SII-SWORD/CoKE huggingface dataset:
Serine-protein kinase YeaG (YeaG)
Type: Family

This entry represents YeaG and similar proteins mainly from proteobacteria.

Serine/threonine kinase YeaG plays a role in bacterial adaptation to sustained nitrogen starvation . It may function by indirectly repressing the transcription of two toxin-antitoxin modules, MqsR/MqsA and DinJ/YafQ, which in turn positively influence the expression of rpoS, the master regulator of the general stress response . In vitro, YeaG exhibits autokinase and casein kinase activity , and can also specifically phosphorylate an unidentified 65 kDa cytoplasmic protein. Additionally, it has been shown to phosphorylate the isocitrate lyase AceA in the presence of malate, suggesting a possible regulatory role during the metabolic shift from glucose to malate .
Speedy E (Speedy_E)
Type: Family

This entry represents Speedy E proteins from mammals.

Speedy (Spy1, also known as RINGO A) is a cell cycle regulatory protein which binds and activates CDK1 and CDK2 , protein kinases that allows progression through G1/S phase and further replication events. Spy1 activates CDK2 inducing a conformational change of the CDK2 T-loop that avoids its phosphorylation . Spy1 expression overcomes a p27-induced cell cycle arrest to allow for DNA synthesis, so cell cycle progression occurs due to an interaction between Spy1 and p27 .
VAL1-3, N-terminal zinc finger domain (Zfn_VAL1-3_N)
Type: Domain

This zinc finger is found at the N-terminal end of B3 domain-containing transcription repressor VAL1-3 from Arabidopsis thaliana, its homologues from rice Os07g0563300 and Os07g0679700 and similar plant proteins. VAL1/2 are transcriptional repressors of gene expression involved in embryonic pathways that play an essential role in regulating the transition from seed maturation to seedling growth . VAL3 may be involved in plant development .
Ochratoxinase-like (OTAase-like)
Type: Domain

This entry describes Ochratoxinase and uncharacterised proteins from bacteria and fungi which are likely Metallo-dependent hydrolases. Proteins represented by this entry have a conserved metal binding site, involving four histidines and one aspartic acid residue.

Ochratoxinase is a carboxypeptidase that catalyses the release of C-terminal amino acids, showing specific catalytic activity towards aromatic amino acids such as phenylalanine . This protein is capable of degrading ochratoxin A, one of the five major mycotoxins most harmful to humans and animals, which is produced by Aspergillus and Penicillium species and found in a wide range of agricultural products . The enzymes possess a characteristic two-domain architecture comprising a TIM-barrel and a β-sandwich domain. The activity of some members of this group is known to be inhibited by Zn(2+)-specific chelators, suggesting a dependence on metal ions for catalytic function.
Outer membrane channel protein CpnT-like, N-terminal domain (CpnT-like_N)
Type: Domain

This entry represents a domain found towards the N-terminal of the Mycobacterium tuberculosis Outer membrane channel protein CpnT (

) and similar sequences from actinomycetes. Members of this group are related to the WXG100 superfamily.

CpmT has a dual function in the uptake of nutrients and the induction of host cell death. It has been suggested that this domain acts as a membrane channel . However, structure prediction does not show any regions of hydrophobic surface that would be expected in a channel protein. The secreted C-terminal toxic domain (TNT,

) acts as a glycohydrolase, which hydrolyses the essential cellular coenzyme NAD+ in the cytosol of infected macrophages, leading to necrotic host cell death. Both functions are required for survival, replication and cytotoxicity of the microorganism in macrophages.
WWC1-like, helical hairpin (WWC1_hairpin)
Type: Domain

This domain is found in human Protein KIBRA (WWC1) and similar animal proteins. WWC1 is a regulator of the Hippo signalling pathway that negatively regulates cell proliferation and organ growth . This domain is predicted to form an helical hairpin.
Nuclear factor related to kappa-B-binding protein, second winged helix domain (NFRKB_WH_2)
Type: Domain

This domain is found in the human Nuclear factor related to kappa-B-binding protein (NFRKB) and related proteins from animals and plants. This domain has a significant similarity to known winged helix domains, and it is predicted to adopt a similar structure.

NFRKB is a putative regulatory component of the chromatin remodelling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair .
WDR47, cross-over region (WDR47_COR)
Type: Domain

This entry represents the cross-over region (COR) of the N-terminal domain of WD repeat-containing protein 47 (WDR47). The COR consists of three α-helices that intertwine to form a dimer interface and contains a non-canonical target-binding pocket. This pocket specifically recognises a basic helical motif (WBR) in Calmodulin-regulated spectrin-associated proteins (Camsaps), which is essential for proper central-pair microtubule formation in motile cilia. Unlike typical LisH-CTLH-containing domains, the WDR47 COR is expanded and forms an acidic pocket that binds to a conserved basic motif in target proteins. The WDR47-Camsap interaction mediated by this domain is crucial for the assembly of non-centrosomal microtubules and for maintaining the proper planar beat pattern of mammalian motile multicilia . Mutations in this protein have been related to serious developmental disorders

WD40-repeat 47, also known as Nemitin, is a microtubule-associated protein that is essential for brain development. It is involved in microtubule dynamics and regulation of autophagic flux for axonal outgrowth and guidance .
Tripartite motif-containing protein 2/3, C-terminal domain (TRIM2/3_C)
Type: Domain

This entry represents the C-terminal domain in human Tripartite motif-containing protein 2/3 (TRIM2/3) and similar animal proteins. It is formed by NHL repeats (

).

TRIM2 is a UBE2D1-dependent E3 ubiquitin-protein ligase that mediates the ubiquitination of NEFL and phosphorylated BCL2L11, playing a neuroprotective role and potentially contributing to rapid ischaemic tolerance in neurones. In addition to its role in neuronal health, TRIM2 also participates in antiviral immunity and restricts New World arenavirus infection independently of its ubiquitin ligase activity . TRIM3, another E3 ubiquitin ligase, is essential for neuronal processes including plasticity, learning, and memory. It functions as part of the cytoskeleton-associated recycling or transport complex in neurones and regulates these processes through the polyubiquitination of gamma-actin and the postsynaptic scaffold GKAP, thereby influencing dendritic spine morphology. Beyond neuronal functions, TRIM3 contributes to innate immunity and cell cycle regulation, promotes TLR3-mediated signalling via Lys-63-linked polyubiquitination, and supports sorting by ESCRT complexes. Additionally, it modulates microtubule motor protein KIF21B and induces growth arrest through RING-dependent E3 ligase activity targeting CDKN1A .
Viral Fc-gamma receptor-like protein UL119-like domain (Viral_FcR_dom)
Type: Domain

This entry represents a viral domain found in Fc-gamma receptor-like protein UL119 (gp68) and similar cytomegalovirus proteins. The domain binds to the Fc part of human IgG and may be involved in interfering with host Ig-mediated immune responses . Unlike host Fc receptors, viral Fc receptors can bind to deglycosylated Fc and interact with the CH2-CH3 interface of immunoglobulin G. The domain contains an immunoglobulin-like fold and binds Fc with nanomolar affinity at a range of pH values.
ORF27-like, Herpesvirus 1 (VG27-like)
Type: Family

This entry represents a conserved protein family that includes the uncharacterised protein encoded by ORF27 from Ictalurid herpesvirus 1 (IcHV-1, Channel catfish herpesvirus), similar proteins in Herpesvirales and related sequences in fish. The specific function of this protein family remains to be determined. IcHV-1 is a member of the Alloherpesviridae family that infects channel catfish.
Cytomegalovirus US29-like (US29-like)
Type: Family

This entry represents the uncharacterised US29 protein from Human cytomegalovirus (HCMV) and similar sequences from betaherpesviruses (Cytomegalovirus). US29 is a membrane protein with two predicted transmembrane helices. The specific function of this protein remains unknown.
Phosphatidylinositol 4-kinase beta/PIK1, catalytic domain (PI4-kinase_beta/PIK1_cat)
Type: Domain

This entry represents the catalytic domain in mammal Phosphatidylinositol 4-kinase beta, its yeast homologue Phosphatidylinositol 4-kinase PIK1 and similar eukaryotic sequences.

Phosphatidylinositol 4-kinase (PI4-kinase) (

) is an enzyme that acts on phosphatidylinositol (PI) in the first committed step in the production of the secondary messenger inositol-1,4,5-trisphosphate. This domain is also present in a wide range of protein kinases, involved in diverse cellular functions, such as control of cell growth, regulation of cell cycle progression, a DNA damage checkpoint, recombination, and maintenance of telomere length. Despite significant homology to lipid kinases, no lipid kinase activity has been demonstrated for any of the PIK-related kinases .

Human Phosphatidylinositol 4-kinase beta phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5-trisphosphate (PIP). This protein may regulate Golgi disintegration/reorganisation during mitosis, possibly via its phosphorylation and is involved in Golgi-to-plasma membrane trafficking. It may also play an important role in the inner ear development .
Netrin receptor UNC5A-D-like, N-terminal domain (UNC5A-D-like_N)
Type: Domain

This entry represents the N-terminal immunoglobulin-like (Ig-like) domain of Netrin receptor UNC5A-D and similar animal proteins. This domain is not present in mice and human UNC5C-like proteins

.

UNC-5 proteins are transmembrane netrin receptors that play a crucial role in axon guidance and neuronal development. Upon binding to secreted netrins (netrin-1, -3, and -4), these receptors mediate axonal repulsion of neuronal growth cones, contributing to proper nervous system patterning . In addition to axonal guidance, UNC-5 receptors are involved in neuronal migration, blood vessel patterning, cell-cell adhesion, cell migration, and apoptosis . Structurally, they possess an extracellular region comprising two immunoglobulin-like repeats and two thrombospondin type-I modules, along with an intracellular region containing ZU-5, UPA, and death domains (DD), which facilitate downstream signalling .
Phosphatidylinositol 3-kinase type3/VPS34-like (PI3-kinase_type3/VPS34_cat)
Type: Domain

This entry represents the catalytic domain in mammal Phosphatidylinositol 3-kinase catalytic subunit type 3, yeast and plant PI3-kinase VPS34 and related PI3-kinases proteins.

Phosphatidylinositol 3-kinase (PI3-kinases) can be divided into three main classes (I, II, and III), defined by their substrate specificity, regulation, and domain structure. Class I PI3-kinases are the only enzymes capable of converting PtdIns(4,5)P2 to the critical second messenger PtdIns(3,4,5)P3. Class I enzymes are heterodimers and exist in multiple isoforms consisting of one catalytic subunit (p110alpha, beta, gamma or delta) and one of several regulatory subunits (p85alpha, beta or gamma). They are further classified into class IA (alpha, beta and delta) and IB (gamma). Class IA enzymes contain an N-terminal p85 binding domain, a Ras binding domain, a lipid binding C2 domain, a PI3-kinase homology domain of unknown function, and a C-terminal ATP-binding catalytic domain. They associate with a regulatory subunit of the p85 family and are activated by tyrosine kinase receptors .
UL78-like, Herpesvirus (UL78-like)
Type: Family

This entry represents the UL78 G protein-coupled receptor (GPCR) found in human cytomegalovirus (HCMV) and related betaherpesviruses. UL78 is one of four viral GPCRs encoded by HCMV, along with US27, US28, and UL33. Unlike the other three viral GPCRs that show approximately 30% similarity to chemokine receptors, UL78 displays negligible similarity to any endogenous receptors. UL78 has been shown to form a unique homotrimeric architecture through an extensive interface covering transmembrane helices 3-6 and intracellular loops 1 and 2. This receptor can form heterodimers with human CXCR4 and CCR5, potentially interrupting normal signalling pathways. UL78 may also modulate the functions of other viral GPCRs and host GPCRs through oligomerisation. Despite being classified as an orphan receptor with no known chemokine ligands, UL78 is believed to regulate viral replication or reactivation .
UL74A-like, Cytomegalovirus (UL74A-like)
Type: Family

This entry represents the UL74A protein found in Human cytomegalovirus (HCMV). It is a small viral envelope protein of approximately 70 amino acids in length with a single transmembrane helix. The specific function of this protein remains to be determined, but it is localised to the virion membrane.
UL148-like, Cytomegalovirus (UL148-like)
Type: Family

This protein family includes the Membrane protein UL148, an endoplasmic reticulum-resident glycoprotein found in human cytomegalovirus (HCMV). UL148 is predicted to play an important role in HCMV tropism by regulating the abundance of gH-gL complexes in virions. It is thought to function as a chaperone that interacts with the host ERAD machinery and slows gO decay which would otherwise be constitutively degraded. UL148 is also likely to reorganise the host endoplasmic reticulum, activate the unfolded protein response and play a role in the evasion of antiviral immune response by down-regulating cell surface expression of host CD58.
UL145-like, Cytomegalovirus (UL145-like)
Type: Family

This entry represents the human cytomegalovirus UL145 protein which exists in two isoforms: pUL145-Long and pUL145-Short. Both isoforms act as viral DDB1-cullin- associated factors (vDCAFs) that mimic cellular DCAFs to exploit the ubiquitin- proteasome system to impede antiviral immunity . pUL145 recruits DDB1-containing ubiquitin ligases via a conserved H-box motif to induce proteasomal degradation of STAT2, thereby disrupting the host interferon response. The pUL145-Short isoform is expressed earlier and more abundantly than pUL145-Long during infection.
UL135-like, Cytomegalovirus (UL135-like)
Type: Family

This entry represents the Human cytomegalovirus UL135 protein, which remodels the actin cytoskeleton to impair immune recognition of infected cells . UL135 interacts directly with abl interactor 1 (ABI1) and ABI2 to recruit the WAVE2 regulatory complex to the plasma membrane, resulting in dramatic actin cytoskeleton remodelling. This modification disrupts immune synapse formation between the infected cell and immune effector cells, thereby inhibiting both natural killer (NK) cell and T cell functions. UL135 also interacts with talin to disrupt cell contacts with the extracellular matrix. The protein is expressed during early phase of viral infection and localises to the Golgi apparatus and plasma membrane.
UL128-like, Cytomegalovirus (UL128-like)
Type: Family

This entry represents the UL128 protein from human cytomegalovirus (HCMV), which is thought to a role in viral entry into host cells and be part of the viral pentameric complex (Pentamer). The Pentamer, comprising gH/gL/UL128/UL130/UL131A, is essential for HCMV entry into dendritic, endothelial, and epithelial cells. UL128 contains an N-terminal region with a chemokine fold of CC-type that packs against a small domain. UL128 is connected to gH/gL by a 50 angstrom-long flexible linker that projects from the small domain to end in a three-turn α-helix docking on a hydrophobic groove formed by the gL three-helix bundle. UL128-Cys162 forms a disulfide bond with gL-Cys144, securing UL128 to the gL helical bundle. The Pentamer is the main target of neutralising antibody responses against HCMV, and multiple neutralising epitopes have been identified on UL128. Antibodies targeting UL128 can prevent Pentamer from binding to cells, suggesting it plays a role in cell receptor interaction.
Ubiquitin carboxyl-terminal hydrolase 40, ubiquitin-like domain (UBL_USP40)
Type: Domain

This entry describes one of the ubiquitin-like (UBL) domains found in ubiquitin carboxyl-terminal hydrolase 40 (USP40) from animals. USP40 is a deubiquitinase (DUB) enzyme that belongs to the USP family . The UBL domain of USP40 has been shown to interact with Yes-associated protein (YAP) . The number of UBL domains varies between different types of USP enzymes. In human USP40, the UBL domain is repeated six times after the catalytic core ; this entry represents the third UBL domain. This domain is predicted to consist of four β-strands surrounding an α-helix.
Serine/threonine-protein kinase D1-3-like, ubiquitin-like domain (Ubiquitin_PRKD1-3_N)
Type: Domain

This presumed ubiquitin domain is found at the N-terminal end of human Serine/threonine-protein kinase D1-3 (PRKD1-3) and similar proteins mainly found in animals. These proteins convert transient diacylglycerol signals into prolonged physiological effects downstream of PKC . PRKD1 is involved in the regulation of MAPK8/JNK1 and Ras signalling, Golgi membrane integrity and trafficking, cell survival and cell migration.

The protein kinase D family of enzymes consists of three isoforms: PKD1 (PKCmu), PKD2, and PKD3 (PKCnu). They all share a similar architecture with regulatory sub-domains that play specific roles in the activation, translocation and function of the enzymes. The PKD enzymes have recently been implicated in very diverse cellular functions, including Golgi organisation and plasma membrane directed transport, metastasis, immune responses, apoptosis and cell proliferation . Each isoform is differentially regulated through phosphorylation .
PHD finger protein MALE STERILITY 1-like, ubiquitin-like domain (MS1-like_ubiquitin)
Type: Domain

This domain is found in MS1 and similar proteins found in plants. This domain is predicted to adopt an ubiquitin-like fold.

PHD finger protein MALE STERILITY 1 (MS1) is a nuclear transcriptional activator essential for anther and post-meiotic pollen development and maturation. It plays a key role in tapetal development, pollen wall biosynthesis, and may also influence inflorescence branching and floral development . MS1 contains both a leucine zipper-like domain and a plant homeodomain (PHD) finger motif, which are critical for its function. MMD1, encoded by the DUET gene, is another PHD finger protein expressed specifically in male meiocytes. It is required for proper male meiotic chromosome organisation and progression, and is thought to regulate gene expression during meiosis. Loss-of-function mutations in MMD1 lead to cell death in male meiocytes, highlighting its essential role in male gametophyte development.
OTU1-like, C-terminal C2H2-type zinc finger (Znf-C2H2_OTU1-like_C)
Type: Domain

This C2H2-type zinc finger is found at the C-terminal end of human Ubiquitin thioesterase OTU1 and similar eukaryotic proteins. This domain is also found in Arabidopsis thaliana OVARIAN TUMOR DOMAIN-containing deubiquitinating enzyme 2	(OTU2) but is not found in other OVARIAN TUMOR DOMAIN related proteins.

The ubiquitin thioesterase OTU1 is a deubiquitinating enzyme, releasing ubiquitin from tagged proteins. It hydrolyses the isopeptide bonds of 'Lys-27'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitin chains . Removal of ubiquitin does not necessarily rescue tagged proteins from degradation, because proteins are often then targeted to endoplasmic reticulum-associated degradation. Removal of the ubiquitin tag may grant access to the VCP/p97 pore, and OTU1 may be a constituent of a complex involved in macroautophagy . OTU1 is also required for endo-lysosomal damage response and is recruited to damaged lysosomes to remove Lys48-linked ubiquitin conjugates to promote autophagosome formation . OTU1 is a cysteine peptidase with a structural fold similar to that of papain ; it is a member of MEROPS peptidase family C85.
UGSC-like domain (UGSC-like_dom)
Type: Domain

This entry represents an uncharacterised domain in a group of bacterial proteins of unknown function. Some proteins represented by this entry are selenoproteins, which are characterised by a UGSC motif where U is a selenocysteine residue as described in

. However, this residue is recoded from a stop codon, and most matches are split into two distinct gene predictions. This entry also includes non-selenoproteins with a CGSC motif and appear as full-length matches in the alignments.
YscD/Y4YQ, C-terminal domain (YscD/Y4YQ_C)
Type: Domain

This entry represents the C-terminal domain of Yop proteins translocation protein D from Yersinia enterocolitica (YscD) and similar proteins from proteobacteria, including the uncharacterised protein Y4YQ from Sinorhizobium fredii. This domain closely resembles the C-terminal domain of type II secretion system proteins B and C from bacteria. Its function is unknown.

YscD is a single-pass inner membrane protein required for the export process of the Yop proteins. It is an essential component of the type III secretion system. YscD contains an N-terminal cytoplasmic domain (

), a transmembrane linker and a large periplasmic region formed by the three BON domains (

), (

) and (

). YscD forms part of the inner membrane component of the bacterial type III secretion injectosome apparatus .

Y4YQ has been observed to be highly expressed in Rhizobium sp. upon treatment with daidzein, a known inductor of nod genes expression for symbiosis initiation .
Unconventional myosin-XVIIIa, SH3 domain (SH3_Myo18a)
Type: Domain

This entry represents the SH3 domain found in Myo18a.

Unconventional myosin-XVIIIa (Myo18a) may play a role in Golgi membrane trafficking and could indirectly give its flattened shape to the Golgi apparatus . In macrophages, it regulates trafficking, expression, and activation of innate immune receptors .

The myosin N-terminal SH3-like domain may mediate some aspect of the conformational communication that occurs within the myosin head during actin and nucleotide binding. Part of this effect may be mediated through interactions with the neck-associated essential light chains that are in close proximity to this portion of the head domain and also transiently interact with actin . The myosin N-terminal SH3-like domain comprises ~50 amino acids and forms a protruding, six-stranded, antiparallel, β-barrel domain with similarities to the SH3 domain .
UMOD/GP2/OIT3-like, D8C domain (D8C_UMOD/GP2/OIT3-like)
Type: Domain

This entry represents the D8C domain (cysteine-rich domain) found in UMOD, GP2, OIT3 and similar proteins mainly found in vertebrates.

Uromodulin (UMOD), glycoprotein 2 (GP2) and oncoprotein-induced transcript 3 (OIT3) constitute a phylogenetically related protein family characterised by the presence of conserved zona pellucida (ZP) and D8C domains. These paralogue proteins exhibit organ-specific expression patterns and analogous biological functions. UMOD, predominantly expressed in the renal tubules, facilitates the formation of urinary casts and mediates host defence by binding to type 1 fimbriated bacteria. UMOD functions in biogenesis and organisation of the apical membrane of epithelial cells of the thick ascending limb of Henle's loop and may serve as a receptor for binding and endocytosis of cytokines (IL-1, IL-2) and TNF . GP2, secreted from pancreatic acinar cells, functions similarly in the gastrointestinal tract, where it binds bacterial fimbriae and contributes to mucosal immunity and pancreatic plug formation in pathological states. OIT3, primarily expressed in hepatic tissue, shares structural homology with both UMOD and GP2, suggesting a comparable protective role in liver physiology. These proteins likely evolved from a common ancestral gene through duplication events, subsequently acquiring tissue-specific functions whilst maintaining their core protective mechanisms against microbial pathogens across different organ systems .