotic protein caudal from Drosophila melanogaster (Cad), homeobox protein CDX-1 from human and similar proteins found in animals and some fungal species. Cad is a transcription factor involved in processes such as anterior/posterior patterning formation, organ morphogenesis and innate immune homeostasis. Postembryonically its function is mostly restricted to the intestine where it regulates antimicrobial peptide (AMP) levels preserving the normal gut flora . CDX-1, is also involved in transcriptional regulation . It may play a role in the terminal differentiation of the intestine. It binds preferentially to methylated DNA .

This entry also includes homeobox protein pal-1 from Caenorhabditis elegans, a transcriptional activator required for posterior V6 neuroectoblast cell fate specification during postembryonic neurogenesis (patterning) which generates the characteristic ray lineage during male tail development .
TRIM45/56/19-like (TRIM45/56/19-like)
Type: Family

This entry represents a group of animal proteins defined by the TRIM/RBCC motif, including TRIM45/56/19 . These protein have been shown to act as SUMO E3 ligases and play important roles in a variety of cellular functions including cell proliferation, differentiation, development, oncogenesis, and apoptosis. TRIM45 may act as a transcriptional repressor in mitogen-activated protein kinase signaling pathway ; TRIM56 plays a key role in innate antiviral immunity by mediating ubiquitination of CGAS and STING1 . TRIM19, also known as PML, acts its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, such as tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. It acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. PML exhibits antiviral activity as it stimulates the SUMOylation of a viral protein which is supposed to serve as a cellular mechanism to compromise specific functions of the viral effector IE1p72 .
Ubiquitin-like protein 4A-like (UBL4A-like)
Type: Family

This entry represents Ubiquitin-like protein 4A from humans (UBL4A) and similar proteins found in animals and fungi. UBL4A is part of a ubiquitin ligase-associated multiprotein complex that chaperones retrotranslocated polypeptides on its way to the proteasome to improve the efficiency of the endoplasmic reticulum-associated degradation (ERAD) . The complex also functions as a sorting platform for proteins of the secretory pathway that are mislocalised to the cytosol either delivering them to the proteasome for degradation or to the endoplasmic reticulum . The homologue in Saccharomyces cerevisiae, Ubiquitin-like protein MDY2, is required for efficient mating .
COMM domain-containing protein 4/6/7/8 (COMMD4/6/7/8)
Type: Family

This entry includes COMM domain-containing proteins 4/6/7/8 (COMMD4/6/7/8), which may modulate the activity of cullin-RING E3 ubiquitin ligase (CRL) complexes .

COMM (copper metabolism gene MURR1) domain proteins constitute a family initially identified as interacting partners of COMMD1 (previously known as MURR1), the prototype member of this protein family. COMMD1 is a multifunctional protein that has been shown to participate in two apparently distinct activities, regulation of the transcription factor NF-kappa-B and control of copper metabolism. The family is defined by the presence of a C-terminal motif termed COMM domain, which functions as an interface for protein-protein interactions. The proteins designated as COMMD or COMM domain containing 1-10 are extensively conserved in multicellular eukaryotic organisms .
Protein teg/CotR/cGAMP-activated phospholipase-like (Teg/CotR/CapV-like)
Type: Family

This family includes a group of proteins mainly found in bacteria, such as Teg from Priestia megaterium, the putative sporulation hydrolase CotR from Bacillus subtilis and the cGAMP-activated phospholipase CapV from Pseudomonas aeruginosa. CapVis an effector phospholipase of a CBASS antiviral system (cyclic oligonucleotide-based antiphage signaling system), which provides immunity against bacteriophages .
PHD and RING finger domain-containing protein 1/Atg35 (PHRF1/Atg35)
Type: Family

This entry represents a group of eukaryotic proteins, including PHD and RING finger domain-containing protein 1	from human and its orthologue from S. pombe. The function of these proteins is unknown.

This entry also includes Autophagy-related protein 36 (also known as Atg35) from Komagataella phaffii, a micropexophagy-specific protein required for efficient micropexophagic apparatus (MIPA) formation but not for general autophagy .
Retinoic acid receptor, ligand-binding domain (NR_LBD_RAR)
Type: Domain

This entry represents the ligand binding domain (LBD) of retinoic acid receptors (RARs) .

The retinoic acid receptors (RARs) belong to the large family of ligand responsive gene regulatory proteins that includes receptors for steroid and thyroid hormones. These proteins contain two highly conserved domains that are involved in determining their DNA and ligand-binding activities . RARs (also known as 1B nuclear receptors) mediate the biological effect of retinoids, including both naturally dietary vitamin A (retinol) metabolites and active synthetic analogs. Retinoids play key roles in a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, differentiation and apoptosis, and homeostasis. RARs function as heterodimers with retinoic X receptors by binding to specific RAR response elements (RAREs) found in the promoter regions of retinoid target genes. In the absence of ligand, the RAR-RXR heterodimer recruits the corepressor proteins NCoR or AMRT, and associated factors such as histone deacetylases or DNA-methyltransferases, leading to an inactive condensed chromatin structure, preventing transcription. Upon ligand binding, the corepressors are released, and coactivator complexes such as histone acetyltransferase or histone arginine methyltransferases are recruited to activate transcription. Three distinct RARs have been identified (termed RAR alpha, beta, and gamma) and are encoded by genes on separate chromosomes. Additional isoforms of the receptors have been described, all of which differ in the N-terminal regions. Comparison of the amino acid sequences of human and mouse RARs indicates that interspecies conservation in members of the RAR subfamily (either alpha, beta or gamma) is much higher than conservation of the receptors within species . These observations indicate that RAR-alpha, -beta and -gamma may perform specific functions. hRAR-gamma RNA has been shown to be the predominant RAR RNA species in human skin, suggesting that hRAR-gamma mediates some of the retinoid effects in this tissue .

The crystal structure of the ligand-binding domain (LBD) of the hRAR-gamma bound to all-trans retinoic acid has been determined to 2.0A resolution . Overall, the fold is similar to that of the human RXR-alpha apo-LBD, except for the C-terminal portion, which folds back towards the LBD core, contributing to the hydrophobic ligand pocket and `sealing' its entry site. A 'mouse trap' mechanism is thus proposed, whereby a ligand-induced conformational transition re-positions the amphipathic α-helix of the activating domain and forms a transcriptionally active receptor .
Retinoic acid receptor, DNA-binding domain (NR_DBD_RAR)
Type: Domain

This entry represents the DNA-binding domain of retinoic acid receptor (RARs) which is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom .

The retinoic acid receptors (RARs) belong to the large family of ligand responsive gene regulatory proteins that includes receptors for steroid and thyroid hormones. These proteins contain two highly conserved domains that are involved in determining their DNA and ligand-binding activities . RARs (also known as 1B nuclear receptors) mediate the biological effect of retinoids, including both naturally dietary vitamin A (retinol) metabolites and active synthetic analogs. Retinoids play key roles in a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, differentiation and apoptosis, and homeostasis. RARs function as heterodimers with retinoic X receptors by binding to specific RAR response elements (RAREs) found in the promoter regions of retinoid target genes. In the absence of ligand, the RAR-RXR heterodimer recruits the corepressor proteins NCoR or AMRT, and associated factors such as histone deacetylases or DNA-methyltransferases, leading to an inactive condensed chromatin structure, preventing transcription. Upon ligand binding, the corepressors are released, and coactivator complexes such as histone acetyltransferase or histone arginine methyltransferases are recruited to activate transcription. Three distinct RARs have been identified (termed RAR alpha, beta, and gamma) and are encoded by genes on separate chromosomes. Additional isoforms of the receptors have been described, all of which differ in the N-terminal regions. Comparison of the amino acid sequences of human and mouse RARs indicates that interspecies conservation in members of the RAR subfamily (either alpha, beta or gamma) is much higher than conservation of the receptors within species . These observations indicate that RAR-alpha, -beta and -gamma may perform specific functions. hRAR-gamma RNA has been shown to be the predominant RAR RNA species in human skin, suggesting that hRAR-gamma mediates some of the retinoid effects in this tissue .

The crystal structure of the ligand-binding domain (LBD) of the hRAR-gamma bound to all-trans retinoic acid has been determined to 2.0A resolution . Overall, the fold is similar to that of the human RXR-alpha apo-LBD, except for the C-terminal portion, which folds back towards the LBD core, contributing to the hydrophobic ligand pocket and `sealing' its entry site. A 'mouse trap' mechanism is thus proposed, whereby a ligand-induced conformational transition re-positions the amphipathic α-helix of the activating domain and forms a transcriptionally active receptor .
G-protein coupled receptor 183-like (GP183-like)
Type: Family

This family includes eukaryotic G-protein coupled receptor 183 (GP183, also known as EBV-induced G-protein coupled receptor 2) and similar proteins such as the orphan receptor GP141 and G-protein coupled receptor homologue FPV206 from Fowlpox virus.

GP183 is a receptor for oxysterol 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC) and other related oxysterols . It regulates migration of astrocytes and is involved in the communication between astrocytes and macrophages . It may also act as a chemotactic receptor for some T-cells upon binding to 7-alpha,25-OHC ligand. Together with CXCR5, it mediates B-cell migration .
ARF GTPase-activating protein Git-like (GIT-like)
Type: Family

This entry represents ARF GTPase-activating protein Git from Drosophila melanogaster, ARF GTPase-activating protein GIT1/2 from humans, and similar proteins from animals. Git is a GTPase-activating protein for ADP ribosylation factor family members, including ARF1. It promotes proper muscle morphogenesis and proper guidance and targeting of subsets of myotubes . Git may be important for brain development . GIT1 plays an important role in dendritic spine morphogenesis and synapse formation . It plays a crucial role in regulating GABA(A) receptor synaptic stability, leading to F-actin stabilization . It may also may regulate activation of the canonical NF-kappa-B signal in bone mesenchymal stem cells, eventually leading to enhanced production of VEGFA and other angiogenic factors .
Apoptosis-stimulating of p53 protein 1/2 (ASPP1/2)
Type: Family

Apoptosis-stimulating of p53 protein 1 (ASPP1/2) which are specific activators of p53. These proteins play a central role in regulation of apoptosis via its interaction with p53/TP53 . Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo. ASPP2 inhibits the ability of APP-BP1 (also known as NEDD8 activating enzyme E1 subunit 1, NAE1) to conjugate NEDD8 to CUL1, and thereby decreases APP-BP1 ability to induce apoptosis . Its apoptosis-stimulating activity is inhibited by its interaction with DDX42 . ASPP1 homologue from C. elegans, apoptotic enhancer 1 protein (aep-1), negatively regulates apoptosis via its interaction with cep-1.
OX-2 membrane glycoprotein-like (OX2G-like)
Type: Family

This entry represents OX-2 membrane glycoprotein (OX2G) from humans and other vertebrates and its viral homologues, including OX-2 membrane glycoprotein homologue (OX2V) from Human herpesvirus 8 (HHV-8). Member of this protein family show two immunoglobulin domains.

OX2G, also known as CD200, co-stimulates T-cell proliferation. It may regulate myeloid cell activity in a variety of tissues . It is involved in regulation of macrophage function . Interaction of CD200 with its receptor acts to suppress inflammatory responses . This protein has been shown to play important roles in controlling autoimmunity, inflammation, the development and spread of cancer, hypersensitivity, and spontaneous fetal loss .

OX2V is encoded by herpesvirurses and has significant homology with cellular OX2. Viral OX2 encodes a glycosylated cell surface protein which has been shown to target myeloid-lineage cells .
Rho GTPase-activating protein 17/44/SH3BP1-like (RHG17/44/SH3BP1-like)
Type: Family

This entry represents a group of GTPase-activating proteins (GAPs) that stimulate the GTPase activity of Rho-type GTPases, including Rho GTPase-activating protein 17 (RHG17, also known as RICH-1), RHG44 (also known as RICH-2), SH3 domain-binding protein 1 (SH3BP1) and bargin from human which are referred to as BAR-domain RhoGAP subfamily . Bargin is an alternative splice product consisting of a modified N-terminal BAR domain, an intermediary RhoGAP domain, and a C-terminal partial CIN module and this is the only BAR-RhoGAP subfamily member that lacks a C-terminal polyproline-rich repeat region, which is replaced by the partial CIN phosphatase module .

These proteins convert GTP-bound Rho-type GTPases including RAC1 and CDC42 in their inactive GDP-bound form. SH3BP1 specifically inactivates RAC1 at the leading edge of migrating cells, it regulates the spatiotemporal organization of cell protrusions which is important for proper cell migration . It is involved in actin remodelling and the formation of epithelial cell junctions, through negative regulation of CDC42 ]. This protein plays a specific role in phagocytosis of large particles as it is specifically recruited by a PI3 kinase/PI3K-dependent mechanism to sites of large particles engagement, where it inactivates RAC1 and/or CDC42 allowing the reorganization of the actin cytoskeleton required for engulfment .
Apoptosis-stimulating protein of p53 protein 2, RA domain (ASPP2_RA)
Type: Domain

This entry represents the RA domain of ASPP2.

ASPP2, also termed Bcl2-binding protein (Bbp), or renal carcinoma antigen NY-REN-51, or tumour suppressor p53-binding protein 2 (53BP2), or p53-binding protein 2 (p53BP2), is a member of ASPP protein family and it functions as a tumour suppressor . ASPP2 binds to p53 and enhances p53-mediated transcription of proapoptotic genes. ASSP2 contains a RA domain at the N-terminal. The RA domain is a ubiquitin-like domain and RA domain-containing proteins are involved in several different functions ranging from tumour suppression to being oncoproteins . All p53 amino acids that are important for ASPP2 binding are mutated in human cancer, and ASPP2 is frequently downregulated in these tumour cells .
Nuclear Factor Erythroid-derived 2-like (NFE2-like)
Type: Family

This entry represents a group of related animal transcription factors, including NFE2 and NFE2-like proteins, such as NFE2-like 1 (also known as NFE2-related factor 1, NFE2L1/Nrf1), NFE2L2 and NFE2L3 (or Nrf3). This family also includes the orthologue CNC from Drosophila, which regulates the activation of genes by oxidative stress and SKN-1 from C. elegans . These 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 .

NFE2 functions in development; it is required for the proper development of platelets. As part of the NF-E2 complex, it is essential for regulating erythroid and megakaryocytic maturation and differentiation. The three Nrfs function in stress responses. Nrf1 is an essential protein that binds to the antioxidant response element (ARE) and is also involved in regulating oxidative stress. In addition, it also regulates genes involved in cell and tissue differentiation, inflammation, and hepatocyte homeostasis. Nrf3 has been linked to differentiation, inflammation, and carcinogenesis .

Nrf2, the most extensively studied member of this subfamily, acts as a xenobiotic-activated receptor that regulates the adaptive response to oxidants and electrophiles . As the master regulator of the antioxidant defense pathway, it plays roles in the biology of inflammation, obesity, and cancer. Mammalian Nrf2 was shown to be protective during infections as diverse as septic shock, pneumonia, chronic granulomatous disease (CGD) and periodontitis .
PX domain-containing protein LEC1-like (LEC1-like)
Type: Family

This is a family of conserved fungal proteins which contain DUF3818 and PXA domains, including LEC1/YPR097W from budding yeast and C663.15c/C1450.12 from fission yeast. LEC1 is a phosphoinositide-binding protein that plays a role in regulation of ergosterol distribution in the cell . It facilitates ergosterol transport between plasma membrane and lipid droplets .
Insulin gene enhancer protein ISL-1/2-like (ISL1/2-like)
Type: Family

This group of proteins includes the DNA-binding transcriptional activators insulin gene enhancer proteins ISL-1/2 (also known as Islet-1/2) and its homologues from animals . ISL1 recognises and binds to the consensus octamer binding site 5'-ATAATTAA-3' in promoter of target genes . The early expression of ISL-1 in the developing hypothalamus determines the fate specification of melanocortinergic neurons and is essential for hypothalamic Pomc expression. It is required for melanocortin-induced satiety and normal adiposity throughout the entire lifespan . ISL2 is a transcriptional factor that may define subclasses of motoneurons that segregate into columns in the spinal cord and select distinct axon pathways.
Tyrosine-protein phosphatase non-receptor type 12/18/22 (PTN12/18/22)
Type: Family

This family represents a group of tyrosine-protein phosphatases, including human tyrosine-protein phosphatase non-receptor type 12/18/22. PTN22 acts as negative regulator of T-cell receptor (TCR) signalling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signalling molecules . PTN12 dephosphorylates a range of proteins, and thereby regulates cellular signaling cascades , such as ERBB2 and PTK2B/PYK2, and thereby regulates signalling via ERBB2 and PTK2B/PYK2 . PTN18 may be involved in growth and differentiation of hematopoietic cells.
Bromodomain adjacent to zinc finger domain protein 1A (BAZ1A)
Type: Family

Bromo adjacent to zinc finger 1A (also known as ACF1) is the regulatory subunit of the ATP-dependent ACF-1 and ACF-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and regulates spacing of nucleosomes using ATP to generate evenly spaced nucleosomes along the chromatin, to facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair .
Ajuba-like (Ajuba-like)
Type: Family

Ajuba-like LIM domain-containing protein family includes three highly homologous proteins Ajuba, LIMD1, and WTIP, adapter or scaffold proteins that participate in the assembly of numerous protein complexes and are involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, mitosis, cell-cell adhesion, cell differentiation, proliferation and migration . They bind to Ago1/2, RCK, Dcp2, and eIF4E in vivo, being required for miRNA-mediated gene silencing. These three proteins bind to the mRNA 5' m(7)GTP cap-protein complex . Members of this family negatively regulates the Hippo signalling pathway . WTIP, the Wt1-interacting protein, was originally identified as an interaction partner of the Wilms tumour protein 1 (WT1). WTIP is involved in kidney and neural crest development. It interacts with the receptor tyrosine kinase Ror2 and inhibits canonical Wnt signaling.

LIMD1 was reported to inhibit cell growth and metastases; it has been described that LIMD1 functions as tumour suppressor to block lung tumour cell line in vitro and in vivo . The inhibition may be mediated through an interaction with the protein barrier-to-autointegration (BAF), a component of SWI/SNF chromatin-remodeling protein; or through the interaction with retinoblastoma protein (pRB), resulting in inhibition of E2F-mediated transcription, and expression of the majority of genes with E2F1-responsive elements. Recently, LIMD1 was shown to interact with the p62/sequestosome protein and influence IL-1 and RANKL signalling by facilitating the assembly of a p62/TRAF6/a-PKC multi-protein complex.

Members of the family contain three tandem C-terminal LIM domains and a proline-rich N-terminal region.
STE20-related kinase adapter protein alpha/beta-like (STRAD_A/B-like)
Type: Family

This family represents a group of pseudokinases including human STE20-related kinase adapter protein alpha/beta (STRADA/B) and related proteins. They contain a domain with similarity to protein kinases but lacks crucial residues for catalytic activity. STRADA/B form a complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) which binds to and activates STK11/LKB1, being STRADA more effective than STRADB . These proteins adopt a closed conformation typical of active protein kinases and binds STK11/LKB1 as a pseudosubstrate, promoting conformational change of STK11/LKB1 in an active conformation .
Tyrosine-protein kinase BAZ1B (BAZ1B)
Type: Family

BAZ1B is an atypical tyrosine-protein kinase that plays a central role in chromatin remodelling and acts as a transcription regulator . It is involved in DNA damage response by phosphorylating 'Tyr-142' of histone H2AX . BAZ1B is one of the regulatory subunits of the ATP-dependent WICH-1 and WICH-5 ISWI chromatin remodelling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair . This protein mediates the recruitment of the WICH-5 ISWI chromatin remodelling complex to replication foci during DNA replication .