SII-SWORD/CoKE huggingface dataset:
5MP1/2, W2 domain (W2_5MP1/2)
Type: Domain

The W2 domain has a globular fold and is exclusively composed out of α-helices . The structure can be divided into a structural C-terminal core onto which the two N-terminal helices are attached. The core contains two aromatic/acidic residue-rich regions (AA boxes), which are important for mediating protein-protein interactions. The structure of this C-terminal W2 domain resembles that of a set of concatenated HEAT repeats

eIF5-mimic proteins 1 and 2 5MP1 and 5MP2 (also known as basic leucine zipper and W2 domain-containing proteins 1 and 2 (BZW1 and BZW2)) act as competitors of eIF5 and can inhibit general translation by interaction with eIF2 and inhibiting the tertiary complex binding to the ribosome . These translation regulatory proteins exist in nearly all eukaryotes except in nematodes, yeasts, and some protozoans. 5MP1/2 contain MA3- and W2-type (

) C-terminal HEAT domains that resemble the HEAT domain of eIF5 . They enable cadherin binding activity . The orthologue in Drosophila melanogaster, known as protein krasavietz (kra), is involved in several processes, including behavioural response to ethanol, long-term memory, and positive regulation of filopodium assembly. Kra is located in several cellular components, including the axonal growth cone, filopodium, and neuronal cell body .

The elf5-mimic protein family functions as translation initiation regulators. They are known to repress non-AUG-initiated translation and repeat-associated non-AUG (RAN)-initiated translation, acting as competitive inhibitors of eukaryotic translation initiation factor 5 (EIF5). These proteins increase the accuracy of translation initiation by competing with EIF5 for interaction with EIF2S2 within the 43S pre-initiation complex, in a manner dependent on binding to EIF3C. Additionally, some members of this family are involved in enhancing histone H4 gene transcription, although they do not directly bind to DNA .
Mu2, C-terminal domain (Mu2_C)
Type: Domain

This entry represents the C-terminal domain of heterotetrameric clathrin-associated adaptor protein complex 2 (AP-2) medium mu2 subunit. Mu2 is ubiquitously expressed in mammals. In higher eukaryotes, AP-2 plays a critical role in clathrin-mediated endocytosis from the plasma membrane in different cells. The membrane-anchored cargo molecules can be linked to the outer lattice of CCVs by AP-2. Those cargo molecules interact with adaptors through short sorting signals in their cytosolic segments. Tyrosine-based endocytotic signals are one of the most important sorting signals. They are of the form Y-X-X-Phi, where Y is tyrosine, X is any amino acid and Phi is a bulky hydrophobic residue that can be Leu, Ile, Met, Phe, or Val. These kinds of sorting signals can be recognized by the C-terminal domain of AP-2 mu2 subunit, also known as Y-X-X-Phi signal-binding domain that contains two hydrophobic pockets, one for the tyrosine-binding and one for the bulky hydrophobic residue-binding. Since the Y-X-X-Phi binding site is buried in the core structure of AP-2, a phosphorylation induced conformational change is required when the cargo molecules binds to AP-2 .
Centromere protein Cenp-F (Cenp-F)
Type: Family

Mitosin or centromere-associated protein-F (Cenp-F) is a coiled-coil protein that dimerizes and localizes to diverse subcellular locations, including microtubule plus-ends, mitochondria, nuclear pores, and kinetochores . It localizes to kinetochores during mitosis and is then rapidly degraded after mitosis. It is required for kinetochore-microtubule interactions and spindle checkpoint function . Cenp-F contains two microtubule-binding domains, and physically associates with dynein motor regulators . Cenp-F has also been shown to couple mitochondria to dynamic microtubule tips .
2-5-oligoadenylate synthetase, N-terminal conserved site (2-5OAS_N_CS)
Type: Conserved_site

In vertebrates, 2-5OASs (2'-5'-oligoadenylate synthetases) are induced by interferon during the innate immune response to protect against RNA virus infections. In the presence of an RNA activator, 2-5OASs catalyze the oligomerization of ATP into 2-5A. 2-5A activates endoribonuclease L, which leads to degradation of the viral RNA. 2-5OASs are also implicated in cell growth control, differentiation, and apoptosis .

Three distinct classes of 2-5A synthetases have been described that correspond to proteins of 40-46 Kd, 69-71 Kd, and 100 Kd. The 40 and 46 Kd forms are produced by alternative splicing of the same gene. The 69 and 71 Kd forms are also produced by alternative splicing of a gene and consist of two adjacent homologous domains whose sequences are highly similar to that of the 40/46 Kd forms. The sequence of the 100 Kd form is not yet known.

This site spans a region rich in glycine residues which has been proposed to be part of the ATP-binding site .
Nucleotidyltransferase superfamily (NT_sf)
Type: Homologous_superfamily

This entry represents the Pol beta-like nucleotidyltransferase (NT) superfamily. In the majority of enzymes in this superfamily, two carboxylates, Dx[D/E], together with a third more distal carboxylate, coordinate two divalent metal cations involved in a two-metal ion mechanism of nucleotide addition. The following functional groups of nucleotidyltransferases have been included in this superfamily :

PolyA polymerases

Protein nucleotidyltransferases, such as GlnD and GlnE

CCA-adding enzyme

Interferon-induced 2'-5' synthetase

DNA polymerase beta and terminal deoxynucleotidyltransferase

Antibiotic nucleotidyltransferases
Spermatogenesis-associated protein 21 (SPT21)
Type: Family

This entry includes the EF-hand calcium-binding domain-containing proteins SPT21 (spermatogenesis-associated protein 21). SPT21 is involved in the differentiation of haploid spermatids .

Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand. This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue α-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand). Ca2 binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers .
Tumor necrosis factor receptor 13C/17 (TNFR_13C/17)
Type: Family

The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern . The cysteines allow formation of an extended rod-like structure, responsible for ligand binding .

Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences . Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved .

TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis . Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease .

This entry includes the TNF receptors 13C and 17. TNFR 17 acts as a receptor for both a proliferation-inducing ligand (APRIL) and B cell-activating factor (BAFF, also called BLyS or TALL-I) . It is preferentially expressed by mature B-cells, suggesting a that it is involved in cell survival and proliferation. It has been demonstrated that it acts through the activation of NF-kappa-B and JNK pathways . TNFR 13C is a B-cell receptor specific for BAFF and it promotes the mature B-cells survival and response .
DNA damage-induced apoptosis suppressor protein (DDIAS)
Type: Family

This entry includes the DNA damage-induced apoptosis suppressor protein (DDIAS), also known as Noxin (Nitric oxide inducible), which is an anti-apoptotic protein involved in DNA repair and cell survival. This protein is induced by a wide range of stressors but it has been shown that it acts when there is DNA damage, suppressing cell death in order to prevent from DNA lesions . This protein is highly expressed in cancer tissues and cells, being a potential therapeutic target in cancer. Recently, it has been demonstrated that DDIAS knockdown caused growth inhibition of lung cancer cells. As it is constitutively activated in malignant cancers, this confirms its utility as therapeutic target .
G protein-coupled receptor 176, rhodopsin-like, 7TM (GPCR_176_Rhodpsn_7TM)
Type: Domain

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

This entry represents the seven transmembrane regions of the G-protein coupled receptor 176 (GPCR176), a member of the rhodopsin-like class A GPCR superfamily. Its endogenous ligand has not yet been identified. It is highly expressed in suprachiasmatic nucleus (SCN) neurons in a circadian rhythm manner, which has a role in setting the pace of the circadian behaviour. This receptor has an agonist-independent basal activity to reduce cAMP signalling and it has been shown that it acts through a unique G-protein subclass Gz to repress the second messenger signalling .
Alpha-protein kinase 1 (ALPK1)
Type: Family

This entry includes the alpha-protein kinase 1, a serine/threonine-protein kinase that has no homology to conventional protein kinases and phosphorylate amino acids located within α-helices . The N-terminal region had several conserved secondary α-helix structures with amphipathic properties . The structure contains 18 helices (α1 to α18), forming seven antiparallel pairs. The one-by-one-packed seven helix pairs form a right-hand solenoid, similar to the tetratricopeptide repeat (TPR) domain structure .

This kinase detects bacterial pathogen-associated molecular pattern metabolites (PAMPs) and initiates an innate immune response, a critical step for pathogen elimination and engagement of adaptive immunity. Specifically recognises and binds ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and some Gram-positive bacteria. ADP-Heptose binds to a narrow pocket of the concave side of the alpha-protein kinase 1 N-terminal which stimulates its kinase activity to phosphorylate and activate TIFA, triggering proinflammatory NF-kappa-B signalling . In addition, alpha-protein kinase 1 may play a role in regulating intracellular trafficking processes through the phosphorylation of myosin MYO1A . It has been shown that this kinase is also involved in monosodium urate monohydrate (MSU)-induced inflammation and gout by phosphorylation of myosin motor protein which enable the vesicle transport of of certain cytokines (like TNF-alpha) to the plasma membrane .
HLA class II histocompatibility antigen, gamma subunit (CD74_antigen)
Type: Family

CD74 is expressed on antigen-presenting cells and was initially demonstrated to function as an MHC class II chaperone . It was originally described as the MHC class II-associated invariant chain and its binding to MHC II alpha and beta chains is crucial for the MHCII antigen presentation pathway. Besides chaperone function, it is also involved in the regulation of endosomal trafficking, cell migration and cellular signalling as surface receptor of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) . Macrophage migration inhibitory factor binding to CD74 induces its intramembrane cleavage and the release of its cytosolic intracellular domain (CD74-ICD), which interacts with the transcription factors RUNX (Runt related transcription factor) and NF-kappaB and binds to proximal and distal regulatory sites enriched for genes involved in apoptosis, immune response, and cell migration. Recently, CD74 has been associated with tumor progression and metastasis .
E3 SUMO-protein ligase CBX4 (CBX4)
Type: Family

Polycomb group (PcG) proteins were first identified in Drosophila but mammalian homologs have been identified. They interact with each other to form multimeric, chromatin-associated protein complexes. The human orthologs of the Drosophila PcG proteins are CBX2, CBX4, CBX6, CBX7 and CBX8, which exhibit distinct nuclear localisations and they contribute differently to transcriptional repression. They have been described as regulators of homeotic gene expression. It has been demonstrated that these proteins maintain the repressed state of these genes, involved in development, signalling or cancer . PcG complexes can be recruited to DNA by interactions with specific DNA binding proteins .

Sumoylation is a reversible conjugation process similar to ubiquitination, in which proteins involved in a wide range of processes are modified, such as DNA repair, chromosome segregation and gene expression. It implies an activating enzyme (E1), a conjugating enzyme (E2), and a ligase (E3) As well as in the ubiquitination process, the E3 ligase determines substrate specificity. Polycomb protein Pc2, also known as CBX4, is a SUMO (small ubiquitin-related modifier) ligase E3. DNA damage activates CBX4 which sumoylates the heterogeneous nuclear ribonucleoprotein K (hnRNP K), a p53 cofactor required for transcriptional regulation of p53 target genes .

This entry includes de E3 SUMO-protein ligase CBX4 (also known as Pc2).
AP-2 complex subunit mu, N-terminal (AP2_Mu_N)
Type: Domain

This entry represents the N-terminal domain of heterotetrameric clathrin-associated adaptor protein complex 2 (AP-2) medium mu2 subunit. Mu2 is ubiquitously expressed in mammals. In higher eukaryotes, AP-2 plays a critical role in clathrin-mediated endocytosis from the plasma membrane in different cells. The membrane-anchored cargo molecules can be linked to the outer lattice of CCVs by AP-2. Those cargo molecules interact with adaptors through short sorting signals in their cytosolic segments. Tyrosine-based endocytotic signals are one of the most important sorting signals. They are of the form Y-X-X-Phi, where Y is tyrosine, X is any amino acid and Phi is a bulky hydrophobic residue that can be Leu, Ile, Met, Phe, or Val. These kinds of sorting signals can be recognized by the C-terminal domain of AP-2 mu2 subunit, also known as Y-X-X-Phi signal-binding domain that contains two hydrophobic pockets, one for the tyrosine-binding and one for the bulky hydrophobic residue-binding. Since the Y-X-X-Phi binding site is buried in the core structure of AP-2, a phosphorylation induced conformational change is required when the cargo molecules binds to AP-2 .
Exo-beta-D-glucosaminidase/Endo-beta-mannosidase (EBDG/EBM)
Type: Family

Exo-beta-D-glucosaminidase (

) is an enzyme found in fungi and bacteria that hydrolyses chitosan and chitooligosaccharides with retention of anomeric configuration. It has no beta-mannosidase activity .

Mannosylglycoprotein endo-beta-mannosidase (

) is a glycosidase that specifically hydrolyses the Man-beta-1,4-GlcNAc linkage in the trimannosyl core structure of N-glycans . This enzyme is found in plants and bacteria.

This entry includes exo-beta-D-glucosaminidase and endo-beta-mannosidase (also known as mannosylglycoprotein endo-beta-mannosidase). They contain an immunoglobulin-like fold.
Tubulin epsilon and delta complex protein 1 (TEDC1)
Type: Family

This entry includes protein 1 found in association with tubulins epsilon and delta complex. This complex is required for centriole maintenance and it has been demonstrated that it is a component of several ciliary structures. It acts as a positive regulator of ciliary hedgehog signalling which plays key roles in embryonic development and in cancers .
Additionally, this protein may play a role in counteracting perturbation of actin filaments, such as after treatment with the actin depolymerising microbial metabolite Chivosazole F .
Host cell factor (HCF1/2)
Type: Family

This entry includes Host cell factor 1 (HCF1) and Host cell factor 2 (HCF2) from humans. They contain an N-terminal kelch domain and a C-terminal FnIII domain. However, HCF2 is smaller than HCF-1, lacking the complete central region including the HCF1 specific repeats and as a result is not subject to proteolytic processing . This entry also includes their Drosophila melanogaster homologue, dHCF, which is involved in both activation and repression of transcription during fly development . Host cell factor homologue hcf-1 from C. elegans controls the cell cycle through mitotic histone phosphorylation modulation and negatively regulates responses to environmental stresses .

HCF1 is associated with the activation and repression of gene expression. It is brought to specific promoters by association with DNA-sequence-specific transcription factors such as Sp1, GABP, YY1, Ronin/THAP11, and E2F1 and E2F4 . HCFC1 recruits and is a part of several different complexes, including the SET1 histone methyltransferase complex (transcription activation), the SIN3 histone deacetylase complex (transcription repression) , the THAP1/THAP3-HCFC1-OGT complex (required for the regulation of the transcriptional activity of RRM1) , and the NSL complex (acetylation of nucleosomal histone H4) .

HCF2 is involved in activation of differentiation and morphogenesis gene expression programs, and in parallel in inhibition of cellular growth and metabolism .
Tiam1/Tiam2/Protein still life (Tiam1/Tiam2/Sif)
Type: Family

T-lymphoma invasion and metastasis-inducing protein 1 (Tiam1) is a guanine exchange factor (GEF) for CDC42 and the Rho-family GTPase Rac1, which plays an important role in cell-matrix adhesion and in cell migration . Tiam1 is involved in multiple steps of tumorigenesis .

Tiam2 has been shown to localise to the nuclear envelope and to regulate Rac1 activity at the nuclear envelope which regulates the perinuclear actin cap . It has been shown to promote invasion and motility of non-small cell lung cancer cells . It has also been shown to promote epithelial-to-mesenchymal transition and results in proliferation and invasion in liver cancer cells .

This entry includes a group of guanine nucleotide exchange factors, including Tiam1/2 from humans and Sif from Drosophila . Tiam1/2 are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity .
Xylosyltransferase (XYLT)
Type: Family

Proteoglycans (PGs) are macromolecules located in the extracellular matrix (ECM) and cell surface of animal cells, and are comprised of a core protein to which one or more glycosaminoglycan (GAG) chain is covalently attached. GAG assembly starts with the attachment of xylose from the uridine diphosphate (UDP)-xylose donor onto a specific serine residue of the core protein by xylosyltransferase . In mammals there are two xylosyltransferases, xylosyltransferase 1 and xylosyltransferase 2 (XT1 and XT2).

This entry includes both xylosyltransferase 1 and xylosyltransferase 2.
Grb2-like (Grb2-like)
Type: Family

Growth factor receptor-bound protein 2 (Grb2) is an SH2 and SH3 domain-containing adaptor protein that links receptor tyrosine kinases to Ras signalling . Grb2 interacts with the cytoplasmic tyrosine kinase ACK1 (activated Cdc42-associated kinase 1) and mediates its interaction with other receptor tyrosine kinases . ACK1 is implicated in metastatic behaviour, cell spreading and migration, and epidermal growth factor receptor (EGFR) signalling .

Human GRAP and its Drosophila homologue, downstream of receptor kinase (drk), have been shown to have a function in hearing .

Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke . They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling . It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 . SLAP2 acts as a negative regulator of FLT3 signaling .

This entry includes a group of adapter proteins including Grb2, GRAP, GRAPL and SLAP/SLAP2 from humans. This entry also includes Sem-5 from Caenorhabditis elegans. Sem-5 is an adapter protein which modulates signaling mediated by several receptor tyrosine kinases such as egl-15 and let-23 probably acting upstream of let-60/ras .
E3 ubiquitin-protein ligase RING1/RING2 (RING1/RING2)
Type: Family

E3 ubiquitin-protein ligase RING1 (

) is one of the three E3 ubiquitin-protein ligases that mediate monoubiquitination of 'Lys-119' of histone H2A, which is a specific tag for repression of epigenetic transcription and particularly for inactivation of chromosome X of female mammals . RING1 is a component of the Polycomb group (PcG) multiprotein PRC1-like complex, the repressive BCOR complex , and the the E2F6.com-1 complex in G0 phase . RING1 has a RING-type zinc finger.

E3 ubiquitin-protein ligase RING2 (

) mediates monoubiquitination of 'Lys-119' of histone H2A (H2AK119Ub) , which is a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals . RING2 is a component of the PRC1 complex , and other chromatin-associated Polycomb (PcG) complexes such as BCOR . It is also a component of the MLL1/MLL complex .

This entry includes E3 ubiquitin-protein ligase RING1/RING2.