SII-SWORD/CoKE huggingface dataset:
Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus (NSP3_NAB_bCoV_sf)
Type: Homologous_superfamily

This superfamily represents the the nucleic acid binding domain (NAB/NAR) domain, which is approximately 100 residues in length, found in the multidomain nonstructural protein NSP3 from betacoronavirus, and described as NSP3e domain. NSP3 is part of Orf1a polyproteins in SARS-CoV . It is an essential component of the replication/transcription complex .

The global domain of the NAB represents a new fold, with a parallel four-strand β-sheet holding two α-helices of three and four turns that are oriented antiparallel to the β-strands. A group of residues form a positively charged patch on the protein surface as the binding site responsible for binding affinity for nucleic acids. When binding to ssRNA, the NAB prefers sequences with repeats of three consecutive Gs, such as (GGGA)5 and (GGGA)2. A positively charged surface patch (Lys75, Lys76, Lys99, and Arg106) is involved in RNA binding .
Carnitine o-acyltransferase, N-terminal (Carn_acyl_trans_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of carnitine o-acetyltransferase (

) .

Carnitine o-acyltransferase catalyzes the reversible acylation of L-carnitine and thus plays a vital role in fatty acid beta-oxidation and maintenance of acyl coenzyme A (acyl-CoA) pools . It is a monomeric protein containing two domains (1 and 2) that interconnect to form an active site tunnel .
GNAT acetyltransferase, N-terminal (GNAT_acetyltra_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain found in GNAT acetyltransferase. Structurally, this domain consists of five antiparallel β strands and four α helices.
Alpha-(1,3)-fucosyltransferase FucT, N-terminal domain superfamily (FucT_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of the alpha chain found in Helicobacter pylori Fucosyltransferase protein which is involved in the production of Lewis x trisaccharide, a major component of lipopolysaccharide. The N-terminal domain contains the catalyst base, Glu-95 which is equivalent to the Asp-100 of other members of the glycosyltransferases-B family. The domain contains the pocket where LacNAc binds. The domain is composed of 2-10 heptad repeats and a conserved N-terminal α-β-α motif which has little sequence similarity to the conserved N-terminal motif in other glycosyltransferases . This N-terminal domain is referred to as the cytoplasmic tail and is less conserved than the C-terminal domain .
Ubiquitin-associated protein 1, C-terminal (UBAP1_C)
Type: Homologous_superfamily

UBAP1 (ubiquitin associated protein 1) is a ubiquitin-binding ESCRT-I subunit (endosomal sorting complexes required for transport) . The C-terminal region of UBAP1 is described as a solenoid of overlapping UBAs (SOUBA) which interacts with ubiquitin . UBAP1-containing ESCRT-I is essential for degradation of antiviral cell-surface proteins.
TRAF3-interacting protein 1, N-terminal domain superfamily (TRAF3IP1_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of TRAF3-interacting protein 1.

TRAF3-interacting protein 1 (TRAF3IP1, also known as IFT54) recruits TRAF3 (tumour necrosis factor receptor-associated factor 3) and DISC1 (Disrupted-In-Schizophrenia 1) to the microtubules and is conserved from worms to humans . The N-terminal region is the microtubule binding domain and is well-conserved; the C-terminal 100 residues, also well-conserved, constitute the coiled-coil region which binds to TRAF3. The central region of the protein is rich in lysine and glutamic acid and carries KKE motifs which may also be necessary for tubulin-binding, but this region is the least well-conserved . In humans, it plays an inhibitory role on IL13 signaling by binding to IL13RA1. It is involved in suppression of IL13-induced STAT6 phosphorylation, transcriptional activity and DNA-binding .
EYA domain, metazoan (EYA_dom_metazoan)
Type: Domain

The Eyes absent proteins are members of a conserved regulatory network implicated in the development of the eye, muscle, kidney and ear. Eyes absent is a nuclear transcription factor, acting through interaction with homeodomain-containing Sine oculis (also known as Six) proteins. Eyes absent is also a protein tyrosine phosphatase , It does not resemble the classical tyrosine phosphatases that use cysteine as a nucleophile and proceed by means of a thiol-phosphate intermediate. Rather, Eyes absent is the prototype for a class of protein tyrosine phosphatases that use a nucleophilic aspartic acid in a metal-dependent reaction. Furthermore, the phosphatase activity of Eyes absent contributes to its ability to induce eye formation in drosophila. Thus, Eyes absent belongs to the phosphatase subgroup of the haloacid dehalogenase (HAD) superfamily and appears to act as a nuclear transcriptional coactivator with intrinsic phosphatase activity.

The Eyes absent proteins contain a divergent 200-300 residue long N-terminal region and a conserved C-terminal domain of approximately 270 residues, the EYA domain, which is critical for activity and believed to participate in protein-protein interactions .
Spike glycoprotein, betacoronavirus (BETA_CORONA_SPIKE)
Type: Family

This entry represents the spike glycoprotein mostly from Betacoronavirus. It can be cleaved into three chains: spike protein S1, S2 and S2'. Spike protein S1 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. Spike protein S2 mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Spike protein S2' acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis .
XIAP/BIRC8, UBA domain (XIAP/BIRC8_UBA)
Type: Domain

XIAP, also called baculoviral IAP repeat-containing protein 4 (BIRC4), is a potent suppressor of apoptosis that directly inhibits specific members of the caspase family of cysteine proteases, including caspase-3, -7, and -9 . It promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death . The ubiquitin-protein ligase (E3) activity of XIAP also exhibits in the ubiquitination of second mitochondria-derived activator of caspases (Smac) . The mitochondrial proteins, Smac/DIABLO and Omi/HtrA2, can inhibit the antiapoptotic activity of XIAP . XIAP has also been implicated in several intracellular signaling cascades involved in the cellular response to stress, such as the c-Jun N-terminal kinase (JNK) pathway, the nuclear factor-kappaB (NF-kappaB) pathway, and the transforming growth factor-beta (TGF-beta) pathway . Moreover, XIAP can regulate copper homeostasis through interacting with MURR1 .
AIRE, PHD finger 2 (AIRE_PHD2)
Type: Domain

AIRE functions as a regulator of gene transcription in the thymus. It is essential for prevention of autoimmunity. AIRE plays a critical role in the induction of central tolerance. It promotes self-tolerance through tissue-specific antigen (TSA) expression. It also acts as an active regulator of chondrocyte differentiation. AIRE contains a homogeneously-staining region (HSR) or caspase-recruitment domain (CARD), a nuclear localization signal (NLS), a SAND (for Sp100, AIRE, nuclear phosphoprotein 41/75 or NucP41/75, and deformed epidermal auto regulatory factor 1 or Deaf1) domain, two plant homeodomain (PHD) fingers, and four LXXLL (where L stands for leucine) motifs .
VAMP5, SNARE motif (VAMP5_R-SNARE_)
Type: Domain

VAMP-5 (vesicle-associated membrane protein 5) belongs to the R-SNARE subgroup of SNAREs . SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins contain coiled-coil helices (called SNARE motifs) which mediate the interactions between SNARE proteins, and a transmembrane domain .

The SNARE complex mediates membrane fusion, important for trafficking of newly synthesized proteins, recycling of pre-existing proteins and organelle formation. SNARE proteins are classified into four groups, Qa-, Qb-, Qc- and R-SNAREs, depending on whether the residue in the hydrophilic centre layer of the four-helical bundle is a glutamine (Q) or arginine (R). Qa-, as well as Qb- and Qc-SNAREs, are localized to target organelle membranes, while R-SNARE is localized to vesicle membranes. They form unique complexes consisting of one member of each subgroup, that mediate fusion between a specific type of vesicles and their target organelle. Their SNARE motifs form twisted and parallel heterotetrameric helix bundles .
Semaphorin-3D, Sema domain (Sema3D_Sema)
Type: Domain

Semaphorin-3D (Sema3D) is a secreted semaphorin expressed during the development of the nervous system . In zebrafish, Sema3D is expressed in the ventral tectum . It guides retinal axons along the dorsoventral axis of the tectum and guides the laterality of retinal ganglion cell (RGC) projections. Both Sema3D knockdown or its ubiquitous overexpression induced aberrant ipsilateral projections. Proper balance of Sema3D is needed at the midline for the progression of RGC axons from the chiasm midline into the contralateral optic tract . Sema3D is a member of the class 3 semaphorin family of proteins. Semaphorins are regulatory molecules in the development of the nervous system and in axonal guidance. They also play important roles in other biological processes, such as angiogenesis, immune regulation, respiration systems and cancer .
MARCH10, RING-CH finger, C4HC3-type (MARCH10_RING_CH-C4HC3)
Type: Domain

MARCH10 is a microtubule-associated E3 ubiquitin ligase of developing spermatids. It is localized to the principal piece of elongating spermatids. MARCH10 is involved in spermiogenesis by regulating the formation and maintenance of the flagella in developing spermatids. Unlike other MARCH proteins, MARCH10 is predicted to have no transmembrane spanning region. It harbours a C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger, that is responsible for its E3 activity .
14-3-3 theta (14-3-3_theta)
Type: Family

14-3-3 tau/theta (tau in humans, theta in mice) isoform is encoded by the YWHAQ gene in humans and plays an important role in controlling apoptosis through interactions with ASK1, c-jun NH-terminal kinase, and p38 mitogen-activated protein kinase (MAPK). Its interaction with CDC25c regulates entry into the cell cycle and subsequent interaction with Bad prevents apoptosis. 14-3-3 theta protein expression is induced in patients with amyotrophic lateral sclerosis . 14-3-3 tau is often overexpressed in breast cancer, which is associated with the downregulation of p21, a p53 target gene, and thus leads to tamoxifen resistance in MCF7 breast cancer cells and shorter patient survival. Therefore, 14-3-3 tau may be a potential therapeutic target in breast cancer . Additionally, 14-3-3 theta mediates nucleocytoplasmic shuttling of the coronavirus nucleocapsid protein which causes severe acute respiratory syndrome . 14-3-3 domain is an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells .
Vertebrate ubiquitin-conjugating enzyme E2 K, UBA domain (UBE2K_UBA)
Type: Domain

Ubiquitin-conjugating enzyme E2 K (UBE2K) is a multi-ubiquitinating enzyme with the ability to synthesize Lys48-linked polyubiquitin chains which is involved in the ubiquitin (Ub)-dependent proteolytic pathway . It interacts with the frameshift mutant of ubiquitin B and functions as a crucial factor regulating amyloid-beta neurotoxicity . It has also been characterised as Huntingtin-interacting protein that modulates the neurotoxicity of Amyloid-beta (Abeta), the principal protein involved in Alzheimer's disease pathogenesis . Moreover, E2-25K increases aggregate the formation of expanded polyglutamine proteins and polyglutamine-induced cell death in the pathology of polyglutamine diseases . UBE2K and its yeast homologue UBC1 are unique class II E2 conjugating enzymes, both of which contain a C-terminal ubiquitin-associated (UBA) domain in addition to an N-terminal catalytic ubiquitin-conjugating enzyme E2 (UBCc) domain .
Ubiquitin-conjugating enzyme E2-22kDa (UbcD4) , UBA domain (UBCD4_UBA)
Type: Domain

UbcD4, also called ubiquitin carrier protein or ubiquitin-protein ligase, is a class II E2 ubiquitin-conjugating enzyme encoded by Drosophila E2 gene which is only expressed in pole cells in embryos. It is a putative E2 enzyme homologous to the Huntingtin interacting protein-2 (HIP2) of human. UbcD4 specifically interacts with the polyubiquitin-binding subunit of the proteasome. It contains a C-terminal ubiquitin-associated (UBA) domain in addition to an N-terminal catalytic ubiquitin-conjugating enzyme E2 (UBCc) domain .
DHX57, UBA domain (DHX57_UBA)
Type: Domain

DHX57, also called DEAH box protein 57, is a multi-domain protein with an N-terminal ubiquitin-association (UBA) domain, a zinc finger domain, a RWD domain, a DEAD-like helicase domain and two C-terminal helicase associated domains. Although the precise biological function of DHX57 remains unclear, it may function as a putative ATP-dependent RNA helicase.
Proline and serine-rich protein 1 (PROSER1)
Type: Family

The function of Proline and serine-rich protein 1 (PROSER1) is not clear.
CST complex subunit CTC1-like (CTC1-like)
Type: Family

In animals and plants, CTC1 is a component of the CST complex (consists of Ten1, Stn1 and CTC1), a complex that binds to single-stranded DNA and is required to protect telomeres from DNA degradation .
Dynein regulatory complex protein 9 (IQCG)
Type: Family

Dynein regulatory complex protein 9, also known as IQ domain-containing protein G (IQCG), is an IQ motif-containing protein that is essential for sperm flagellum formation during spermiogenesis .
BBSome complex assembly protein BBS10 (BBS10)
Type: Family

Bardet-Biedl syndrome (BBS) is a human genetic disorder associated with ciliary dysfunction, resulting in obesity, retinal degeneration, polydactyly, and nephropathy. Twelve BBS genes (BBS1-12) have been identified. BBS6, BBS10, and BBS12 have sequence homology to the CCT (also known as TRiC) family of group II chaperonins. They form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly .
Putative methyltransferase NSUN7 (NSUN7)
Type: Family

The function of NSUN7 is not clear. It plays a role in sperm motility .
Tetratricopeptide repeat protein TTC23/TTC23L (TTC23/TTC23L)
Type: Family

This entry includes a group of tetratricopeptide repeat proteins, such as TTC23 and TTC23L from mammals. Their function is not clear.
Zinc finger protein 106 (Znf106)
Type: Family

Zinc finger protein 106 (Znf106) is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes . It is essential for maintenance of peripheral motor neuron and skeletal muscle function .
Transmembrane protein 205 (TMEM205)
Type: Family

Transmembrane protein 205 (TMEM205) has been linked to chemotherapeutic drug cisplatin resistance .
GRAM domain-containing protein 2A (RAMD2A)
Type: Family

GRAM domain-containing protein 2A (GRAMD2A) contains a GRAM domain and an ER-anchoring hydrophobic transmembrane domain. It localizes to ER and the plasma membrane (ER-PM) contact sites .
Junctional adhesion molecule B (JAM2)
Type: Family

Junctional adhesion molecule 2 (JAM2), also known as VE-JAM or JAM-B, is a type I integral membrane protein that contains two Ig-like folds and three N-linked glycosylation sites in the extracellular domain . JAM2 was initially identified as an endothelial adhesion molecule that plays a role in the architecture of interendothelial junctions and control leukocyte migration to inflammatory sites . JAM2 interacts with T, NK, and dendritic cells through JAM3 .
THO complex subunit 6 (THOC6)
Type: Family

In humans, THOC6 is a component of the THO subcomplex of the TREX complex . The THO complex is a conserved RNA binding complex that has been implicated in mRNA export of subsets of mRNAs.It plays an essential role in dopamine synaptogenesis . Mutations in the THOC6 genes have been linked to intellectual disability . In flies, THO complex is required for cell proliferation and for proper export of heat-shock mRNAs under heat stress .
F-box/WD repeat-containing protein 2 (FBXW2)
Type: Family

F-box/WD repeat-containing protein 2 (FBXW2) is a substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex . It inhibits tumour migration, invasion and metastasis in lung cancer cells by targeting beta-catenin for degradation .
Quinone oxidoreductase-like protein 1 (CRYZL1)
Type: Family

The function of Quinone oxidoreductase-like protein 1 (CRYZL1) is not clear .
Homeobox protein MOX-1/MOX-2 (MOX-1/MOX-2)
Type: Family

MEOX1 and MEOX2 are homeodomain transcription factors that have been shown to be partially functionally redundant during development. They regulate the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells . Nevertheless, MEOX1 also plays important, non-redundant roles in maintaining sclerotome polarity and the formation of cranio-cervical joints . Mutations in the MEOX1 gene cause Klippel-Feil syndrome 2, autosomal recessive (KFS2), a skeletal disorder characterised by congenital fusion of cervical vertebrae .
MEGF10/SREC1/2-like (MEGF10/SREC1/2-like)
Type: Family

This family includes a group of transmembrane receptors containing multiple EGF-like domains, involved in phagocytosis. It includes Multiple epidermal growth factor-like domains protein 10 (MEGF10) and its homologues, namely CED1 from C. elegans and draper from Drosophila melanogaster. MEGF10 is expressed in skeletal muscles, the retina and in CNS glial cells involved in phagocytosis by macrophages and astrocytes of apoptotic cells and it also promotes the formation of large intracellular vacuoles and may be responsible for the uptake of amyloid-beta peptides. Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is a rare disorder caused by biallelic mutations in MEGF10 .

This entry also includes Scavenger receptor class F members 1 and 2. SCARF1/SREC-I is an endocytic receptor for acetylated low density lipoprotein, HSP70, HSP90, calreticulin, gp96, and GP2 . Dendritic cells (DCs), macrophages and endothelial cells use SCARF1 to recognize and engulf apoptotic cells via the complement component C1q; this mediates apoptotic cells clearance, antigen clearance and prevents autoimmunity . SREC-II in contrast to SREC-I, SREC-II had little activity to internalize modified low density lipoproteins (LDL). SREC-II and SREC-I display strong heterophilic trans-interaction through the extracellular domains . They are expressed in a specific temporal and spatial pattern during epidermal development . Mutations in the SCARF2 gene cause Van den Ende-Gupta syndrome (VDEGS), a syndrome characterised by craniofacial and skeletal abnormalities .
Ankyrin repeat domain-containing protein 11 (ANKRD11)
Type: Family

Ankyrin repeat domain-containing protein 11 (ANKRD11) is a is a chromatin regulator that controls histone acetylation and gene expression during neural development . Mutations of the ANKRD11 gene cause KBG syndrome (KBGS), a rare genetic disorder characterised by intellectual disability, autism spectrum disorder, and craniofacial abnormalities .
Ankyrin repeat domain-containing protein AN34A/B/C (AN34A/B/C)
Type: Family

This entry includes AN34A/B/C from animals. Their function is not clear.
ASZ1, SAM domain (Asz1_SAM)
Type: Domain

ASZ1 (Ankyrin, SAM, leucine Zipper), also known as GASZ (Germ cell-specific Ankyrin, SAM, leucine Zipper), is a potential protein-protein interaction domain . Proteins containing this domain are involved in the repression of transposable elements during spermatogenesis, oogenesis, and preimplantation embryogenesis. They support synthesis of PIWI-interacting RNA via association with some PIWI proteins, such as MILI and MIWI. This association is required for initiation and maintenance of retrotransposon repression during the meiosis. In mice lacking ASZ1, DNA damage and delayed germ cell maturation was observed due to retrotransposons releasing from their repressed state .
Regulator of G-protein signaling 22 (Rgs22)
Type: Family

Rgs22 is a testis-specific regulator of G-protein signaling involved in human and mouse spermiogenesis. It interacts with guanine nucleotide binding protein GNA12/13 . It has been shown to inhibit pancreatic adenocarcinoma cell migration through the G12/13 alpha subunit/F-actin pathway .
CDK2-associated and cullin domain-containing protein 1 (CACUL1)
Type: Family

CDK2-associated and cullin domain-containing protein 1 (CACUL1) interacts with cyclin-dependent kinase 2 (CDK2), which regulates cell proliferation and allows progression from the G1 to S phase of the cell cycle . It has been linked to the proliferation of colorectal carcinoma, lung and gastric cancers .
Leukocyte receptor cluster member 9 (Leng9)
Type: Family

The function of Leukocyte receptor cluster member 9 (Leng9) is not clear.
Leucine-rich repeat-containing protein 72 (LRC72)
Type: Family

The function of Leucine-rich repeat-containing protein 72 (LRC72) is not clear.
E3 ubiquitin-protein ligase TRIM68, RING finger, HC subclass (TRIM68_RING-HC)
Type: Domain

TRIM68 is an E3 ubiquitin-protein ligase that negatively regulates Toll-like receptor (TLR)- and RIG-I-like receptor (RLR)-driven type I interferon production by degrading TRK fused gene (TFG), a novel driver of IFN-beta downstream of anti-viral detection systems . It also functions as a cofactor for androgen receptor-mediated transcription through regulating ligand-dependent transcription of androgen receptor in prostate cancer cells . Moreover, TRIM68 is a cellular target of autoantibody responses in Sjogren"s syndrome (SS), as well as systemic lupus erythematosus (SLE). It is also an auto-antigen for T cells in SS and SLE .

TRIM68 belongs the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.
Serine/threonine-protein kinase Nek10, catalytic domain (Nek10_STKc)
Type: Domain

STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. No function has yet been ascribed to Nek10. The gene encoding Nek10 is a putative causative gene for breast cancer; it is located within a breast cancer susceptibility loci on chromosome 3p24 . Nek10 is one in a family of 11 different Neks (Nek1-11) that are involved in cell cycle control. The Nek family is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase .
E3 ubiquitin-protein ligase TRIM63, RING finger, HC subclass (TRIM63_RING-HC)
Type: Domain

Tripartite motif-containing protein 63 (TRIM63), also known as MURF-1 is an E3 ubiquitin-protein ligase involved in ubiquitin-mediated muscle protein turnover . It is predominantly fast (type II) fibre-associated in skeletal muscle and can bind to many myofibrillar proteins, including titin, nebulin, the nebulin-related protein NRAP, troponin-I (TnI), troponin-T (TnT), myosin light chain 2 (MLC-2), myotilin, and T-cap. The early and robust upregulation of MuRF-1 is triggered by disuse, denervation, starvation, sepsis, or steroid administration resulting in skeletal muscle atrophy. It also plays a role in maintaining titin M-line integrity . It associates with the periphery of the M-line lattice and may be involved in the regulation of the titin kinase domain . It also participates in muscle stress response pathways and gene expression .