SII-SWORD/CoKE huggingface dataset:
Peptidase family M49 (Peptidase_M49)
Type: Family

Peptidase family M49 contains exopeptidases that remove dipeptides from the N terminus of peptides and proteins and are known as dipeptidyl-peptidases (DPP). The best characterised of these is dipeptidyl-peptidase III and represents the prototype for the M49 family of metallopeptidases. It consists of two domains that form a wide cleft containing the catalytic metal ion (DPPIII;

; MEROPS identifier M49.001) . The exopeptidases in M49 are metal-dependent, and bind a single zinc ion via the histidines in an HEXXXH motif, in which the distance between the histidines in one residue longer than in the HEXXH zinc-binding motif found in endopeptidases of clan MA. The importance of the histidines and the glutamic acid was identified by site-directed mutagenesis . Some members of family M49, notably from bacteria such as
Colwelia
and plants possess the more usual HEXXH motif . A third zinc ligand occurs within a motif that has been described as EECRAE . DPPIII releases N-terminal dipeptides sequentially from peptides such as angiotensins II and III, Leu-enkephalin, prolactin and alpha-melanocyte-stimulating hormone, but tripeptides are poor substrates and polypeptides of more than ten residues are not cleaved . DPPIII is a soluble, cytosolic enzyme with a housekeeping role, but is elevated in retroplacental serum may participate in the increased angiotensin hydrolysis seen during pregnancy .

This family also includes Nudix hydrolase 3 (NUDT3) from plants, which is thought to hydrolyse nucleoside diphosphate derivatives because of the presence of a Nudix box. Isopentenyl diphosphate (IPP), a universal precursor for the biosynthesis of isoprenoid compounds, is hydrolysed; purine nucleotides such as 8-oxo-dATP are dephosphorylated; and the enzyme acts as a dipeptidyl-peptidase against dipeptidyl-2-arylamide substrates .
Nucleoporin Nup159/Nup146, N-terminal (Nup159/Nup146_N)
Type: Domain

This entry represents the N-terminal domain of nucleoporin Nup146 from Schizosaccharomyces pombe and Nup159 from Saccharomyces cerevisiae. These are components of the nuclear pore complex (NPC), which is the only means by which macromolecules enter and exit the nucleus. Nup146 and Nup159 contain Phe-Gly (FG) repeats . Nup159 is part of the Nup82 subcomplex required for mRNA export . Nup159 is important for nuclear export of poly(A)+ RNA, pre-ribosome, and proteins . The N-terminal domain of Nup159 has a seven-bladed, β-propeller structure which functions in mRNA export by tethering the helicase Dbp5 to the nuclear pore .

This domain is also found in Nuclear pore complex protein Nup214 from animals which is part of the nuclear pore complex and has a critical role in nucleocytoplasmic transport .
Sip3/Lam1, BAR domain (Sip3/Lam1_BAR)
Type: Domain

This entry represents the BAR domain found in a group of fungal proteins including Sip3 and Lam1 from budding yeasts. They contain an N-terminal BAR domain followed by a Pleckstrin Homology (PH) domain. Sip3 interacts with SNF1 protein kinase and activates transcription when anchored to DNA. It may function in the SNF1 pathway. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions .

BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions including organelle biogenesis, membrane trafficking or remodeling, and cell division and migration .
Gag-Pol polyprotein, Zinc-finger like domain (Gag-pol_Znf-H3C2)
Type: Domain

This entry represents a probable DNA-binding zinc-finger domain found in Gag-Pol polyproteins from mouse retroviruses.
Interleukin-17 receptor-like (IL-17_rcpt-like)
Type: Family

The interleukin-17 receptors, including IL-17RA to IL-17RE, are cytokine receptors that mediates chronic inflammatory and autoimmune disorders . The orthologs in Caenorhabditis elegans are interleukin cytokine receptor-related protein 1 and 2 (ILCR1-2).
Transcription factor TFIIIB component B'', Myb domain (TFIIIB_B''_Myb)
Type: Domain

This entry represents the Myb domain found in transcription factor TFIIIB component B''.

Transcription by RNA polymerase III (pol III) is a complex molecular process orchestrated by the two main transcription factors, TFIIIB and TFIIIC. The TFIIIB complex can be recruited by TFIIIC to upstream DNA and form an exceptionally kinetically stable TFIIIB-DNA complex, which then recruits the Pol III enzymatic complex and helps maintain it for multiple transcription cycles in a process called facilitated recycling . Saccharomyces cerevisiae TFIIIB is a complex of three subunits, the TATA box-binding protein TBP, the TFIIB-related factor BRF, and the beta'' protein.

The myb-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of approximately 55 amino acids, typically occurring in a tandem repeat in eukaryotic transcription factors. The domain is named after the retroviral oncogene v-myb, and its cellular counterpart c-myb, which encode nuclear DNA-binding proteins that specifically recognise the sequence YAAC(G/T)G .
WDR19, WD40 repeat domain (WDR19_WD40_rpt)
Type: Domain

This entry represents the WD-40 repeat domain found in the human WD repeat-containing protein 19 (WDR19) and its homologue, dyf-2 from Caenorhabditis elegans. They are part of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), being involved in cilia function and/or assembly .

WD-40 repeats (also known as WD or beta-transducin repeats) are short ~40 amino acid motifs, often terminating in a Trp-Asp (W-D) dipeptide. WD40 repeats usually assume a 7-8 bladed β-propeller fold, but proteins have been found with 4 to 16 repeated units, which also form a circularised β-propeller structure. WD-repeat proteins are a large family found in all eukaryotes and are implicated in a variety of functions ranging from signal transduction and transcription regulation to cell cycle control and apoptosis. Repeated WD40 motifs act as a site for protein-protein or protein-DNA interaction, and proteins containing WD40 repeats are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins . The specificity of the proteins is determined by the sequences outside the repeats themselves. Examples of such complexes are G proteins (beta subunit is a β-propeller), TAFII transcription factor, and E3 ubiquitin ligase . In Arabidopsis spp., several WD40-containing proteins act as key regulators of plant-specific developmental events.
Nucleoside 2-deoxyribosyltransferase-like (Nuc_deoxyri_tr2)
Type: Family

This entry includes a group of nucleoside 2-deoxyribosyltransferase like proteins, including (

) (PDBe:4mcj).
Uncharacterized protein CXorf65-like (CXorf65-like)
Type: Family

The function of this group of proteins is not known. Proteins in this entry includes CXorf65 and C22orf15 from humans.
Cell surface hyaluronidase, PANDER-like domain (TMEM2_PANDER-like)
Type: Domain

This entry represents a domain found in cell surface hyaluronidase (also known as TMEM2) and CEMIP. This domain is similar to Pancreatic-derived factor PANDER (also known as FAM3B) , and is found C-terminal to a glycine rich G8-domain. The function of the PANDER-like domain in TMEM2 is not clear.

TMEM2 is a cell surface hyaluronidase that mediates the initial cleavage of extracellular high-molecular-weight hyaluronan into intermediate-size hyaluronan of approximately 5kDa fragments . CEMIP is a hyaluronan binding protein involved in hyaluronan depolymerisation .
Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1, PANDER-like domain (POMGNT1_PANDER-like)
Type: Domain

O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) participates in O-mannosyl glycosylation and may be responsible for creating GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moieties on alpha dystroglycan and other O-mannosylated proteins . POMGnT1 consists of a stem domain, a catalytic domain, and an extended linker region connecting the two domains. The fold of the stem domain resembles that of PANDER (pancreatic-derived factor); a protein involved in the regulation of glucose homeostasis, but whose the molecular function has not been determined .
FAM3C (ILEI) domain (ILEI_FAM3C)
Type: Domain

The secreted factor FAM3C or ILEI (InterLeukin-like Emt Inducer) has been identifed as a protein involved in the epithelial-mesenchymal transition (EMT) and in processes associated with metastasis formation and the progression of cancer. The protein had initially been predicted to be a member of the four-helical cytokine family, hence the FAM3C designation. ILEI has been found to be widely expressed, and to be involved in retinal development .
Pyridinium-3,5-biscarboxylic acid mononucleotide synthase (P2CMN_synthase_LarB)
Type: Family

The lactate racemase enzyme (LarA) of Lactobacillus plantarum harbors a (SCS)Ni(II) pincer complex. Pyridinium-3,5-biscarboxylic acid mononucleotide synthase (LarB), together with LarC and LarE, is involved in the synthesis of the nickel-pincer cofactor of LarA . LarB, LarC, and LarE are widely distributed in microorganisms. LarB carboxylates the pyridinium ring of nicotinic acid adenine dinucleotide (NaAD) and cleaves the phosphoanhydride bond to release AMP. Therefore, LarB converts NaAD into pyridinium-3,5-biscarboxylic acid mononucleotide (P2CMN). Subsequently LarE incorporates two sulfur atoms to yield P2TMN, and LarC donates Ni, so that the mature cofactor becomes covalently attached to LarA. In species where larA is absent, this pathway could be used to generate a pincer complex in other enzymes .
ILEI/PANDER domain (ILEI/PANDER_dom)
Type: Domain

This entry represents the ILEI/PANDER domain found in FAM3 family members and related proteins. Both PANDER and ILEI share a similar β-β-α fold, strikingly different from the classical cytokines .

FAM3C, also known as interleukin-like EMT inducer ILEI, is a secreted signaling protein involved in epithelial-mesenchymal transition and tumor progression .

FAM3B, also known as PANDER (PANcreatic DERived factor), is a cytokine-like protein that induces apoptosis of insulin-secreting beta-cells and functions as a hormone by regulating glucose levels .
Protein FAM184A/B, N-terminal (FAM184A/B_N)
Type: Domain

This entry represents the N terminus of protein FAM184A/B. The function of FAM184A/B is not known. This domain can also be found in protein tag-278 from C. elegans.
Single CXXC unit (Mono-CXXC)
Type: Domain

This is a solo version of the Znf-CXXC domain with a conserved CXXCXXCX(n)C, zinc-binding motif . Structural comparisons show that the mono-CXXC is homologous to the structural- zinc binding domain of medium chain dehydrogenases . The regular Znf-CXXC domain binds nonmethyl-CpG dinucleotides.
C-C bond lyase-like (C-C_Bond_Lyase-like)
Type: Family

This family of TIM-Barrel fold C-C bond lyase is related to citrate-lyase. These genes are found in the biosynthetic operon, with other enzymatic domains, associated with the Ter stress response operon and are predicted to be involved in the biosynthesis of a ribo-nucleoside involved in stress response .
Exocyst complex component EXOC2/Sec5, N-terminal domain (EXOC2/Sec5_N_dom)
Type: Domain

This entry represent a domain found at the N terminus of Sec5 from budding yeasts and EXOC2/VPS51 from animals.

In S. cerevisiae, Sec5 is an essential component of the exocyst complex, which is composed of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84 . The exocyst complex tethers post-Golgi secretory vesicles to the plasma membrane before soluble NSF attachment protein receptor (SNARE)-mediated membrane fusion .

In mammals, active form (GTP-bound) of Ral GTPase interacts with EXOC2 and Exo84 and regulates the assembly interface of a full octameric exocyst complex . Similar to yeast exocyst, the mammalian exocyst has been directly linked to post-Golgi targeting of secretory vesicles to discreet membrane sites .
Neuronal tyrosine-phosphorylated phosphoinositide-3-kinase adapter, N-terminal (NYAP_N)
Type: Domain

This entry represents the N-terminal domain of a group of eukaryotic proteins that are substrates of tyrosine kinase in the brain. When first identified, the family members were referred to as unconventional myosin XVI, or Myr 8 . However, proteins have now been identified as being integrally involved in neuronal function and morphogenesis. The family is involved in both the activation of phosphoinositide 3-kinase (PI3K) and the recruitment of the downstream effector WAVE complex to the close vicinity of PI3K; it also appears to regulate the brain size and neurite outgrowth in mice .
Meiotic expression up-regulated protein 6, PH domain (Meu6_PH_dom)
Type: Domain

This entry represents the PH domain found in Meu6 (meiotic expression up-regulated protein 6). The function of Meu6 is not clear.
Mug56/Spo71, PH domain (Mug56/Spo71_PH)
Type: Domain

This entry represents the PH domain found in Spo71 (sporulation-specific protein 71) from budding yeasts and Mug56 (meiotically up-regulated gene 56 protein) from fission yeasts .
Transmembrane protein 207 (TMEM207)
Type: Family

The function of TMEM207 is not known. Homologues are known only from vertebrates.
Required for excision 1-B domain-containing protein (REX1-B)
Type: Family

This entry represents required for excision 1-B domain-containing protein (REX1-B) proteins from eukaryotes. REX1-B from Schizosaccharomyces pombe (heterochromatin silencing protein rss1) is required for heterochromatin silencing within pericentromeric repeats and at telomers. It facilitates the recruitment of Clr6 histone deacetylase (HDAC) by interacting with histones. Also interacts with Rad25, which mediates heterochromatin silencing in DNA repeats by recruiting the RITS complex. Together with Rad25, it forms a regulatory hub that defines heterochromatin silencing within tandem repeats via linking RNAi and HDAC . The function of REX1-B in mammals has not been fully characterised yet. This entry also includes Chlamydomonas reinhardtii REX1-B, which is involved in a light-independent DNA repair pathway .
Transmembrane protein 109 (TMEM109)
Type: Family

TMEM109, also known as Mg23, is a endoplasmic reticulum protein that facilitates DNA damage-induced apoptosis . It plays a protective role against UVC by accumulating alphaBC in the close vicinity of the ER .
TMEM248/TMEM219 (TMEM248/TMEM219)
Type: Family

This entry includes TMEM248 and TMEM219 (also known as insulin-like growth factor-binding protein 3 receptor, IGFBP-3R) from animals. TMEM219 is a cell death receptor and is essential for the IGFBP-3-induced apoptosis and tumor suppression . The function of TMEM248 is not clear.
Factor VIII intron 22 protein (F8A)
Type: Family

Factor VIII intron 22 protein, also known as CpG island protein, is contained within the largest factor VIII intron. Unlike factor VIII, it is produced abundantly in a wide variety of cell types .
TATA box-binding protein-associated factor RNA polymerase I subunit A (TAF1A)
Type: Family

TATA box binding protein associated factor RNA Polymerase I subunit A (TAF1A/TAFI48) is found in eukaryotes and is encoded by the gene TAF1A in humans. Its function is to aid transcription of DNA into RNA by binding to the promoter at the -10 TATA box site. It is a component of the transcription factor SL1/TIF-IB complex, involved in PIC assembly (pre-initiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation depends on the rate of association of this protein. This protein also stabilises nucleolar transcription factor 1/UBTF on rDNA .

This entry also includes TAF1A homologues from plants.
CCDC92/74, N-terminal (CCDC92/74_N)
Type: Domain

This entry represents a coiled-coil section found at the N-terminal of CCDC92 and CCDC74A/B.

Coiled-coil domain-containing protein 92 (CCDC92) is an interferon-stimulated protein that plays a role in innate immunity. It strongly inhibits ebolavirus transcription and replication through the formation of a complex with viral RNA-bound nucleocapsid (NP) that prevents the transport of NP to the cell surface . It has also been shown to interact with centrosomal protein CEP164 , which is required for primary (nonmotile) cilium formation . CCDC92 is associated with obesity and type 2 diabetes in humans. Studies in wild-type (WT) and CCCDC92 whole-body knockout (KO) mice, it was found that CCDC92 KO reduced obesity and increased insulin sensitivity under high-fat diet (HFD) conditions, it inhibited macrophage infiltration and fibrosis in white adipose tissue (WAT), which might protect against adipose tissue dysfunction. This suggests a critical role of CCDC92 in metabolism, and may be a potential target for treating obesity and insulin resistance .

Coiled-coil domain-containing protein 74A/B are spindle-localized proteins that bind directly to microtubules through two separate domains and bundle microtubules, being important K-fiber crosslinkers required for bipolar spindle formation and chromosome alignment .
CCDC144C-like, coiled-coil domain (CC144C-like_CC_dom)
Type: Domain

This entry represents the coiled-coil domain found in the human protein CCDC144C (

), the ankyrin repeat domain-containing protein 26-like 1, members of the POTE ankyrin domain family and related proteins . The function of CCDC144C remains unknown. The ankyrin repeat which features in CCDC144C is a common amino acid motif.
Uncharacterised nucleotidyltransferase (NTP_transf_5)
Type: Family

This family is likely to be an uncharacterised group of nucleotidyltransferases.
Leucine rich adaptor protein 1/25 (LURA1/LRA25)
Type: Family

This entry includes a group of leucine rich adaptor proteins, including LURAP1 (LRAP35A), LURAP1L and LRAP25. LURAP1 activates the canonical NF-kappa-B pathway, promotes proinflammatory cytokine production and promotes the antigen presenting and priming functions of dendritic cells .

LRAP25, also known as C184M or MMTV receptor, is a Ski (a transcriptional co-repressor) binding protein that negatively regulates tumour growth factor-beta signaling by sequestering the Smad proteins in the cytoplasm . LRA25 also serves as an adaptor protein of MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) .
EVA1 domain (EVA1_dom)
Type: Domain

This entry represents the EVA1 domain found in a group of proteins, including EVA1A/B/C. EVA1A, also known as TMEM166, regulates cell autophagy and apoptosis and has been shown to promote papillary thyroid cancer progression and epithelial-mesenchymal transition via upregulating immune-related signaling pathways .

This domain can be found in the C terminus of the human EVA1C, which serves as the Slit receptor that may mediate neural circuit formation in the developing nervous system. The EVA1C gene is located within the Down syndrome critical region (21q21-21q22.3) .
BARD1, Zinc finger, RING-type (BARD1_Znf-RING)
Type: Domain

The RING domain of the breast and ovarian cancer tumour-suppressor BRCA1 interacts with multiple cognate proteins, including the RING protein BARD1. Proper function of the BRCA1 RING domain is critical, as evidenced by the many cancer-predisposing mutations found within this domain. A dimer is formed between the RING domains of BRCA1 and BARD1. The BRCA1-BARD1 structure provides a model for its ubiquitin ligase activity, illustrates how the BRCA1 RING domain can be involved in associations with multiple protein partners and provides a framework for understanding cancer-causing mutations at the molecular level .
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3, EF hand domain (PLC-delta3_EF-hand)
Type: Domain

This entry represents the EF-hand domain found in 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLC-delta3).

PLC-delta-3 is essential for trophoblast and placental development . It locates at the cleavage furrow where it may participate in cytokinesis .
Dynein regulatory complex protein 1/2, N-terminal (DRC1/2_N)
Type: Domain

This entry represents the N-terminal domain of dynein regulatory complex protein 1/2 (DRC1/2). DRC1 is a key component of the nexin-dynein regulatory complex (N-DRC), essential for N-DRC integrity. It is required for the assembly and regulation of specific classes of inner dynein arm motors. It may also function to restrict dynein-driven microtubule sliding, thus aiding in the generation of ciliary bending .
SpoOB, alpha-helical domain (SPOB_a)
Type: Domain

Sporulation initiation phospho-transferase B or SpoOB is part of a phospho-relay that initiates sporulation in Bacillus subtilis. Spo0B is a two-domain protein consisting of an N-terminal α-helical hairpin domain and a C-terminal α/β domain. Two subunits of Spo0B dimerise by a parallel association of helical hairpins to form a novel four-helix bundle from which the active histidine - involved in the auto-phosphorylation - protrudes. In the phospho-relay, the signal-receptor histidine kinases are dephosphorylated by a common response regulator, Spo0F. Spo0B then takes phosphorylated Spo0F as substrate thereby mediating the transfer of a phosphoryl group to Spo0A, the ultimate transcription factor. The exact function of this α-helical domain is not known; it does not always occur just as the N-terminal domain of SPOB_ab,

. SCOP describes this domain as a histidine kinase-like fold lacking the kinase ATP-binding site .
Phosphatidylinositol N-acetylglucosaminyltransferase subunit PIG-A/GPI3 (PIG-A/GPI3)
Type: Family

Glycosylphosphatidylinositols (GPIs) are found in all eukaryotes and are synthesized in a pathway that starts with the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). This reaction is carried out by a protein complex consisting of four subunits in humans, three of which, Gpi1p, Pig-C and Pig-A, have sequence and functional counterparts in the
S. cerevisiae Gpi1, Gpi2 and Gpi3 proteins, respectively . Pig-A/Gpi3 is the UDPGlcNAc-binding and catalytic subunit of the complex .

Pig-A is an X-linked gene in humans; mutations in this gene have been associated with the hematological disorder Paroxysmal Nocturnal Hemoglobinuria (PNH) .
Protein KASH5, EF-hand-like domain (KASH5_EF-hand-like_dom)
Type: Domain

This entry represents the EF-hand-like domain found in protein KASH5. KASH5 is a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton . It interacts (via the last 22 AA) with SUN1; this interaction mediates telomere localisation .
SPATA31 (SPATA31)
Type: Domain

This entry represents a domain found in SPATA31. This domain is often found associated with

.

Spermatogenesis-associated protein 3 (SPATA3), also known as Aep1, is a testis-specific protein primarily expressed during the haploid stage of spermatogenesis, from round spermatids to mature sperm. SPATA3 localizes to the acrosome region of developing spermatids and plays a role in spermiogenesis. While its precise function remains unclear, SPATA3 is involved in sperm formation and function. Deletion of the Spata3 gene in mice leads to in vitro fertility defects and ultrastructural anomalies in sperm . SPATA3 has been found to interact with beta-actin and syntaxin 1 in vitro .
Vint domain (Vint_dom)
Type: Domain

The Vint domain is a Hint-like domain. This short domain is a conserved region of intein-containing proteins from lower eukaryotes .
RBM26-like, RNA recognition motif 2 (RBM26-like_RRM2)
Type: Domain

This entry represents the RNA recognition motif 2 (RRM2) of RBM26, also known as cutaneous T-cell lymphoma (CTCL) tumour antigen se70-2, which represents a cutaneous lymphoma (CL)-associated antigen. RBM26 contains two RNA recognition motifs (RRMs), also known as RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains). The RRMs may play some functional roles in RNA-binding or protein-protein interactions .