SII-SWORD/CoKE huggingface dataset:
Calcium binding protein 1/2/4/5 (CaBP1/2/4/5)
Type: Family

Calcium-binding proteins (CaBPs) are a family of Ca(2+)-binding proteins related to calmodulin with strong sequence similarity to Calmodulin (CaM), which is an important component of Ca(2+)-mediated cellular signal transduction in the central nervous system . Like calmodulin, CaBP family members regulate effectors such as voltage-gated Ca2+ channels in a Ca2+-dependent manner . CaBPs are localised in the brain and sensory organs. Mutations in calcium-binding protein 2 (CaBP2) cause hearing loss, revealing a role for CaBP2 in the mammalian auditory system .

This family contains calcium binding protein 1, 2, 4 and 5.
Zinc finger protein WIP (WIP1/2/3/4/5/6)
Type: Family

WIP proteins form a plant specific subfamily of C2H2 zinc finger (ZF) proteins . Arabidopsis TRANSPARENT TESTA 1 protein (At1g34790, also known as WIP1 or TT1) may act as a transcriptional regulator involved in the differentiation of young endothelium .

WIP2, also known as NTT, is a transcription factor that promotes replum development in Arabidopsis fruits .
Protein phosphatase Slingshot-like (Phosphatase_SSH-like)
Type: Family

Slingshot (SSH) is a cofilin-specific phosphatase. Dephosphorylation reactivates cofilin, which in turn depolymerizes actin and is thus required for actin filament reorganisation . Slingshot is a member of the dual-specificity protein phosphatase family . The N-terminal SSH region may be involved in P-cofilin binding (the model C terminus plus the DEK_C-like domain, which are characterised as the "B" domain in some of the literature), and may be required for the F-actin mediated activation of slingshot .
Slingshot, N-terminal (SSH-N)
Type: Domain

This entry represents the N-terminal conserved SSH region of Slingshot.

Slingshot (SSH) is a cofilin-specific phosphatase. Dephosphorylation reactivates cofilin, which in turn depolymerizes actin and is thus required for actin filament reorganisation . Slingshot is a member of the dual-specificity protein phosphatase family . The N-terminal SSH region may be involved in P-cofilin binding (the model C terminus plus the DEK_C-like domain, which are characterised as the "B" domain in some of the literature), and may be required for the F-actin mediated activation of slingshot .
Formin-like protein, animal (FMNL_animal)
Type: Family

This entry represents a group of formin-like proteins mostly from animals, including FMNL1/2/3 from humans. They contain the FH2 domain and belong to the formin homology family. They play a role in the regulation of cell morphology and cytoskeletal organisation. They are required in the cortical actin filament dynamics and cell shape .
Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein (ASAP)
Type: Family

ASAPs (ASAP1, ASAP2, and ASAP3) function as Arf-specific GTPase-activating proteins (GAPs), participate in rhodopsin trafficking, are associated with tumour cell metastasis, modulate phagocytosis, promote cell proliferation, facilitate vesicle budding, Golgi exocytosis, and regulate vesicle coat assembly via a Bin/Amphiphysin/Rvs domain . Each member has a BAR, PH, Arf GAP, Ank repeat and proline rich domains. ASAP1 and ASAP2 also have a SH3 domain at the C terminus . The ASAP family is named for the first identified member, ASAP1 .
HMG-CoA lyase (HMGL)
Type: Family

3-hydroxy-3-methylglutaryl-CoA lyase (HMGL) catalyses the cleavage of HMG-CoA to acetyl-CoA and acetoacetate, one of the terminal steps in ketone body generation and leucine degradation, and is a key enzyme in the pathway that supplies metabolic fuel to extrahepatic tissues. Mutations in HMGL cause a human autosomal recessive disorder called primary metabolic aciduria that affects ketogenesis and leucine catabolism and can be fatal due to an inability to tolerate hypoglycemia .
Feruloyl esterase B/C/D (FaeB/C/D)
Type: Family

Feruloyl esterases (Fae) catalyse the hydrolysis of the 4-hydroxy-3-methoxycinnamoyl (feruloyl) group from an esterified sugar, which is usually arabinose in 'natural' substrates. This entry includes FaeB, FaeC and FaeD. FaeC from Aspergillus oryzae and Emericella nidulans have been shown to display hydrolytic activity towards arabinoxylan and methyl ferulate, among other substrates . FaeD from Neurospora crassa also exhibits feruloyl esterase activity .
CFAP53/TCHP (CFAP53/TCHP)
Type: Family

This entry includes CFAP53 and TCHP.

Cilia- and flagella-associated protein 53 (CFAP53), also known as coiled-coil domain-containing protein 11 (CCDC11), is a novel centriolar satellite protein essential for the assembly and function of motile cilia and establishment of left-right asymmetry . In zebrafish, it is required for cilia rotation specifically in Kupffer's vesicle, the zebrafish laterality organ .

Trichoplein keratin filament-binding protein (TCHP) may act as a 'capping' or 'branching' protein for keratin filaments in the cell periphery. It may regulate K8/K18 filament and desmosome organisation mainly at the apical or peripheral regions of simple epithelial cells . In human, it acts as a tumor suppressor which has the ability to inhibit cell growth and be pro-apoptotic during cell stress. It inhibits cell growth in bladder and prostate cancer cells by a down-regulation of HSPB1 by inhibiting its phosphorylation .
Trichohyalin-plectin-homology domain (TPH_dom)
Type: Domain

This entry represents the trichohyalin-plectin-homology domain. This domain can be found in mitostatin (also known as trichoplein keratin filament-binding protein, TCHP) and related proteins .

Trichoplein keratin filament-binding protein (TCHP) may act as a 'capping' or 'branching' protein for keratin filaments in the cell periphery. It may regulate K8/K18 filament and desmosome organisation mainly at the apical or peripheral regions of simple epithelial cells . In human, it acts as a tumor suppressor which has the ability to inhibit cell growth and be pro-apoptotic during cell stress. It inhibits cell growth in bladder and prostate cancer cells by a down-regulation of HSPB1 by inhibiting its phosphorylation .
R-spondin, Fu-CRD domain (Rspo_Fu-CRD_dom)
Type: Domain

The R-spondin (RSPO) family is a small group of four secreted proteins (RSPO1-RSPO4) that have pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. They contain an N-terminal secretory signal peptide sequence, two tandem furin-like cysteine-rich (Fu-CRD) domains, a thrombospondin type I repeat (TSP) domain, and a C-terminal basic amino acid-rich (BR) domain. Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs .

This entry represents the two tandem furin-like cysteine-rich domains found in R-spondin.
Cation efflux system protein CusB-like, domain 1 (CusB-like_dom_1)
Type: Domain

CusB can be divided into four different domains. The first three domains of the protein are mostly β-strands. However, the fourth domain forms an all α-helical domain, which is folded into a three-helix bundle secondary structure .

This entry represents the first β-domain (domain 1) of cation efflux system protein CusB from E. coli. It is formed by the N and C-terminal ends of the polypeptide (residues 89-102 and 324-385) . CusB is part of the copper-transporting efflux system CusCFBA . This domain can also be found in other membrane-fusion proteins, such as HlyD, MdtN, MdtE and AaeA.
Phlebovirus glycoprotein G2, C-terminal domain (Phlebo_G2_C)
Type: Domain

HRTV is an insect-borne virus found in America that can infect humans. It belongs to the newly defined family Phenuiviridae, order Bunyavirales. HRTV contains three single-stranded RNA segments (L, M, and S). The M segment of the virus encodes a polyprotein precursor that is cleaved into two glycoproteins, Gn and Gc. Gc is a fusion protein facilitating virus entry into host cells . G2 (also known as Gc) is necessary for optimal glycoprotein G1 (also found as Gn) expression and efficient production or viral-like particles and possibly for the cell infection, as G2 is determinant for cell fusion . Phleboviral G2 fusion glycoprotein is both functionally and structurally analogous to the fusion glycoproteins of alphaviruses and flaviviruses, all of them recognize DC-SIGN receptor to enable viral attachment .

This domain is found at the C-terminal of several Phlebovirus glycoprotein G2 sequences. Two prefusion conformation structures of bunyavirus Gc from RVFV in the Phenuiviridae family and Hantaan virus (HTNV) in the Hantaviridae family have been solved.
DUF883, N-terminal domain (DUF883_N)
Type: Domain

This domain is found at the N terminus of several bacterial proteins, including ElaB, YgaM and YqjD from Escherichia coli.

YqjD is an inner membrane and ribosome binding protein expressed during the stationary growth phase. It is possible that YqjD inactivates ribosomes by localizing a part of the ribosome to the membrane during the stationary phase . Its expression is regulated by stress response sigma factor RpoS. The two paralogues of YqjD, ElaB and YgaM, are expressed and bind to ribosomes in a similar manner to YqjD . These proteins may have important cellular roles during the stress response. ElaB has been shown to protect cells against oxidative and heat shock stress .
DUF883, C-terminal domain (DUF883_C)
Type: Domain

This entry represents the C-terminal presumed transmembrane helix found in a group of bacterial proteins, including ElaB, YgaM and YqjD from Escherichia coli. The helix contains a glycine zipper motif suggestive of dimerisation.

YqjD is an inner membrane and ribosome binding protein expressed during the stationary growth phase. It is possible that YqjD inactivates ribosomes by localizing a part of the ribosome to the membrane during the stationary phase . Its expression is regulated by stress response sigma factor RpoS. The two paralogues of YqjD, ElaB and YgaM, are expressed and bind to ribosomes in a similar manner to YqjD . These proteins may have important cellular roles during the stress response. ElaB has been shown to protect cells against oxidative and heat shock stress .
Coronavirus replicase NSP15, N-terminal oligomerization (CoV_NSP15_N)
Type: Domain

The unique coronavirus transcription/replication machinery comprised of multiple virus-encoded non structural proteins (NSP) plays a vital role during initial and intermediate phases of the viral life cycle. NSP15 forms a hexamer made of dimers of trimers which is suggested to be a functional unit, responsible for the endoribonuclease activity. The NSP15 monomer consists of three domains: N-terminal, middle and C-terminal . The catalytic function of NSP15 resides in the C-terminal NendoU domain. The active site carries six key residues conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, suggesting that its activity is important for sustained replication in the host .

This entry represents the N-terminal oligomerization domain of the NSP15, which stabilises the hexamer and is critical for its formation . This domain is composed of three-stranded antiparallel β-sheet and two α-helices .
Coronavirus spike glycoprotein S1, C-terminal (CoV_S1_C)
Type: Domain

The coronavirus spike is an envelope glycoprotein which aids viral entry into the host cell. The precursor spike protein 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 .

S1 contains two major domains: an N-terminal domain (NTD) and a receptor-binding domain (S1 RBD) also referred to as the S1 CTD or domain B. Either the S1 NTD or S1 RBD, or occasionally both, are involved in binding the host receptors .

This entry represents an additional, short domain found at the very C terminus of the S1 protein. It is found across a range of alpha, beta and gamma coronaviruses. This small all-β-stranded domain is known as subdomain 2 in the structure of the porcine epidemic diarrhea virus spike protein .
Nonstructural protein 15, middle domain, coronavirus (CoV_NSP15_M)
Type: Domain

The unique coronavirus transcription/replication machinery comprised of multiple virus-encoded non structural proteins (NSP) plays a vital role during initial and intermediate phases of the viral life cycle. NSP15 forms a hexamer made of dimers of trimers which is suggested to be a functional unit, responsible for the endoribonuclease activity. The NSP15 monomer consists of three domains: N-terminal, middle and C-terminal . The catalytic function of NSP15 resides in the C-terminal NendoU domain. The active site carries six key residues conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, suggesting that its activity is important for sustained replication in the host .

This entry represents the non-catalytic middle domain from NSP15. This domain is formed by ten β-strands organised into threeβ-hairpins. It creates concave surfaces that may serve as interaction hubs with other proteins and RNA .
NendoU domain, nidovirus (NendoU_nidovirus)
Type: Domain

Nidovirus endoribonucleases (NendoUs) are uridylate-specific endoribonucleases, which release a cleavage product containing a 2',3'-cyclic phosphate at the 3' terminal end. They are conserved among this order and a genetic marker of nidoviruses . A feature of these viruses' evolutionary relationship is the organisation and processing of the genome, which is translated in two large precursor polyproteins (pp1a and pp1ab) from the replicase gene, that are proteolytically processed by virus proteases into 13 to 16 nonstructural proteins (NSPs) .

Proteins containing the NendoU domain include NSP15 from coronaviruses and NSP11 from arteriviruses, both of which participate in the viral replication process and in the evasion of the host immune system. Although they are similar and conserved, they only share 27% identical residues and show structural differences . NSP11 has an N-terminal domain and a C-terminal NendoU catalytic domain. NSP11 functions as a dimer and Mg2 is dispensable for its activity. In Porcine reproductive and respiratory syndrome virus (PRRSV), NSP11 induces STAT2 degradation to inhibit interferon signaling. Mutagenesis studies revealed that the amino acid residue K59 located at the N-terminal domain of NSP11 is indispensable for inducing STAT2 reduction . This domain is not conserved in those nidovirus branches that replicate in invertebrate hosts (Mesoniviridae, Roniviridae), suggesting specific roles in vertebrate hosts.

The NendoU domain packs into two β-sheets which constitute the catalytic-site cleft located at one side of the domain. A group of small α-helices packed at the other side of the domain face the concave surface of the β-sheets. The active site, located in the shallow groove between the two β-sheets, carries the catalytic triad made of two histidines and a lysine .
Non-structural protein 6, coronavirus (NSP6_CoV)
Type: Domain

This entry represents the Non-structural Protein 6 (NSP6) found in coronaviruses. Coronaviruses encode large replicase polyproteins which are proteolytically processed by viral proteases to generate mature Nonstructural Proteins (NSPs) . NSP6 is a membrane protein containing 6 transmembrane domains with a large C-terminal tail . NSP6 from the avian coronavirus, infectious bronchitis virus (IBV) and the mouse hepatitis virus (MHV) have been shown to localise to the ER and to generate autophagosomes . Coronavirus NSP6 proteins have also been shown to limit autophagosome expansion. This may favour coronavirus infection by reducing the ability of autophagosomes to deliver viral components to lysosomes for degradation . NSP6 from IBV, MHV and severe acute respiratory syndrome coronavirus (SARS-CoV) have also been found to activate autophagy .
Coronavirus replicase NSP3, C-terminal (CoV_NSP3_C)
Type: Domain

Non-structural protein NSP3 is a multi-domain protein, the largest product of coronavirus ORF1a which encodes the poyprotein 1a/1ab (pp1a/1ab). NSP3 is released from pp1a/1ab by the papain-like protease domain(s), which is (are) part of NSP3 itself. NSP3 plays many roles in the viral life cycle. It can act as a scaffold protein to interact with itself and to bind other viral Nsps or host proteins. In particular, Nsp3 is essential for the formation of the the replication/ transcription complex (RTC). The RTC associates with host ER membranes producing convoluted membranes and double-membrane vesicles. It is also involved in post-translational modifications of host proteins to antagonise its innate immune response .

NSP3 comprises up to 16 different domains and regions, their organisation differs between coronaviruses (CoV). However, eight domains and two transmembrane regions are conserved in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (hypervariable region), a macrodomain (X domain), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro, depending on the CoV there are one or two PLpro), the NSP3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1, Y2 and Y3 of unknown functions. The Y1 domain is conserved in all viruses of the order Nidovirales, while Y2 and Y3 are conserved in all coronaviruses. The three domains from the Y region (Y1 to Y3) are located at the cytosolic side of the ER. The level of their conservation is close to that for the enzymatic domains of Nsp3 and exceeds nonenzymatic ones. From the consistently high conservation of Y1, Y2, and Y3, it has been hypothesize that Y1 to Y3 may form a single functional unit with a conserved enzymatic function .

This entry represents the C-terminal region of NSP3 found in coronaviruses.
Non-structural protein NSP4, N-terminal, coronavirus (CoV_NSP4_N)
Type: Domain

Nonstructural protein 4 (NSP4/nsp4) is encoded by ORF1a/1ab and proteolytically released from the pp1a/1ab polyprotein in coronaviruses (CoVs). It is a membrane-spanning protein which is thought to anchor the viral replication-transcription complex (RTC) to modified endoplasmic reticulum membranes which forms double-membrane vesicles (DMVs) or convoluted membranes (CMs). NSP4 is required for RTC formation .

This is the N-terminal domain of the coronavirus NSP4 which represents the membrane spanning region, covering four transmembrane regions .
Non-structural protein 2, C-terminal domain, coronavirus (CoV_NSP2_C)
Type: Domain

Coronavirus non-structural protein 2 (NSP2) is encoded by ORF1a/1ab and proteolytically released from the pp1a/1ab polyprotein. This protein has been implicated in processes ranging from translation repression to endosomal transport, ribosome biogenesis, and actin filament binding. NSP2 in SARS-CoV-2 and other coronaviruses have been observed to localise to endosomes and replication-transcription complexes (RTC). It may be involved in binding nucleic acids and regulating intracellular signalling pathways. Viral-host protein interaction studies in SARS-CoV and SARS-CoV-2 found that this protein could interact with several host proteins, including prohibitin 1 (PHB1) and PHB2, which are implicated in a number of cellular functions, including cellular migration, differentiation and apoptosis . NSP2 structure from SARS-CoV-2 has been recently solved and revealed that it consists of an N-terminal, middle and C-terminal domains . NSP2 has been pointed as an interesting target to develop anti-SARS-CoV-2 therapies as it may play important roles during viral infection .

This domain is found at the C-terminal of NSP2 in alpha and betacoronaviruses. It is found in two copies in some viral NSP2 proteins.
Nonstructural protein 2, N-terminal domain, coronavirus (NSP2_N_CoV)
Type: Domain

Coronavirus non-structural protein 2 (NSP2) is encoded by ORF1a/1ab and proteolytically released from the pp1a/1ab polyprotein. This protein has been implicated in processes ranging from translation repression to endosomal transport, ribosome biogenesis, and actin filament binding. NSP2 in SARS-CoV-2 and other coronaviruses have been observed to localise to endosomes and replication-transcription complexes (RTC). It may be involved in binding nucleic acids and regulating intracellular signalling pathways. Viral-host protein interaction studies in SARS-CoV and SARS-CoV-2 found that this protein could interact with several host proteins, including prohibitin 1 (PHB1) and PHB2, which are implicated in a number of cellular functions, including cellular migration, differentiation and apoptosis . NSP2 structure from SARS-CoV-2 has been recently solved and revealed that it consists of an N-terminal, middle and C-terminal domains . NSP2 has been pointed as an interesting target to develop anti-SARS-CoV-2 therapies as it may play important roles during viral infection .

This entry represents the N-terminal of NSP2 which consists of ten α-helices (α1-α10) and fourteen β-sheets (β1-β14) with three zinc fingers, belonging to the C2H2, C4, and C2HC types, respectively (see

). The three zinc fingers are not involved in binding nucleic acids directly but may play other unknown functions. The interaction of NSP2 and nucleic acid is mainly dependent on a large positively charged region on the electrostatic surface of the NSP2 N-terminal domain .
DAZ domain (DAZ_dom)
Type: Domain

DAZ (Deleted in Azoospermia) proteins are found almost exclusively in germ cells in distant animal species. Deletion or mutations of their encoding genes usually impair either oogenesis or spermatogenesis or both. The family includes three members, Boule (or Boll), Dazl (or Dazla) and DAZ, encoding RNA binding proteins. Boule is the ancestral gene that is conserved from flies to humans, whereas, Dazl arose in the early vertebrate lineage and Daz arrived on Y chromosome during primate evolution. Basically, DAZ family proteins have been proposed to function as adaptors for target mRNA transport and activators of their translation. These proteins have a highly conserved RNA recognition motif (RRM) for binding target mRNAs and one (Boule and Dazl) or multiple copies (Daz) of the DAZ domain, a 24 amino acids motif rich in Asn, Tyr, and Gln residues. The function of the DAZ domain is not known, but may be involved in protein-protein interactions .
Salyut domain (Salyut_dom)
Type: Domain

This entry represents the Salyut domain found in the replicase from the viral family Tymoviridae, composed of viruses that infect plants and insects. It is located within a long, hypervariable, proline-rich hinge region located between the alphavirus-like methyltransferase (Vmethyltransf)

and the peptidase C21

. It is located 150-200 aa downstream the Iceberg region that forms the C terminus of Vmethyltransf . The function of this domain is unknown.
Sgo0707, N-terminal domain (Sgo0707_N1)
Type: Domain

This entry represents a domain that is found at the N terminus of the bacterial cell surface Sgo0707 protein . This domain is called the N1 domain and is involved in host colonisation. The N1 domain comprises a putative binding cleft with a single cysteine located in its centre and exhibits an unexpected structural similarity to the variable domains of the streptococcal Antigen I/II adhesins .
QPE repeat (QPE_rpt)
Type: Repeat

This repeat is found in a group of bacterial cell surface proteins with an N-terminal collagen binding domain. We have named this repeat QPE after the most conserved sequence motif.
L1 transposable element, RRM domain (L1_RRM_dom)
Type: Domain

This domain represents a conserved component in the protein ORF1 of the long interspersed nuclear element 1 (LINE-1 or L1) retrotransposon. This domain is designated RRM, which stands for RNA recognition motif, and is involved in RNA binding. Cooperation between this RRM domain and the C-terminal domain is required to achieve this, despite the fact that these two domains do not contact each other .