SII-SWORD/CoKE huggingface dataset:
A-kinase anchor protein 7, RI-RII subunit-binding domain (AKAP7_RI-RII-bd_dom)
Type: Domain

This entry represents the RI-RII subunit-binding domain found at the C-terminal of the cyclic AMP-dependent protein kinase A (PKA) anchor protein, AKAP7 (also known as AKAP18) . This protein anchors PKA, for its role in regulating PKA-mediated gene transcription in both somatic cells and oocytes, by binding to its regulatory subunits, RI and RII, hence being known as a dual-specific AKAP . The 25 crucial amino acids of RII-binding domains in general form structurally conserved amphipathic helices with unrelated sequences; hydrophobic amino acid residues form the backbone of the interaction and hydrogen bond- and salt-bridge-forming amino acid residues increase the affinity of the interaction . AKAP7 contains a nuclear localisation signal (NLS) at the N terminus, a conserved central domain member of the 2H phosphoesterase family in addition to the RI-RII subunit-binding domain .
Protein phosphatase 1, regulatory subunit 15B, N-terminal (Prot_Pase1_reg-su15B_N)
Type: Domain

This entry represents the conserved N-terminal domain of the regulatory subunit (15B) of protein phosphatase 1 (also known as CReP, or the constitutive repressor of eIF2alpha phosphorylation). The CReP catalytic subunit functions in the dephosphorylation of eIF2-alpha under basal conditions in the absence of stress. In response to translation inhibition, there is reduced synthesis of the labile CReP that contributes to elevated levels of eIF2-alpha phosphorylation . The C terminus, family PP1c, is shared with the apoptosis-associated protein Gadd34 and herpes simplex virus .
Centromere protein Cenp-F, leucine-rich repeat-containing domain (Centromere_CenpF_leu-rich_rpt)
Type: Domain

Cenp-F, a centromeric kinetochore, microtubule-binding protein consisting of two 1,600-amino acid-long coils, is essential for the full functioning of the mitotic checkpoint pathway . There are several leucine-rich repeats along the sequence of LEK1 that are considered to be zippers, though they do not appear to be binding DNA directly in this instance .
Syndetin, C-terminal (Syndetin_C)
Type: Domain

The function of this domain is not known, but it is found at the C terminus of syndetin (VPS50), a unique component of the endosome-associated retrograde protein (EARP) complex. The EARP complex otherwise shares four of its five subunits with the Golgi-associated retrograde protein (GARP) complex. The EARP complex is localized to recycling endosomes where it acts as a tethering complex for recycling of plasma membrane receptors .
Vacuolar protein sorting-associated protein 54, N-terminal (VPS54_N)
Type: Domain

This entry represents a domain found in vacuolar protein sorting-associated protein 54 (VPS54), which acts as component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN). VPS54 is required to tether the complex to the TGN. However, it is not involved in endocytic recycling .

Proteins containing this domain also includes VPS50 (also known as Syndetin), which is a component of the EARP complex that is involved in endocytic recycling. It is required to tether the EARP complex to recycling endosomes. Nevertheless, it is involved in retrograde transport from early and late endosomes to the TGN .
Glomulin/ALF4 (Glomulin/ALF4)
Type: Family

In the human adult, FKBP-12, also known as FAP68 or FK506-binding protein, (protein product of the gene glomulin) is expressed at high levels in skeletal muscle, heart, brain and kidney, and at low levels in smaller arteries and veins. The high expression of glomulin in murine vasculature suggests an important role in blood vessel development and/or maintenance, which is supported by the vascular phenotype seen in GVM patients with mutations in this gene . It is a cytoplasmic protein, specifically bound by the non-phosphorylated form of the hepatocyte growth factor, HGF, receptor and is released upon HGF stimulation and receptor phosphorylation, suggesting a potential role for FKBP12 in linking HGF signaling to the regulation of protein synthesis . FKBP12 is found to regulate Ca
2+
release from the sarcoplasmic reticulum (SR) by its action on the IP3 receptors (IP3Rs), which crucially regulate diverse cell signalling processes from reproduction to apoptosis, possibly via the kinase rapamycin (mTOR), that potentiates Ca2+ release from the IP3R in smooth muscle .
Integrin binding protein, ICAP-1 (Integrin-bd_ICAP-1)
Type: Family

ICAP-1 is a serine/threonine-rich protein that binds to the cytoplasmic domains of beta-1 integrins in a highly specific manner, binding to a NPXY sequence motif on the beta-1 integrin. The cytoplasmic domains of integrins are essential for cell adhesion, and the fact that phosphorylation of ICAP-1 by interaction with the cell-matrix implies an important role of ICAP-1 during integrin-dependent cell adhesion . Over expression of ICAP-1 strongly reduces the integrin-mediated cell spreading on extracellular matrix and inhibits both Cdc42 and Rac1. In addition, ICAP-1 induces release of Cdc42 from cellular membranes and prevents the dissociation of GDP from this GTPase . An additional function of ICAP-1 is to promote differentiation of osteoprogenitors by supporting their condensation through modulating the integrin high affinity state .
DNA endonuclease Ctp1, N-terminal (CtIP_N)
Type: Domain

CtIP is predominantly a nuclear protein that complexes with both BRCA1 and the BRCA1-associated RING domain protein (BARD1). At the protein level, CtIP expression varies with cell cycle progression in a pattern identical to that of BRCA1. Thus, the steady-state levels of CtIP polypeptides, which remain low in resting cells and G1 cycling cells, increase dramatically as Dividing cells traverse the G1/S boundary. CtIP can potentially modulate the functions ascribed to BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control . This N-terminal domain carries a coiled-coil region and is essential for homodimerisation of the protein . The C-terminal domain is family CtIP_C and carries functionally important CxxC and RHR motifs, absence of which lead cells to grow slowly and show hypersensitivity to genotoxins .
Elongator complex protein 5 (Elp5)
Type: Family

Elongator is a 6 subunit protein complex highly conserved in eukaryotes. The human Elongator six-subunit complex, known as holo-Elongator, has histone acetyltransferase activity directed against histone H3 and H4 . It consists of two subcomplexes, a core subcomplex (ELP1-3), and an accessory subcomplex (ELP4-6) . The elongator complex has been associated with many cellular activities, including transcriptional elongation , but its main function is tRNA modification . It is required for the formation of 5-methoxy-carbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) groups on uridine nucleosides present at the wobble position of many tRNAs .

This entry represents Elongator complex protein 5 (ELP5).
Small ribosomal subunit protein mS23, metazoa (Ribosomal_mS23_met)
Type: Family

This entry represents the small ribosomal subunit protein mS23, previously known as MRP-S23, one of the proteins that makes up the 55S ribosome in eukaryotes. It does not appear to carry any common motifs; either RNA binding or ribosomal . All of the mammalian MRPs are encoded in nuclear genes that are evolving more rapidly than those encoding cytoplasmic ribosomal proteins. The MRPs are imported into mitochondria where they assemble in co-ordination with mitochondrially transcribed rRNAs into ribosomes that are responsible for translating the 13 mRNAs for essential proteins of the oxidative phosphorylation system . MRP-S23 is significantly up-regulated in uterine cancer cells .
Phosphoinositide 3-kinase regulatory subunit 5/6 (PIK3R5/6)
Type: Family

Phosphoinositide 3-kinase regulatory subunit5/6 are regulatory subunits of the PI3K gamma complex. Class I PI3Ks are dual-specific lipid and protein kinases involved in numerous intracellular signaling pathways .
Protein phosphatase 1, regulatory subunit 15A/B, C-terminal (Prot_Pase1_reg-su15A/B_C)
Type: Domain

This entry represents the conserved C terminus of the regulatory subunit (15A and 15B) of protein phosphatase 1. This C-terminal domain appears to be a binding region for the catalytic subunit (PP1C) of protein phosphatase-1, which may in some circumstances also be retroviral in origin since it is found in both herpes simplex virus and in mouse and man. This domain is found in Gadd-34 apoptosis-associated proteins as well as the constitutive repressor of eIF2-alpha phosphorylation/protein phosphatase 1, regulatory (inhibitor) subunit 15b, otherwise known as CReP. Diverse stressful conditions are associated with phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2-alpha) on serine 51. This signaling event, which is conserved from yeast to mammals, negatively regulates the guanine nucleotide exchange factor, eIF2-B and inhibits the recycling of eIF2 to its active GTP bound form. In mammalian cells eIF2-alpha phosphorylation emerges as an important event in stress signaling that impacts on gene expression at both the translational and transcriptional levels .
Beta-soilenoid domain, diatom-type (B-solenoid_diatom-type)
Type: Domain

This entry represents a domain found mainly in diatom proteins and is predicted to adopt a β-solenoid domain.
Nuclear respiratory factor 1, NLS/DNA-binding, dimerisation domain (Nrf1_NLS/DNA-bd_dimer)
Type: Domain

Nuclear respiratory factor-1 is a transcriptional activator that has been implicated in the nuclear control of respiratory chain expression in vertebrates. The first 26 amino acids of nuclear respiratory factor-1 are required for the binding of dynein light chain. The interaction with dynein light chain is observed for both ewg and Nrf-1, transcription factors that are structurally and functionally similar between humans and Drosophila .

In Drosophila, the erect wing (ewg) protein is required for proper development of the central nervous system and the indirect flight muscles. The fly ewg gene encodes a novel DNA-binding domain that is also found in four genes previously identified in sea urchin, chicken, zebrafish, and human .

The highest level of expression of both ewg and Nrf-1 was found in the central nervous system, somites, first branchial arch, optic vesicle, and otic vesicle. In the mouse Nrf-1 protein,

, there is also an NLS domain at 88-116, and a DNA binding and dimerisation domain at 127-282. Ewg is a site-specific transcriptional activator, and evolutionarily conserved regions of ewg contribute both positively and negatively to transcriptional activity .
RZZ complex, subunit KNTC1/ROD, C-terminal (RZZ-complex_KNTC1/ROD_C)
Type: Domain

Rod, the Rough deal protein (also known as Kinetochore-associated protein 1) displays a dynamic intracellular staining pattern, localising first to kinetochores in pro-metaphase, but moving to kinetochore microtubules at metaphase. Early in anaphase the protein is once again restricted to the kinetochores, where it persists until the end of telophase. This behaviour is in all respects similar to that described for ZW10 , and indeed the two proteins function together, localisation of each depending upon the other . These two proteins are found at the kinetochore in complex with a third, Zwilch, in both flies and humans. The C- terminus is the most conserved part of the protein. During pro-metaphase, the ZW10-Rod complex, dynein/dynactin, and Mad2 all accumulate on unattached kinetochores; microtubule capture leads to Mad2 depletion as it is carried off by dynein/dynactin; ZW10-Rod complex accumulation continues, replenishing kinetochore dynein. The continuing recruitment of the ZW10-Rod complex during metaphase may serve to maintain adequate dynein/dynactin complex on kinetochores for assisting chromatid movement during anaphase. The ZW10-Rod complex acts as a bridge whose association with Zwint-1 links Mad1 and Mad2, components that are directly responsible for generating the diffusible 'wait anaphase' signal, to a structural, inner kinetochore complex containing Mis12 and KNL-1AF15q14, the last of which has been proved to be essential for kinetochore assembly in Caenorhabditis elegans. Removal of ZW10 or Rod inactivates the mitotic checkpoint .
Pericentrin/AKAP-450 centrosomal targeting domain (PACT_domain)
Type: Domain

This entry represents a coiled-coil region close to the C terminus of centrosomal proteins that is directly responsible for recruiting AKAP-450 and pericentrin to the centrosome. Hence the suggested name for this region is a PACT domain (pericentrin-AKAP-450 centrosomal targeting). This domain is also present at the C terminus of coiled-coil proteins from Drosophila and Schizosaccharomyces pombe (Fission yeast), and in the Drosophila protein it is sufficient for targeting to the centrosome in mammalian cells. The function of these proteins is unknown but they seem good candidates for having a centrosomal or spindle pole body location. The final 22 residues of this domain in AKAP-450 appear specifically to be a calmodulin-binding domain, indicating that this protein at least is likely to contribute to centrosome assembly .
SNARE-complex protein Syntaxin-18, N-terminal (Syntaxin-18_N)
Type: Domain

This is the conserved N-terminal of Syntaxin-18. Syntaxin-18 is found in the SNARE complex of the endoplasmic reticulum and functions in the trafficking between the ER intermediate compartment and the cis-Golgi vesicle. In particular, the N-terminal region is important for the formation of ER aggregates . More specifically, syntaxin-18 is involved in endoplasmic reticulum-mediated phagocytosis, presumably by regulating the specific and direct fusion of the ER with the plasma or phagosomal membranes .
Intra-flagellar transport protein 57 (Intra-flagellar_transport_57)
Type: Family

Eukaryotic cilia and flagella are specialised organelles found at the periphery of cells of diverse organisms. Intra-flagellar transport (IFT) is required for the assembly and maintenance of eukaryotic cilia and flagella, and consists of the bi-directional movement of large protein particles between the base and the distal tip of the organelle. IFT particles contain multiple copies of two distinct protein complexes, A and B, which contain at least 6 and 11 protein subunits. IFT57 is part of complex B but is not, however, required for the core subunits to stay associated . This protein is known as Huntington-interacting protein-1 in humans.
Peroxisomal membrane protein 4 (Pmp4)
Type: Family

Peroxisomes are single membrane bound organelles, present in practically all eukaryotic cells, and involved in a variety of metabolic pathways; the deduced protein is extremely basic, a characteristic of many other peroxisomal intrinsic membrane proteins. They carry two short stretches of hydrophobic residues shown to be necessary for the correct targeting of these proteins. This entry represent Pmp4.
Nuclear RNA-splicing-associated protein, SR-25 (Nucl_RNA-splicing_assoc_SR-25)
Type: Family

SR-25, otherwise known as ADP-ribosylation factor-like factor 6-interacting protein 4, is expressed in virtually all tissue types. At the N terminus there is a repeat of serine-arginine (SR repeat), and towards the middle of the protein there are clusters of both serines and of basic amino acids. The presence of many nuclear localisation signals strongly implies that this is a nuclear protein that may contribute to RNA splicing . SR-25 is also implicated, along with heat-shock-protein-27, as a mediator in the Rac1 (GTPase ras-related C3 botulinum toxin substrate 1; also see

) signalling pathway .
Peptidase S26 (Peptidase_S26)
Type: Domain

This entry represents a domain found in some members of the S26A family of serine endopeptidases. Peptidases S26A (signal peptidase I) removes the hydrophobic, N-terminal signal peptides as proteins are translocated across membranes. The type I signal peptidases are unique serine proteases that utilize a serine/lysine catalytic dyad mechanism in place of the classical serine/histidine/aspartic acid catalytic triad mechanism . Peptidases S26B includes eukaryotic microsomal signal peptidases involved in the removal of signal peptides from secretory proteins as they pass into the endoplasmic reticulum lumen . Peptidases 26C (TraF signal peptidase) are found in operons that encode elements of conjugative transfer systems.
Protein of unknown function DUF2452 (DUF2452)
Type: Family

This entry contains proteins that have no known function.
Little elongation complex subunit 2 , C-terminal (ICE2_C)
Type: Domain

This entry represents the C-terminal of little elongation complex subunit 2 (ICE2, also known as NARG2). ICE2 is a component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III . This C-terminal domain belongs to the PD-(D/E)XK nuclease superfamily .
Harmonin-binding protein USHBP1, PDZ-binding domain (USHBP1_PDZ-bd)
Type: Domain

The entry represents the PDZ-binding domain of Harmonin-binding protein USHBP1 (also known as MCC2, mutated in colon cancer-2). USHBP1 has high homology to tumour suppressor MCC1 (mutated in colon cancer-1).

MCC2 protein binds the first PDZ domain of AIE-75 (also known as Harmonin) with its C-terminal amino acids -DTFL. A possible role of MCC2 as a tumour suppressor has been put forward. The carboxyl terminus of the predicted protein was DTFL which matched the consensus motif X-S/T-X-phi (phi: hydrophobic amino acid residue) for binding to the PDZ domain of AIE-75 .
Transmembrane protein 65 (TMEM65)
Type: Family

TMEM65 is an intercalated disc protein that interacts with with connexin 43 (Cx43) and is required for correct localization of Cx43 to the intercalated disc. It is is essential for cardiac function in zebrafish .
26S proteasome non-ATPase regulatory subunit 5 (PSMD5)
Type: Family

The 26S proteasome is an enzymatic complex that degrades ubiquitinated proteins in eukaryotic cells. 26S proteasome non-ATPase regulatory subunit 5 (PSMD5) is one of a number of chaperones that are involved in the assembly of the proteasome. The chaperones dissociate before 26S proteasome formation is complete .

TNF-alpha/NFkB inhibits 26S proteasome assembly via abnormal expression of PSMD5, establishing a link between inflammation and chronic neurodegenerative diseases with altered ubiquitin-proteasome system function .
Galactokinase, N-terminal domain (GalKase_N)
Type: Domain

This entry represents an N-terminal conserved domain found in all galactokinases, irrespective of how many other ATP binding sites, etc that they carry . The function of this domain appears to be to bind galactose , and it is normally located at the N terminus of these enzymes . It is associated with

and

. While all enzymes in this entry posses galactokinase activity, some are annotated as N-acetylgalactosamine kinases as they also posses this enzyme activity.

This domain can also be found in mevalonate kinase and related proteins from all domains of life. It can also be found in arabinose kinase from Arabidopsis .
Phosphatidylinositol-glycan biosynthesis class S protein (PtdIno-glycan_biosynth_class_S)
Type: Family

Phosphatidylinositol-glycan biosynthesis class S protein (PIG-S, also known as Gpi17 in budding yeasts) is one of several key, core components of the glycosylphosphatidylinositol (GPI) trans-amidase complex that adds GPIs to newly synthesized proteins . Mammalian GPI transamidase consists of at least five components: Gaa1, Gpi8, PIG-S, PIG-T, and PIG-U, all five of which are required for its function. It is possible that Gaa1, Gpi8, PIG-S, and PIG-T form a tightly associated core that is only weakly associated with PIG-U .
Trappin protein transglutaminase-binding repeat (Trappin_transglut-bd_rpt)
Type: Repeat

Trappin-2,a protease inhibitor, has a unique N-terminal domain that enables it to become cross-linked to extracellular matrix proteins by transglutaminase . This domain contains several repeated motifs (represented by this entry) with the consensus sequence Gly-Gln-Asp-Pro-Val-Lys, and these together can anchor the whole molecule to extracellular matrix proteins, such as laminin, fibronectin, beta-crystallin, collagen IV, fibrinogen, and elastin, by transglutaminase-catalysed cross-links. The whole domain is rich in glutamine and lysine, thus allowing and transglutaminase(s) to catalyse the formation of an intermolecular epsilon-(gamma-glutamyl)lysine isopeptide bond . Cementoin is associated with the WAP family,

, at the C terminus.

This short repeated motif is also found in some bacterial proteins.
Enhancer of polycomb-like, N-terminal (Enhancer_polycomb-like_N)
Type: Domain

This domain is found at the N-terminal of EPL1 (Enhancer of polycomb-like) proteins. The EPL1 protein is a member of a histone acetyltransferase complex which is involved in transcriptional activation of selected genes . It is also present at the N terminus of Jade family proteins.
Beta-amyloid precursor protein C-terminal (APP_amyloid_C)
Type: Domain

This is the amyloid, C-terminal, protein of the beta-Amyloid precursor protein (APP) which is a conserved and ubiquitous transmembrane glycoprotein strongly implicated in the pathogenesis of Alzheimer's disease but whose normal biological function is unknown. The C-terminal 100 residues are released and aggregate into amyloid deposits which are strongly implicated in the pathology of Alzheimer's disease plaque-formation. The domain is associated with

, further towards the N terminus.
Tetratricopeptide, SHNi-TPR domain (Tetratricopeptide_SHNi-TPR_dom)
Type: Domain

The tetratrico peptide repeat region (TPR) is a structural motif present in a wide range of proteins . It mediates protein-protein interactions and the assembly of multiprotein complexes . The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.

The X-ray structure of a domain containing three TPRs from protein phosphatase 5 revealed that TPR adopts a helix-turn-helix arrangement, with adjacent TPR motifs packing in a parallel fashion, resulting in a spiral of repeating anti-parallel α-helices . The two helices are denoted helix A and helix B. The packing angle between helix A and helix B is ~24 degrees within a single TPR and generates a right-handed superhelical shape. Helix A interacts with helix B and with helix A' of the next TPR. Two protein surfaces are generated: the inner concave surface is contributed to mainly by residue on helices A, and the other surface presents residues from both helices A and B.

This entry represents SHNi-TPR (Sim3-Hif1-NASP interrupted TPR), a sequence that is an interrupted form of TPR repeat .
DM13 domain (DM13_domain)
Type: Domain

The DM13 domain has been identified in animal proteins containing a DOMON domain likely to function as cytochromes involved in as yet unidentified redox reactions potentially related to protein hydroxylation or oxidative cross-linking. However, it is also found in bacteria. The DM13 domain contains a nearly absolutely conserved cysteine, which can be potentially involved in a redox reaction either as a nacked thiol group or by binding a prosthetic group like heme .

The DM13 domain is predicted to have a β-strand-rich fold .